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LIG4

LIG4 DNA ligase 4 is an enzyme that in humans is encoded by the LIG4 gene. # Function The protein encoded by this gene is an ATP-dependent DNA ligase that joins double-strand breaks during the non-homologous end joining pathway of double-strand break repair. It is also essential for V(D)J recombination. Lig4 forms a complex with XRCC4, and further interacts with the DNA-dependent protein kinase (DNA-PK) and XLF/Cernunnos, which are also required for NHEJ. The crystal structure of the Lig4/XRCC4 complex has been resolved. Defects in this gene are the cause of LIG4 syndrome. The yeast homolog of Lig4 is Dnl4. # LIG4 Syndrome In humans, deficiency of DNA ligase 4 results in a clinical condition known as LIG4 syndrome. This syndrome is characterized by cellular radiation sensitivity, growth retardation, developmental delay, microcephaly, facial dysmorphisms, increased disposition to leukemia, variable degrees of immunodeficiency and reduced number of blood cells. # Haematopoietic stem cell aging Accumulation of DNA damage leading to stem cell exhaustion is regarded as an important aspect of aging. Deficiency of lig4 in pluripotent stem cells impairs Non-homologous end joining (NHEJ) and results in accumulation of DNA double-strand breaks and enhanced apoptosis. Lig4 deficiency in the mouse causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during aging. The sensitivity of haematopoietic stem cells to lig4 deficiency suggests that lig4-mediated NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time. # Interactions LIG4 has been shown to interact with XRCC4 via its BRCT domain. This interaction stabilizes LIG4 protein in cells; cells that are deficient for XRCC4, such as XR-1 cells, have reduced levels of LIG4. # Mechanism LIG4 is an ATP-dependent DNA ligase. LIG4 uses ATP to adenylate itself and then transfers the AMP group to the 5' phosphate of one DNA end. Nucleophilic attack by the 3' hydroxyl group of a second DNA end and release of AMP yield the ligation product. Adenylation of LIG4 is stimulated by XRCC4 and XLF.

LIG4 DNA ligase 4 is an enzyme that in humans is encoded by the LIG4 gene.[1] # Function The protein encoded by this gene is an ATP-dependent DNA ligase that joins double-strand breaks during the non-homologous end joining pathway of double-strand break repair. It is also essential for V(D)J recombination. Lig4 forms a complex with XRCC4, and further interacts with the DNA-dependent protein kinase (DNA-PK) and XLF/Cernunnos, which are also required for NHEJ. The crystal structure of the Lig4/XRCC4 complex has been resolved.[2] Defects in this gene are the cause of LIG4 syndrome. The yeast homolog of Lig4 is Dnl4. # LIG4 Syndrome In humans, deficiency of DNA ligase 4 results in a clinical condition known as LIG4 syndrome. This syndrome is characterized by cellular radiation sensitivity, growth retardation, developmental delay, microcephaly, facial dysmorphisms, increased disposition to leukemia, variable degrees of immunodeficiency and reduced number of blood cells.[3][4] # Haematopoietic stem cell aging Accumulation of DNA damage leading to stem cell exhaustion is regarded as an important aspect of aging.[5][6] Deficiency of lig4 in pluripotent stem cells impairs Non-homologous end joining (NHEJ) and results in accumulation of DNA double-strand breaks and enhanced apoptosis.[4] Lig4 deficiency in the mouse causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during aging.[7] The sensitivity of haematopoietic stem cells to lig4 deficiency suggests that lig4-mediated NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time.[4][7] # Interactions LIG4 has been shown to interact with XRCC4 via its BRCT domain.[8][2] This interaction stabilizes LIG4 protein in cells; cells that are deficient for XRCC4, such as XR-1 cells, have reduced levels of LIG4.[9] # Mechanism LIG4 is an ATP-dependent DNA ligase. LIG4 uses ATP to adenylate itself and then transfers the AMP group to the 5' phosphate of one DNA end. Nucleophilic attack by the 3' hydroxyl group of a second DNA end and release of AMP yield the ligation product. Adenylation of LIG4 is stimulated by XRCC4 and XLF.[10]

https://www.wikidoc.org/index.php/LIG4

5b6b83445ef985cbdd35f8a0b530f61e11985d88

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LIM2

LIM2 Lens fiber membrane intrinsic protein is a protein that in humans is encoded by the LIM2 gene. The mammalian lens fiber cell membrane contains 5 major proteins ranging from 70 kD to 19 kD in size. The specific function of these proteins is unknown. Some of them have been shown to be involved in the formation of cataracts, e.g., crystalline-gamma-1 (CRYG1; MIM 123660). The second most abundant intrinsic membrane protein of the lens fiber cell is MP19, so named for major lens protein having a molecular weight of 19.5 kD. This protein appears to contain 4 transmembrane domains, is a substrate for cAMP-dependent protein kinase and protein kinase C, and binds with calmodulin. Taken together, these suggest that MP19 functions in some way as a junctional component, possibly involved with lens cell communication. It has been shown to be involved with cataractogenesis.

LIM2 Lens fiber membrane intrinsic protein is a protein that in humans is encoded by the LIM2 gene.[1][2] The mammalian lens fiber cell membrane contains 5 major proteins ranging from 70 kD to 19 kD in size. The specific function of these proteins is unknown. Some of them have been shown to be involved in the formation of cataracts, e.g., crystalline-gamma-1 (CRYG1; MIM 123660). The second most abundant intrinsic membrane protein of the lens fiber cell is MP19, so named for major lens protein having a molecular weight of 19.5 kD. This protein appears to contain 4 transmembrane domains, is a substrate for cAMP-dependent protein kinase and protein kinase C, and binds with calmodulin. Taken together, these suggest that MP19 functions in some way as a junctional component, possibly involved with lens cell communication. It has been shown to be involved with cataractogenesis.[supplied by OMIM][2]

https://www.wikidoc.org/index.php/LIM2

b4a8caffc022c8ed5c45bc5bd6cc139ac5124e49

wikidoc

LL37

LL37 LL-37 (or CAP-18 for cathelicidin antimicrobial peptide, 18 kDa) is a gene encoding for the only member of the human cathelicidin family. Cathelicidin-related antimicrobial peptides are a family of polypeptides found in lysosomes of macrophages and polymorphonuclear leukocytes (PMNs), and keratinocytes. Cathelicidins serve a critical role in mammalian innate immune defense against invasive bacterial infection. # Clinical significance NOTE: This article appears to be split into two parts; more on cathelicidin's clinical significance can be found on the cathelicidin page. Patients with rosacea have elevated levels of cathelicidin. Cathelicidin is cleaved into the antimicrobial peptide LL-37 by both kallikrein 5 and kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea. Higher plasma levels of LL-37, which are up-regulated by vitamin D, appear to significantly reduce the risk of death from infection in dialysis patients. Patients with a high level of LL-37 were 3.7 times more likely to survive kidney dialysis for a year without a fatal infection. Vitamin D up-regulates genetic expression of cathelicidin, which exhibits broad-spectrum microbicidal activity against bacteria, fungi, and viruses. SAAP-148 (a synthetic antimicrobial and antibiofilm peptide) is a modified version of LL-37 that has enhanced antimicrobial activities compared to LL-37. In particular, SAAP-148 was more efficient in killing bacteria under physiological conditions.

LL37 LL-37 (or CAP-18 for cathelicidin antimicrobial peptide, 18 kDa) is a gene encoding for the only member of the human cathelicidin family. Cathelicidin-related antimicrobial peptides are a family of polypeptides found in lysosomes of macrophages and polymorphonuclear leukocytes (PMNs), and keratinocytes.[1] Cathelicidins serve a critical role in mammalian innate immune defense against invasive bacterial infection.[2] # Clinical significance NOTE: This article appears to be split into two parts; more on cathelicidin's clinical significance can be found on the cathelicidin page. Patients with rosacea have elevated levels of cathelicidin. Cathelicidin is cleaved into the antimicrobial peptide LL-37 by both kallikrein 5 and kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea.[3] Higher plasma levels of LL-37, which are up-regulated by vitamin D, appear to significantly reduce the risk of death from infection in dialysis patients. Patients with a high level of LL-37 were 3.7 times more likely to survive kidney dialysis for a year without a fatal infection.[4] Vitamin D up-regulates genetic expression of cathelicidin, which exhibits broad-spectrum microbicidal activity against bacteria, fungi, and viruses.[5][6] SAAP-148 (a synthetic antimicrobial and antibiofilm peptide) is a modified version of LL-37 that has enhanced antimicrobial activities compared to LL-37. In particular, SAAP-148 was more efficient in killing bacteria under physiological conditions.[7]

https://www.wikidoc.org/index.php/LL37

d99c08ef0e9d8a9da129de5ebb05a0ba91af57f3

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LMNA

LMNA Lamin A/C also known as LMNA is a protein that in humans is encoded by the LMNA gene. Lamin A/C belongs to the lamin family of proteins. # Function In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, resulting in an accumulation of farnesyl-prelamin A. In Hutchinson–Gilford progeria syndrome, a 50-amino acid deletion in prelamin A (amino acids 607–656) removes the site for the second endoproteolytic cleavage. Consequently, no mature lamin A is formed, and a farnesylated mutant prelamin A (progerin) accumulates in cells. The nuclear lamina consist of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Through alternate splicing, this gene encodes three type A lamin isoforms. Early in mitosis, maturation promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-phase-promoting factor) phosphorylates specific serine residues in all three nuclear lamins, causing depolymerization of the lamin intermediate filaments. The phosphorylated lamin B dimers remain associated with the nuclear membrane via their isoprenyl anchor. Lamin A is targeted to the nuclear membrane by an isoprenyl group but it is cleaved shortly after arriving at the membrane. It stays associated with the membrane through protein-protein interactions of itself and other membrane associated proteins, such as LAP1. Depolymerization of the nuclear lamins leads to disintegration of the nuclear envelope. Transfection experiments demonstrate that phosphorylation of human lamin A is required for lamin depolymerization, and thus for disassembly of the nuclear envelope, which normally occurs early in mitosis. # Clinical significance Mutations in the LMNA gene are associated with several diseases, including Emery–Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot–Marie–Tooth disease, restrictive dermopathy, and Hutchinson–Gilford progeria syndrome. A truncated version of lamin A, commonly known as progerin, causes Hutchinson–Gilford progeria syndrome. To date over 1,400 SNPs are known . They can manifest in changes on mRNA, splicing or protein (e.g. Arg471Cys, Arg482Gln, Arg527Leu, Arg527Cys, Ala529Val ) level. # DNA damage DNA double-strand damages can be repaired by either homologous recombination (HR) or non-homologous end joining (NHEJ). LMNA promotes genetic stability by maintaining the levels of proteins that have key roles in HR and NHEJ. Mouse cells that are deficient for maturation of prelamin A have increased DNA damage and chromosome aberrations, and show increased sensitivity to DNA damaging agents. In progeria, the inadequacy of DNA repair, due to defective LMNA, may cause features of premature aging (see DNA damage theory of aging). # Interactions LMNA has been shown to interact with: - ALOX12 - EMD - NARF - SREBF1 - TMPO - ZNF239 - SIRT1

LMNA Lamin A/C also known as LMNA is a protein that in humans is encoded by the LMNA gene.[1][2] Lamin A/C belongs to the lamin family of proteins. # Function [3] In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, resulting in an accumulation of farnesyl-prelamin A. In Hutchinson–Gilford progeria syndrome, a 50-amino acid deletion in prelamin A (amino acids 607–656) removes the site for the second endoproteolytic cleavage. Consequently, no mature lamin A is formed, and a farnesylated mutant prelamin A (progerin) accumulates in cells.[4] The nuclear lamina consist of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Through alternate splicing, this gene encodes three type A lamin isoforms.[5] Early in mitosis, maturation promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-phase-promoting factor) phosphorylates specific serine residues in all three nuclear lamins, causing depolymerization of the lamin intermediate filaments. The phosphorylated lamin B dimers remain associated with the nuclear membrane via their isoprenyl anchor. Lamin A is targeted to the nuclear membrane by an isoprenyl group but it is cleaved shortly after arriving at the membrane. It stays associated with the membrane through protein-protein interactions of itself and other membrane associated proteins, such as LAP1. Depolymerization of the nuclear lamins leads to disintegration of the nuclear envelope. Transfection experiments demonstrate that phosphorylation of human lamin A is required for lamin depolymerization, and thus for disassembly of the nuclear envelope, which normally occurs early in mitosis. # Clinical significance Mutations in the LMNA gene are associated with several diseases, including Emery–Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot–Marie–Tooth disease, restrictive dermopathy, and Hutchinson–Gilford progeria syndrome. A truncated version of lamin A, commonly known as progerin, causes Hutchinson–Gilford progeria syndrome.[7][8] To date over 1,400 SNPs are known [2]. They can manifest in changes on mRNA, splicing or protein (e.g. Arg471Cys,[9] Arg482Gln,[10] Arg527Leu,[11] Arg527Cys,[12] Ala529Val [13] ) level. # DNA damage DNA double-strand damages can be repaired by either homologous recombination (HR) or non-homologous end joining (NHEJ). LMNA promotes genetic stability by maintaining the levels of proteins that have key roles in HR and NHEJ.[14][15] Mouse cells that are deficient for maturation of prelamin A have increased DNA damage and chromosome aberrations, and show increased sensitivity to DNA damaging agents.[16] In progeria, the inadequacy of DNA repair, due to defective LMNA, may cause features of premature aging (see DNA damage theory of aging). # Interactions LMNA has been shown to interact with: - ALOX12[17] - EMD[18][19][20][21] - NARF[22] - SREBF1[23] - TMPO[24][25] - ZNF239[26] - SIRT1[27]

https://www.wikidoc.org/index.php/LMNA

8950a34c755a17e37acd3f7f8eb210b74a2bbc94

wikidoc

LMO2

LMO2 LIM domain only 2 (rhombotin-like 1), also known as LMO2, RBTNL1, RBTN2, RHOM2, LIM Domain Only Protein 2, TTG2, and T-Cell Translocation Protein 2, is a protein which in humans is encoded by the LMO2 gene. # Function LMO2 encodes a cysteine-rich, two LIM domain protein that is required for yolk sac erythropoiesis. The LMO2 protein has a central and crucial role in hematopoietic development and is highly conserved. # Clinical significance The LMO2 transcription start site is located approximately 25 kb downstream from the 11p13 T-cell translocation cluster (11p13 ttc), where a number of T-cell acute lymphoblastic leukemia-specific translocations occur. # Interactions LMO2 has been shown to interact with: - GATA1, - GATA2, - JARID1A, - MLLT4, and - TAL1

LMO2 LIM domain only 2 (rhombotin-like 1), also known as LMO2, RBTNL1, RBTN2, RHOM2, LIM Domain Only Protein 2, TTG2, and T-Cell Translocation Protein 2, is a protein which in humans is encoded by the LMO2 gene.[1] # Function LMO2 encodes a cysteine-rich, two LIM domain protein that is required for yolk sac erythropoiesis.[2] The LMO2 protein has a central and crucial role in hematopoietic development and is highly conserved. # Clinical significance The LMO2 transcription start site is located approximately 25 kb downstream from the 11p13 T-cell translocation cluster (11p13 ttc), where a number of T-cell acute lymphoblastic leukemia-specific translocations occur.[3] # Interactions LMO2 has been shown to interact with: - GATA1,[4] - GATA2,[4] - JARID1A,[5] - MLLT4,[6] and - TAL1[4][7][8][9]

https://www.wikidoc.org/index.php/LMO2

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wikidoc

LMO4

LMO4 LIM domain transcription factor LMO4 is a protein that in humans is encoded by the LMO4 gene. LIM domain only 4 is a cysteine-rich, two LIM domain-containing protein that may play a role as a transcriptional regulator or possibly an oncogene. Its mRNA is characterized by a GC-rich 5' region and by multiple ATTT motifs in the 3' region. A variant transcript missing a portion of the 5' region has been identified but cannot be confirmed because of the GC-rich nature of the region. # Interactions LMO4 has been shown to interact with LDB1, RBBP8 and BRCA1.

LMO4 LIM domain transcription factor LMO4 is a protein that in humans is encoded by the LMO4 gene.[1] LIM domain only 4 is a cysteine-rich, two LIM domain-containing protein that may play a role as a transcriptional regulator or possibly an oncogene. Its mRNA is characterized by a GC-rich 5' region and by multiple ATTT motifs in the 3' region. A variant transcript missing a portion of the 5' region has been identified but cannot be confirmed because of the GC-rich nature of the region.[1] # Interactions LMO4 has been shown to interact with LDB1,[2][3] RBBP8[2][4] and BRCA1.[2][4]

https://www.wikidoc.org/index.php/LMO4

c279739b7a4c3c2486143d0539c3af1bcfa6a2bb

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LQT1

LQT1 # Overview LQT1 is the most common subtype of long QT syndrome making up to 55% of all cases of long QT syndrome. It often presents as a cardiac event that occurs after exercise, and especially during underwater exercise such as swimming or diving. Homozygous recessive mutations in the gene for LQT1 appear to cause the Jervell and Lange-Nielsen syndrome which is characterized clinically by LQTS and sensorineural deafness. Romano-Ward syndrome is an autosomal dominant form of LQTS that is not associated with deafness. Events before the age of 10 years old only occur in the LQT1 subtype of LQTS. Patients with LQT1 paradoxically show a prolongation in the QT segment on EKG after an infusion of epinephrine, which is also used to unmask latent carriers. LQT1 patients are most likely to have the greatest positive response to therapy with beta blockers when compared with the other LQTS subtypes. The mutation occurs on the short arm of chromosome 11. # LQT1 Subtype ## Genetics and Pathophysiology LQT1 is the most common type of long QT syndrome, making up about 40 to 55 percent of all cases. This variant will sometimes come to the attention of the cardiologist following a cardiac event during exercise like swimming. The LQT1 gene is KCNQ1 which has been isolated to chromosome 11p15.5. KCNQ1 codes for the voltage-gated potassium channel KvLQT1 that is highly expressed in the heart. It is believed that the product of the KCNQ1 gene produces an alpha subunit that interacts with other proteins (particularly the minK beta subunit) to create the IKs ion channel, which is responsible for the delayed potassium rectifier current of the cardiac action potential. Mutations to the KCNQ1 gene can be inherited in an autosomal dominant or an autosomal recessive pattern in the same family. In the autosomal recessive mutation of this gene,homozygous mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the IKs ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness. This variant of LQT1 is known as the Jervell and Lange-Nielsen syndrome. Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of epinephrine. This can also unmark latent carriers of the LQT1 gene. Many missense mutations of the LQT1 gene have been identified. These are often associated with a high risk percentage of symptomatic carriers and sudden death. Mutations that occur in the transmembrane region in the cells of affected persons, are more likely to lead to symptoms and manifestations such as syncope, aborted cardiac arrest and sudden cardiac death, when compared with mutations that occur in the C-terminal region. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. - In LQT1, syncope, prodrome or other events particularly occur in the setting of exercise or underwater activities. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death. ## Genotype-specific Therapy Recommendations for therapy that are particularly specific to LQT1 patients are: - To limit strenuous exercise or emotional stress, as these are common triggers for an event in LQT1 patients - That the patient be treated with a beta-blocker, as LQT1 patients are highly likely to have a positive response to beta-blockers - To avoid unsupervised swimming unless the patient has an ICD

LQT1 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview LQT1 is the most common subtype of long QT syndrome making up to 55% of all cases of long QT syndrome. It often presents as a cardiac event that occurs after exercise, and especially during underwater exercise such as swimming or diving. Homozygous recessive mutations in the gene for LQT1 appear to cause the Jervell and Lange-Nielsen syndrome which is characterized clinically by LQTS and sensorineural deafness. Romano-Ward syndrome is an autosomal dominant form of LQTS that is not associated with deafness. Events before the age of 10 years old only occur in the LQT1 subtype of LQTS. Patients with LQT1 paradoxically show a prolongation in the QT segment on EKG after an infusion of epinephrine, which is also used to unmask latent carriers. LQT1 patients are most likely to have the greatest positive response to therapy with beta blockers when compared with the other LQTS subtypes. The mutation occurs on the short arm of chromosome 11. # LQT1 Subtype ## Genetics and Pathophysiology LQT1 is the most common type of long QT syndrome, making up about 40 to 55 percent of all cases. This variant will sometimes come to the attention of the cardiologist following a cardiac event during exercise like swimming. The LQT1 gene is KCNQ1 which has been isolated to chromosome 11p15.5. KCNQ1 codes for the voltage-gated potassium channel KvLQT1 that is highly expressed in the heart. It is believed that the product of the KCNQ1 gene produces an alpha subunit that interacts with other proteins (particularly the minK beta subunit) to create the IKs ion channel, which is responsible for the delayed potassium rectifier current of the cardiac action potential. Mutations to the KCNQ1 gene can be inherited in an autosomal dominant or an autosomal recessive pattern in the same family. In the autosomal recessive mutation of this gene,homozygous mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the IKs ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness. This variant of LQT1 is known as the Jervell and Lange-Nielsen syndrome. Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of epinephrine. This can also unmark latent carriers of the LQT1 gene. Many missense mutations of the LQT1 gene have been identified. These are often associated with a high risk percentage of symptomatic carriers and sudden death. Mutations that occur in the transmembrane region in the cells of affected persons, are more likely to lead to symptoms and manifestations such as syncope, aborted cardiac arrest and sudden cardiac death, when compared with mutations that occur in the C-terminal region. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. - In LQT1, syncope, prodrome or other events particularly occur in the setting of exercise or underwater activities. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. [1] - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death. ## Genotype-specific Therapy Recommendations for therapy that are particularly specific to LQT1 patients are: - To limit strenuous exercise or emotional stress, as these are common triggers for an event in LQT1 patients - That the patient be treated with a beta-blocker, as LQT1 patients are highly likely to have a positive response to beta-blockers - To avoid unsupervised swimming unless the patient has an ICD

https://www.wikidoc.org/index.php/LQT1

5e35d54605837fed3a18b5c7070e51d8d629ca6f

wikidoc

LQT2

LQT2 # Overview LQT2 is the second most common subtype of mutations within long QT syndrome, occurring in 35-45% of LQTS patients. This subtype has been known to come to the attention of the cardiologist as a result of a cardiac event during the post-partum period, or after being triggered by an alarm clock or other auditory stimuli. The LQT2 mutation involves the HERG gene on chromosome 7, which regulates the channel responsible for the potassium rectifying current, which terminates the cardiac action potential. Most drugs that cause acquired long QT syndrome, do so by blocking the potassium rectifying current via the HERG gene. These drugs include antiarrhythmic drugs, certain non-sedating antihistamines, macrolide antibiotics, certain psychotropic medications, and certain gastric motility agents. # LQT2 Subtype ## Genetics and Pathophysiology This form of long QT syndrome most likely involves mutations of the human ether-a-go-go related gene (HERG) on chromosome 7. The HERG gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (IKr). (The IKr current is mainly responsible for the termination of the cardiac action potential, and therefore the length of the QT interval.) The normally functioning HERG gene allows protection against early after depolarizations (EADs). There is a possibility, that like in LQT1 mutations, the location of the mutation may have a differing impact on the individual who is affected. A study of 201 patients showed that persons with mutations in the pore region had a greater risk of cardiac events and sudden cardiac death, and that these manifestations occurred earlier than in persons with mutations in the non-pore regions . ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. - In LQT2, syncope, prodrome, or other events may particularly occur in the post-partum period, or in response to auditory stimuli. - Undiagnosed LQT2 may be present in certain individuals who develop acquired long QT syndrome in response to certain medications. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death. # Acquired LQTS with Medications In some patients, drug associated LQTS appears to be due to a congenital form of LQTS which is clinically latent until until the patient is exposed to a drug, or another factor which may bring forth the manifestations of long QT syndrome. Most drugs that cause long QT syndrome do so by blocking the IKr current via the HERG gene. This causes rapid closure of the potassium channels and an abnormal rise in IKr. Similar to LQT1 this also causes results in a delayed ventricular repolarization and a lengthened QT interval.These include erythromycin, terfenadine, and ketoconazole. The HERG channel is very sensitive to unintended drug binding due to two aromatic amino acids, the tyrosine at position 652 and the phenylalanine at position 656. These amino acid residues are poised so drug binding to them will block the channel from conducting current. Other potassium channels do not have these residues in these positions and are therefore not as prone to blockage. Treatment of drug induced LQTS includes acute therapy for the arrhythmia, discontinuation of the drug that precipitated the long QT syndrome, and the correction of any co-existing metabolic abnormalities such as hypomagnesemia and hypokalemia.

LQT2 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview LQT2 is the second most common subtype of mutations within long QT syndrome, occurring in 35-45% of LQTS patients. This subtype has been known to come to the attention of the cardiologist as a result of a cardiac event during the post-partum period, or after being triggered by an alarm clock or other auditory stimuli. The LQT2 mutation involves the HERG gene on chromosome 7, which regulates the channel responsible for the potassium rectifying current, which terminates the cardiac action potential. Most drugs that cause acquired long QT syndrome, do so by blocking the potassium rectifying current via the HERG gene. These drugs include antiarrhythmic drugs, certain non-sedating antihistamines, macrolide antibiotics, certain psychotropic medications, and certain gastric motility agents. # LQT2 Subtype ## Genetics and Pathophysiology This form of long QT syndrome most likely involves mutations of the human ether-a-go-go related gene (HERG) on chromosome 7. The HERG gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (IKr). (The IKr current is mainly responsible for the termination of the cardiac action potential, and therefore the length of the QT interval.) The normally functioning HERG gene allows protection against early after depolarizations (EADs). There is a possibility, that like in LQT1 mutations, the location of the mutation may have a differing impact on the individual who is affected. A study of 201 patients showed that persons with mutations in the pore region had a greater risk of cardiac events and sudden cardiac death, and that these manifestations occurred earlier than in persons with mutations in the non-pore regions [1]. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. - In LQT2, syncope, prodrome, or other events may particularly occur in the post-partum period, or in response to auditory stimuli. - Undiagnosed LQT2 may be present in certain individuals who develop acquired long QT syndrome in response to certain medications. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. [2] - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death. # Acquired LQTS with Medications In some patients, drug associated LQTS appears to be due to a congenital form of LQTS which is clinically latent until until the patient is exposed to a drug, or another factor which may bring forth the manifestations of long QT syndrome. Most drugs that cause long QT syndrome do so by blocking the IKr current via the HERG gene. This causes rapid closure of the potassium channels and an abnormal rise in IKr. Similar to LQT1 this also causes results in a delayed ventricular repolarization and a lengthened QT interval.These include erythromycin, terfenadine, and ketoconazole. The HERG channel is very sensitive to unintended drug binding due to two aromatic amino acids, the tyrosine at position 652 and the phenylalanine at position 656. These amino acid residues are poised so drug binding to them will block the channel from conducting current. Other potassium channels do not have these residues in these positions and are therefore not as prone to blockage. Treatment of drug induced LQTS includes acute therapy for the arrhythmia, discontinuation of the drug that precipitated the long QT syndrome, and the correction of any co-existing metabolic abnormalities such as hypomagnesemia and hypokalemia.

https://www.wikidoc.org/index.php/LQT2

2876f4dbc65dea1514d186fdf23996f4b08ccdd8

wikidoc

LQT3

LQT3 # Overview LQT3 is the third most common subtype of long QT syndrome, occurring in 5-10% of LQTS cases. It is most commonly associated with cardiac events that occur during sleep. It is also associated with Brugada syndrome and sudden infant death syndrome. This subtype is highly likely to show shortening of the QT interval in response to administration of mexilitine. This subtype is caused by a mutation in the SCN5A gene on chromosome 3, which affects the sodium channels. The slow leakage of sodium into the cells causes cell membrane instability, and a prolonged QT interval on EKG. # LQT3 Subtype ## Genetics and Pathophysiology The LQT3 type of long QT syndrome accounts for 5-10% of cases, and cardiac events can occur during sleep. Patients with LQT3 are less likely than patients with LQT1 and LQT2 to have events due to exercise or stress. This is because patients with LQT3 shorten their QT interval with tachycardia, and therefore are less susceptible to catecholamine induced arrhythmias. This variant involves a mutation of the gene that encodes the alpha subunit of the Na+ ion channel. This gene is located on chromosome 3p21-24, and is known as SCN5A (also hH1 and NaV1.5). The mutations involved in LQT3 slow the inactivation of the Na+ channel, resulting in prolongation of the Na+ influx during depolarization. As the sodium channel is not adequately inactivated, the membrane remains slightly depolarized by the slow leaking of sodium into the cell. This leads to instability of the membrane, and early after-depolarizations. Paradoxically, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential. There have been sporadic mutations in SCN5A that have been reported where neither parent of the affected individual had a mutation or a prolonged QT interval. Individuals affected with this sporadic mutation had the added factors of prolonged opening and early re-opening of the sodium channel, resulting in an even greater prolongation of the sodium channel decay time. These sporadic mutations have also bee associated with sudden infant death syndrome . There have been certain polymorphisms of SCN5A that have been noted in about 13 percent of the African American population. These polymorphisms, named Y1102 and S1103Y are associated with a faster sodium channel activation, however are only shown to create a minimal increase in the risk of arrhythmia. Most of the affected subjects never develop an arrhythmia, however they may be at greater risk of long QT syndrome than the general population if they take certain medications or develop hypokalemia . ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. - In LQT3, events may particularly occur during sleep. ## Therapy - Medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death. ## Genotype-specific Therapy Patients with the LQT3 subtype should especially consider the following therapeutic options: - Consider not using a beta-blocker as therapy, as these patients have less or no benefit with beta blockers compared with the other subtypes. - Consider treatment with mexilitine as this is sodium-channel blocker and LQT3 is associated with the failure to inactivate sodium channels. - Consider placement of a pacemaker, as bradycardia is common among these patients, and can lead to pause-dependent arrhythmias. ## Other Manifestations of SCN5A Mutations A large number of mutations in the same gene that causes LQT3, called SCN5A have been shown to have a variety of cardiac manifestations. Calcium has been suggested as a regulator of SCN5A, and the effects of calcium on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3. Some of the manifestations that mutations in SCN5A can cause are: - Brugada syndrome - Cardiac conduction disease - Dilated cardiomyopathy - Sudden unexpected nocturnal death syndrome - Isolated familial AV conduction defect - Congenital sick sinus syndrome - Familial dilated cardiomyopathy

LQT3 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview LQT3 is the third most common subtype of long QT syndrome, occurring in 5-10% of LQTS cases. It is most commonly associated with cardiac events that occur during sleep. It is also associated with Brugada syndrome and sudden infant death syndrome. This subtype is highly likely to show shortening of the QT interval in response to administration of mexilitine. This subtype is caused by a mutation in the SCN5A gene on chromosome 3, which affects the sodium channels. The slow leakage of sodium into the cells causes cell membrane instability, and a prolonged QT interval on EKG. # LQT3 Subtype ## Genetics and Pathophysiology The LQT3 type of long QT syndrome accounts for 5-10% of cases, and cardiac events can occur during sleep. Patients with LQT3 are less likely than patients with LQT1 and LQT2 to have events due to exercise or stress. This is because patients with LQT3 shorten their QT interval with tachycardia, and therefore are less susceptible to catecholamine induced arrhythmias. This variant involves a mutation of the gene that encodes the alpha subunit of the Na+ ion channel. This gene is located on chromosome 3p21-24, and is known as SCN5A (also hH1 and NaV1.5). The mutations involved in LQT3 slow the inactivation of the Na+ channel, resulting in prolongation of the Na+ influx during depolarization. As the sodium channel is not adequately inactivated, the membrane remains slightly depolarized by the slow leaking of sodium into the cell. This leads to instability of the membrane, and early after-depolarizations. Paradoxically, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential. There have been sporadic mutations in SCN5A that have been reported where neither parent of the affected individual had a mutation or a prolonged QT interval. Individuals affected with this sporadic mutation had the added factors of prolonged opening and early re-opening of the sodium channel, resulting in an even greater prolongation of the sodium channel decay time. These sporadic mutations have also bee associated with sudden infant death syndrome [1]. There have been certain polymorphisms of SCN5A that have been noted in about 13 percent of the African American population. These polymorphisms, named Y1102 and S1103Y are associated with a faster sodium channel activation, however are only shown to create a minimal increase in the risk of arrhythmia. Most of the affected subjects never develop an arrhythmia, however they may be at greater risk of long QT syndrome than the general population if they take certain medications or develop hypokalemia [2]. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. - In LQT3, events may particularly occur during sleep. ## Therapy - Medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. [3] - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death. ## Genotype-specific Therapy Patients with the LQT3 subtype should especially consider the following therapeutic options: - Consider not using a beta-blocker as therapy, as these patients have less or no benefit with beta blockers compared with the other subtypes. - Consider treatment with mexilitine as this is sodium-channel blocker and LQT3 is associated with the failure to inactivate sodium channels. - Consider placement of a pacemaker, as bradycardia is common among these patients, and can lead to pause-dependent arrhythmias. ## Other Manifestations of SCN5A Mutations A large number of mutations in the same gene that causes LQT3, called SCN5A have been shown to have a variety of cardiac manifestations. Calcium has been suggested as a regulator of SCN5A, and the effects of calcium on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3. Some of the manifestations that mutations in SCN5A can cause are: - Brugada syndrome - Cardiac conduction disease - Dilated cardiomyopathy - Sudden unexpected nocturnal death syndrome - Isolated familial AV conduction defect - Congenital sick sinus syndrome - Familial dilated cardiomyopathy

https://www.wikidoc.org/index.php/LQT3

7c62d386d38e1ee681a88bc3e4354a7e88ce11a6

wikidoc

LQT4

LQT4 # Overview The LTQ4 subtype of long QT syndrome is caused by a mutation in the genes which code for proteins cause ankyrins. People with this mutation experience sinus bradycardia, junctional escape rhythms, atrial fibrillation, and sudden death after physical or emotional stress. Ankyrins are important proteins that bind to various types of vital cell membrane channels which regulate the concentration of intracellular electrolytes. Abnormalities in the channels as a result of defective ankyrin proteins can lead to dangerous levels of intracellular calcium, and fatal arrhythmias. LQT4 is the only subtype of LQTS that does not involve sudden cardiac death as a part of another genetic disorder called Rett syndrome. # LQT4 Subtype ## Genetics and Pathophysiology The LQT4 genes are ANK2 and ANKB which are located on chromosome 4q25-27 , and code for proteins called ankyrins. They are proteins which affect the function of several important ion channel proteins such as the chloride-bicarbonate anion exchanger, ATPase, calcium release channels, and the voltage gated sodium channel. The proteins physically link the lipid bilayer of the cell membrane to the skeleton of the membrane. A mutation in the LTQ4 genes that code for ankyrins can cause increased intracellular concentrations of calcium, and can therefore cause fatal arrhythmias. People with this mutation experience sinus bradycardia, junctional escape rhythms, atrial fibrillation, and sudden death after physical or emotional stress has also been known to occur. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. - In LQT4, events may particularly occur after physical or emotional stress. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

LQT4 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [3] # Overview The LTQ4 subtype of long QT syndrome is caused by a mutation in the genes which code for proteins cause ankyrins. People with this mutation experience sinus bradycardia, junctional escape rhythms, atrial fibrillation, and sudden death after physical or emotional stress. Ankyrins are important proteins that bind to various types of vital cell membrane channels which regulate the concentration of intracellular electrolytes. Abnormalities in the channels as a result of defective ankyrin proteins can lead to dangerous levels of intracellular calcium, and fatal arrhythmias. LQT4 is the only subtype of LQTS that does not involve sudden cardiac death as a part of another genetic disorder called Rett syndrome. # LQT4 Subtype ## Genetics and Pathophysiology The LQT4 genes are ANK2 and ANKB which are located on chromosome 4q25-27 [1], and code for proteins called ankyrins. They are proteins which affect the function of several important ion channel proteins such as the chloride-bicarbonate anion exchanger, ATPase, calcium release channels, and the voltage gated sodium channel. The proteins physically link the lipid bilayer of the cell membrane to the skeleton of the membrane. A mutation in the LTQ4 genes that code for ankyrins can cause increased intracellular concentrations of calcium, and can therefore cause fatal arrhythmias. People with this mutation experience sinus bradycardia, junctional escape rhythms, atrial fibrillation, and sudden death after physical or emotional stress has also been known to occur. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. - In LQT4, events may particularly occur after physical or emotional stress. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. [2] - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

https://www.wikidoc.org/index.php/LQT4

d60e9ef7575b502184ae65bf70148fa1a8d98e7b

wikidoc

LQT5

LQT5 # Overview LQT5 subtype of long QT syndrome is an autosomal dominant mutation that leads to a defect in the potassium channel. In its rare homozygous form it can cause Jervell and Lange-Nielsen syndrome. # LQT5 Subtype ## Genetics and Pathophysiology LQT5 is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE1 which encodes for the potassium channel beta subunit MinK. In its rare homozygous forms it can lead to Jervell and Lange-Nielsen syndrome. As in LQT1, LQT5 can lead to a decreased excretion of potassium from the cell and will show prolongation of the QT interval on EKG. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. - History of sensorineural deafness as occurs in Jervell and Lange-Nielsen syndrome. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

LQT5 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview LQT5 subtype of long QT syndrome is an autosomal dominant mutation that leads to a defect in the potassium channel. In its rare homozygous form it can cause Jervell and Lange-Nielsen syndrome. # LQT5 Subtype ## Genetics and Pathophysiology LQT5 is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE1 which encodes for the potassium channel beta subunit MinK. In its rare homozygous forms it can lead to Jervell and Lange-Nielsen syndrome. As in LQT1, LQT5 can lead to a decreased excretion of potassium from the cell and will show prolongation of the QT interval on EKG. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. - History of sensorineural deafness as occurs in Jervell and Lange-Nielsen syndrome. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. [1] - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

https://www.wikidoc.org/index.php/LQT5

f1c936bd8092333a0863ae2d0f2758f24b01a488

wikidoc

LQT6

LQT6 # Overview LQT6 is a rare form of long QT syndrome. # LQT6 Subtype LQT6 is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE2 which encodes for the potassium channel beta subunit MiRP1, constituting part of the IKr repolarizing K+ current. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

LQT6 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview LQT6 is a rare form of long QT syndrome. # LQT6 Subtype LQT6 is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE2 which encodes for the potassium channel beta subunit MiRP1, constituting part of the IKr repolarizing K+ current. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. [1] - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

https://www.wikidoc.org/index.php/LQT6

348efdfd2e850278958cc719102a7953913d7a06

wikidoc

LQT8

LQT8 # Overview LQT8 subtype of long QT syndrome, also known as Timothy's syndrome is due to mutations causing abnormalities in calcium channels. LQT8 is associated with the finding of syndactyly. # LQT8 Subtype Timothy's syndrome is due to mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c. Since the Calcium channel Cav1.2 is abundant in many tissues, patients with Timothy's syndrome have many clinical manifestations including congenital heart disease, autism, syndactyly and immune deficiency. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. ## Physical Exam - Physical exam may show syndactyly. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

LQT8 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [3] # Overview LQT8 subtype of long QT syndrome, also known as Timothy's syndrome is due to mutations causing abnormalities in calcium channels. LQT8 is associated with the finding of syndactyly. # LQT8 Subtype Timothy's syndrome is due to mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c. Since the Calcium channel Cav1.2 is abundant in many tissues, patients with Timothy's syndrome have many clinical manifestations including congenital heart disease, autism, syndactyly and immune deficiency. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. ## Physical Exam - Physical exam may show syndactyly. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. [1] - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

https://www.wikidoc.org/index.php/LQT8

b41034f3e67cb81ff833e27532eb22819025d854

wikidoc

LQT9

LQT9 # Overview LQT9 subtype is a variant of long QT syndrome, which causes abnormalities in a membrane protein called caveolin. # LQT9 This newly discovered variant is caused by mutations in the membrane structural protein,caveolin-3. Caveolins form specific membrane domains called caveolae in which among others the NaV1.5 voltage-gated sodium channel sits. Similar to LQT3, these particular mutations increase so-called 'late' sodium current which impairs cellular repolarization. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

LQT9 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview LQT9 subtype is a variant of long QT syndrome, which causes abnormalities in a membrane protein called caveolin. # LQT9 This newly discovered variant is caused by mutations in the membrane structural protein,caveolin-3. Caveolins form specific membrane domains called caveolae in which among others the NaV1.5 voltage-gated sodium channel sits. Similar to LQT3, these particular mutations increase so-called 'late' sodium current which impairs cellular repolarization. ## History and Symptoms - Seizures - due to oxygen deprivation that occurs during arrhythmia. - Fainting - fainting or syncope is the most common symptom LQTS. - A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness. - Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death. ## Therapy - Beta-blockers are the first line treatment in LQTS, even in asymptomatic carriers, as they reduce the incidence of syncope and sudden cardiac death. - Other medications to control non-malignant arrhythmias. - Electrolytes should be repleted as neccesary. - Avoidance of triggers (drugs, supplements, loud noises, exercise). - LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events. [1] - Placement of a pacemaker may be indicated. - Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate. - Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

https://www.wikidoc.org/index.php/LQT9

a83152f8075eba98bd78f66a3b89f70755d3bf0e

wikidoc

LRBA

LRBA Lipopolysaccharide-responsive and beige-like anchor protein is a protein that in humans is encoded by the LRBA gene. Patients with Chediak-Higashi syndrome (CHS1; MIM 214500) suffer from a systemic immunodeficiency involving defects in polarized trafficking of vesicles in a number of immune system cell types. In mouse, this syndrome is reproduced in strains with a mutation in the 'beige' gene that results in proteins lacking the BEACH (beige and CHS1) domain and C-terminal WD repeats. LRBA contains key features of both beige/CHS1 and A kinase anchor proteins (AKAPs; see MIM 602449). Deficiency of this protein in humans causes the codntion known as LPS-responsive beige-like anchor protein deficiency.

LRBA Lipopolysaccharide-responsive and beige-like anchor protein is a protein that in humans is encoded by the LRBA gene.[1][2][3] Patients with Chediak-Higashi syndrome (CHS1; MIM 214500) suffer from a systemic immunodeficiency involving defects in polarized trafficking of vesicles in a number of immune system cell types. In mouse, this syndrome is reproduced in strains with a mutation in the 'beige' gene that results in proteins lacking the BEACH (beige and CHS1) domain and C-terminal WD repeats. LRBA contains key features of both beige/CHS1 and A kinase anchor proteins (AKAPs; see MIM 602449).[supplied by OMIM][3] Deficiency of this protein in humans causes the codntion known as LPS-responsive beige-like anchor protein deficiency.

https://www.wikidoc.org/index.php/LRBA

94eb5d1eb0e1922e1acddae4984ccc92c9499ffa

wikidoc

LRG1

LRG1 Leucine-rich alpha-2-glycoprotein 1 is a protein which in humans is encoded by the gene LRG1. # Function The leucine-rich repeat (LRR) family of proteins, including LRG1, have been shown to be involved in protein-protein interaction, signal transduction, and cell adhesion and development. LRG1 is expressed during granulocyte differentiation. LRG1 has been shown to be involved in promoting neovascularization (new blood vessel growth) through causing a switch in transforming growth factor beta (TGFbeta) signaling in endothelial cells. LRG1 binds to the accessory receptor endoglin and promotes signaling via the ALK1-Smad1/5/8 pathway. # Application Levels of the LRG protein are markedly elevated in acute appendicitis and therefore could be used as a diagnostic aid. LRG1 may be a potential therapeutifc target for the treatment of diseases where there is aberrant neovascularization.

LRG1 Leucine-rich alpha-2-glycoprotein 1 is a protein which in humans is encoded by the gene LRG1.[1] # Function The leucine-rich repeat (LRR) family of proteins, including LRG1, have been shown to be involved in protein-protein interaction, signal transduction, and cell adhesion and development. LRG1 is expressed during granulocyte differentiation.[1][2] LRG1 has been shown to be involved in promoting neovascularization (new blood vessel growth) through causing a switch in transforming growth factor beta (TGFbeta) signaling in endothelial cells. LRG1 binds to the accessory receptor endoglin and promotes signaling via the ALK1-Smad1/5/8 pathway.[3] # Application Levels of the LRG protein are markedly elevated in acute appendicitis and therefore could be used as a diagnostic aid.[4] LRG1 may be a potential therapeutifc target for the treatment of diseases where there is aberrant neovascularization.[3]

https://www.wikidoc.org/index.php/LRG1

cfeb1b534d201dd1d392044bec0e1328ef1a641b

wikidoc

LRP1

LRP1 Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer. # Structure The LRP1 gene encodes a 600 kDa precursor protein that is processed by furin in the trans-Golgi complex, resulting in a 515 kDa alpha-chain and an 85 kDa beta-chain associated noncovalently. As a member of the LDLR family, LRP1 contains cysteine-rich complement-type repeats, EGF (gene) repeats, β-propeller domains, a transmembrane domain, and a cytoplasmic domain. The extracellular domain of LRP1 is the alpha-chain, which comprises four ligand-binding domains (numbered I-IV) containing two, eight, ten, and eleven cysteine-rich complement-type repeats, respectively. These repeats bind extracellular matrix proteins, growth factors, proteases, protease inhibitor complexes, and other proteins involved in lipoprotein metabolism. Of the four domains, II and IV bind the majority of the protein’s ligands. The EGF repeats and β-propeller domains serve to release ligands in low pH conditions, such as inside endosomes, with the β-propeller postulated to displace the ligand at the ligand binding repeats. The transmembrane domain is the β-chain, which contains a 100-residue cytoplasmic tail. This tail contains two NPxY motifs that are responsible for the protein’s function in endocytosis and signal transduction. # Function LRP1 is a member of the LDLR family and ubiquitously expressed in multiple tissues, though it is most abundant in vascular smooth muscle cells (SMCs), hepatocytes, and neurons. LRP1 plays a key role in intracellular signaling and endocytosis, which thus implicate it in many cellular and biological processes, including lipid and lipoprotein metabolism, protease degradation, platelet derived growth factor receptor regulation, integrin maturation and recycling, regulation of vascular tone, regulation of blood brain barrier permeability, cell growth, cell migration, inflammation, and apoptosis, as well as diseases such as neurodegenerative diseases, atherosclerosis, and cancer. To elaborate, LRP1 mainly contributes to regulation of protein activity by binding target proteins as a co-receptor, in conjunction with integral membrane proteins or adaptor proteins like uPA, to the lysosome for degradation. In lipoprotein metabolism, the interaction between LRP1 and APOE stimulates a signaling pathway that leads to elevated intracellular cAMP levels, increased protein kinase A activity, inhibited SMC migration, and ultimately, protection against vascular disease. While membrane-bound LRP1 performs endocytic clearance of proteases and inhibitors, proteolytic cleavage of its ectodomain allows the free LRP1 to compete with the membrane-bound form and prevent their clearance. Several sheddases have been implicated in the proteolytic cleavage of LRP1 such as ADAM10, ADAM12, ADAM17 and MT1-MMP. LRP1 is alsocontinuously endocytosed from the membrane and recycled back to the cell surface. Though the role of LRP1 in apoptosis is unclear, it is required for tPA to bind LRP1 in order to trigger the ERK1/2 signal cascade and promote cell survival. # Clinical significance ## Alzheimer's disease Neurons require cholesterol to function. Cholesterol is imported into the neuron by apolipoprotein E (apoE) via LRP1 receptors on the cell surface. It has been theorized that a causal factor in Alzheimer's is the decrease of LRP1 mediated by the metabolism of the amyloid precursor protein, leading to decreased neuronal cholesterol and increased amyloid beta. LRP1 is also implicated in the effective clearance of Aβ from the brain to the periphery across the blood-brain barrier. In support of this, LRP1 expression is reduced in endothelial cells as a result of normal aging and Alzheimer's disease in humans and animal models of the disease. This clearance mechanism is modulated by the apoE isoforms, with the presence of the apoE4 isoform resulting in reduced transcytosis of Aβ in in vitro models of the blood-brain barrier. The reduced clearance appears to be, at least in part, as a result of an increase in the ectodomain shedding of LRP1 by sheddases, resulting in the formation of soluble LRP1 which is no longer able to transcytose the Aβ peptides. In addition, over-accumulation of copper in the brain is associated with reduced LRP1 mediated clearance of amyloid beta across the blood brain barrier. This defective clearance may contribute to the buildup of neurotoxic amyloid-beta that is thought to contribute to Alzheimer's disease. ## Cardiovascular disease Studies have elucidated different roles for LRP1 in cellular processes relevant for cardiovascular disease. Atherosclerosis is the primary cause of cardiovascular disease such as stroke and heart attacks. In the liver LRP1 is important for the removal of atherogenic lipoproteins (Chylomicron remnants, VLDL) and other proatherogenic ligands from the circulation. LRP1 has a cholesterol-independent role in atherosclerosis by modulating the activity and cellular localization of the PDGFR-β in vascular smooth muscle cells. Finally, LRP1 in macrophages has an effect on atherosclerosis through the modulation of the extracellular matrix and inflammatory responses. ## Cancer LRP1 is involved in tumorigenesis, and is proposed to be a tumor suppressor. Notably, LRP1 functions in clearing proteases such as plasmin, urokinase-type plasminogen activator, and metalloproteinases, which contributes to prevention of cancer invasion, while its absence is linked to increased cancer invasion. However, the exact mechanisms require further study, as other studies have shown that LRP1 may also promote cancer invasion. One possible mechanism for the inhibitory function of LRP1 in cancer involves the LRP1-dependent endocytosis of 2′-hydroxycinnamaldehyde (HCA), resulting in decreased pepsin levels and, consequently, tumor progression. Alternatively, LRP1 may regulate focal adhesion disassembly of cancer cells through the ERK and JNK pathways to aid invasion. Moreover, LRP1 interacts with PAI-1 to recruit mast cells (MCs) and induce their degranulation, resulting in the release of MC mediators, activation of an inflammatory response, and development of glioma. # Interactions LRP1 has been shown to interact with: - A2-Macroglobulin, - β-amyloid precursor protein, - APBB1, - APOE, - Aprotinin, - C1S/C1q inhibitor, - CALR, - CD44, - Chylomicron, - Circumsporozoite protein, - Collectin, - Complement C3, - CTGF, - DLG4, - Elastase, - Factor IXa, - Factor VIIa, - Fibronectin, - Gentamicin, - GIPC1, - Heat shock proteins: gp96, hsp70, hsp90, - heparin cofactor II, - Hepatic lipase, - ITGB1BP1, - Lactoferrin, - Lipoprotein lipase, - LPL, - MAPK8IP1, - MAPK8IP2, - Midkine, - MMP13, - MMP2, - MMP9, - Neuroserpin, - Nexin-1, - NOS1AP, - PAI 2, - PAI-1, - PDGF, - tPA, - uPA, - Polymyxin B, - Protein C inhibitor, - Pseudomonas exotoxin A, - RAP, - Ricin A, - SHC1, and - Sphingolipid activator protein, - SYNJ2BP. - Tat, - Thrombin, - THBS1, - Thrombospondin 2, - TIMP1, - TIMP2, - TIMP3, - Tissue factor pathway inhibitor, - PLAT, - Transforming growth factor-β, - PLAUR, - VLDL, ## Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

LRP1 Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene.[1][2][3] LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.[4][5] # Structure The LRP1 gene encodes a 600 kDa precursor protein that is processed by furin in the trans-Golgi complex, resulting in a 515 kDa alpha-chain and an 85 kDa beta-chain associated noncovalently.[4][6][7] As a member of the LDLR family, LRP1 contains cysteine-rich complement-type repeats, EGF (gene) repeats, β-propeller domains, a transmembrane domain, and a cytoplasmic domain.[5] The extracellular domain of LRP1 is the alpha-chain, which comprises four ligand-binding domains (numbered I-IV) containing two, eight, ten, and eleven cysteine-rich complement-type repeats, respectively.[4][5][6][7] These repeats bind extracellular matrix proteins, growth factors, proteases, protease inhibitor complexes, and other proteins involved in lipoprotein metabolism.[4][5] Of the four domains, II and IV bind the majority of the protein’s ligands.[7] The EGF repeats and β-propeller domains serve to release ligands in low pH conditions, such as inside endosomes, with the β-propeller postulated to displace the ligand at the ligand binding repeats.[5] The transmembrane domain is the β-chain, which contains a 100-residue cytoplasmic tail. This tail contains two NPxY motifs that are responsible for the protein’s function in endocytosis and signal transduction.[4] # Function LRP1 is a member of the LDLR family and ubiquitously expressed in multiple tissues, though it is most abundant in vascular smooth muscle cells (SMCs), hepatocytes, and neurons.[4][5] LRP1 plays a key role in intracellular signaling and endocytosis, which thus implicate it in many cellular and biological processes, including lipid and lipoprotein metabolism, protease degradation, platelet derived growth factor receptor regulation, integrin maturation and recycling, regulation of vascular tone, regulation of blood brain barrier permeability, cell growth, cell migration, inflammation, and apoptosis, as well as diseases such as neurodegenerative diseases, atherosclerosis, and cancer.[3][4][5][6][7] To elaborate, LRP1 mainly contributes to regulation of protein activity by binding target proteins as a co-receptor, in conjunction with integral membrane proteins or adaptor proteins like uPA, to the lysosome for degradation.[5][6][7] In lipoprotein metabolism, the interaction between LRP1 and APOE stimulates a signaling pathway that leads to elevated intracellular cAMP levels, increased protein kinase A activity, inhibited SMC migration, and ultimately, protection against vascular disease.[5] While membrane-bound LRP1 performs endocytic clearance of proteases and inhibitors, proteolytic cleavage of its ectodomain allows the free LRP1 to compete with the membrane-bound form and prevent their clearance.[4] Several sheddases have been implicated in the proteolytic cleavage of LRP1 such as ADAM10,[8] ADAM12,[9] ADAM17[10] and MT1-MMP.[9] LRP1 is alsocontinuously endocytosed from the membrane and recycled back to the cell surface.[5] Though the role of LRP1 in apoptosis is unclear, it is required for tPA to bind LRP1 in order to trigger the ERK1/2 signal cascade and promote cell survival.[11] # Clinical significance ## Alzheimer's disease Neurons require cholesterol to function. Cholesterol is imported into the neuron by apolipoprotein E (apoE) via LRP1 receptors on the cell surface. It has been theorized that a causal factor in Alzheimer's is the decrease of LRP1 mediated by the metabolism of the amyloid precursor protein, leading to decreased neuronal cholesterol and increased amyloid beta.[12] LRP1 is also implicated in the effective clearance of Aβ from the brain to the periphery across the blood-brain barrier.[13][14] In support of this, LRP1 expression is reduced in endothelial cells as a result of normal aging and Alzheimer's disease in humans and animal models of the disease.[15][16] This clearance mechanism is modulated by the apoE isoforms, with the presence of the apoE4 isoform resulting in reduced transcytosis of Aβ in in vitro models of the blood-brain barrier.[17] The reduced clearance appears to be, at least in part, as a result of an increase in the ectodomain shedding of LRP1 by sheddases, resulting in the formation of soluble LRP1 which is no longer able to transcytose the Aβ peptides.[18] In addition, over-accumulation of copper in the brain is associated with reduced LRP1 mediated clearance of amyloid beta across the blood brain barrier. This defective clearance may contribute to the buildup of neurotoxic amyloid-beta that is thought to contribute to Alzheimer's disease.[19] ## Cardiovascular disease Studies have elucidated different roles for LRP1 in cellular processes relevant for cardiovascular disease. Atherosclerosis is the primary cause of cardiovascular disease such as stroke and heart attacks. In the liver LRP1 is important for the removal of atherogenic lipoproteins (Chylomicron remnants, VLDL) and other proatherogenic ligands from the circulation.[20][21] LRP1 has a cholesterol-independent role in atherosclerosis by modulating the activity and cellular localization of the PDGFR-β in vascular smooth muscle cells.[22][23] Finally, LRP1 in macrophages has an effect on atherosclerosis through the modulation of the extracellular matrix and inflammatory responses.[24][25] ## Cancer LRP1 is involved in tumorigenesis, and is proposed to be a tumor suppressor. Notably, LRP1 functions in clearing proteases such as plasmin, urokinase-type plasminogen activator, and metalloproteinases, which contributes to prevention of cancer invasion, while its absence is linked to increased cancer invasion. However, the exact mechanisms require further study, as other studies have shown that LRP1 may also promote cancer invasion. One possible mechanism for the inhibitory function of LRP1 in cancer involves the LRP1-dependent endocytosis of 2′-hydroxycinnamaldehyde (HCA), resulting in decreased pepsin levels and, consequently, tumor progression.[5] Alternatively, LRP1 may regulate focal adhesion disassembly of cancer cells through the ERK and JNK pathways to aid invasion.[4] Moreover, LRP1 interacts with PAI-1 to recruit mast cells (MCs) and induce their degranulation, resulting in the release of MC mediators, activation of an inflammatory response, and development of glioma.[6] # Interactions LRP1 has been shown to interact with: - A2-Macroglobulin,[5] - β-amyloid precursor protein,[5] - APBB1,[26] - APOE,[5][27][28] - Aprotinin,[5] - C1S/C1q inhibitor,[5] - CALR,[5][29] - CD44,[4] - Chylomicron,[5] - Circumsporozoite protein,[5] - Collectin,[5] - Complement C3,[5] - CTGF,[5] - DLG4,[30] - Elastase,[5] - Factor IXa,[5] - Factor VIIa,[5] - Fibronectin,[5] - Gentamicin,[5] - GIPC1,[30] - Heat shock proteins: gp96, hsp70, hsp90,[31] - heparin cofactor II,[5] - Hepatic lipase,[5] - ITGB1BP1,[30] - Lactoferrin,[5] - Lipoprotein lipase,[5] - LPL,[32][33][34] - MAPK8IP1,[30] - MAPK8IP2,[30] - Midkine,[5] - MMP13,[4][5] - MMP2,[4] - MMP9,[4][5] - Neuroserpin,[5] - Nexin-1,[5] - NOS1AP,[30] - PAI 2,[4] - PAI-1,[4][6] - PDGF,[5] - tPA,[4][5] - uPA,[4][5] - Polymyxin B,[5] - Protein C inhibitor,[5] - Pseudomonas exotoxin A,[5] - RAP,[5] - Ricin A,[5] - SHC1,[35][36] and - Sphingolipid activator protein,[5] - SYNJ2BP.[30] - Tat,[5] - Thrombin,[5] - THBS1,[5][37][38][39] - Thrombospondin 2,[5] - TIMP1,[4] - TIMP2,[4] - TIMP3,[4] - Tissue factor pathway inhibitor,[5] - PLAT,[40][41] - Transforming growth factor-β,[5] - PLAUR,[42] - VLDL,[5] ## Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/LRP1

eecf1fda0cba5aa49405eaba2a30a6f36e2b87fe

wikidoc

LRP2

LRP2 Low density lipoprotein-related protein 2 also known as LRP2 or megalin is a protein which in humans is encoded by the LRP2 gene. # Function LRP2 was identified as the antigen of rat experimental membranous nephropathy (Heyman nephritis) and originally named gp330 and subsequently megalin and later LRP2. LRP2/megalin is a multiligand binding receptor found in the plasma membrane of many absorptive epithelial cells. LRP2/megalin is a member of a family of receptors with structural similarities to the low density lipoprotein receptor (LDLR). LRP2/megalin functions to mediate endocytosis of ligands leading to degradation in lysosomes or transcytosis. LRP2/megalin can also form complexes with cubilin: those complexes are able to reabsorb several molecules and can be inhibited by sodium maleate. LRP2 is expressed in epithelial cells of the thyroid (thyrocytes), where it can serve as a receptor for the protein thyroglobulin (Tg). # Clinical significance Mutations in the LRP2 gene are associated with Donnai-Barrow syndrome. # Interactions LRP2 has been shown to interact with: - DAB2, - DLG4, - GIPC1, - ITGB1BP1, - LDL-receptor-related protein associated protein, - LDLRAP1, - MAGI1, - MAPK8IP1, - MAPK8IP2, - NOS1AP, and - SYNJ2BP.

LRP2 Low density lipoprotein-related protein 2 also known as LRP2 or megalin is a protein which in humans is encoded by the LRP2 gene.[1][2][3] # Function LRP2 was identified as the antigen of rat experimental membranous nephropathy (Heyman nephritis) and originally named gp330 and subsequently megalin[4] and later LRP2. LRP2/megalin is a multiligand binding receptor found in the plasma membrane of many absorptive epithelial cells. LRP2/megalin is a member of a family of receptors with structural similarities to the low density lipoprotein receptor (LDLR). LRP2/megalin functions to mediate endocytosis of ligands leading to degradation in lysosomes or transcytosis. LRP2/megalin can also form complexes with cubilin: those complexes are able to reabsorb several molecules and can be inhibited by sodium maleate.[5] LRP2 is expressed in epithelial cells of the thyroid (thyrocytes), where it can serve as a receptor for the protein thyroglobulin (Tg).[6] # Clinical significance Mutations in the LRP2 gene are associated with Donnai-Barrow syndrome.[7] # Interactions LRP2 has been shown to interact with: - DAB2,[8] - DLG4,[9][10] - GIPC1,[9][11][12] - ITGB1BP1,[9] - LDL-receptor-related protein associated protein,[11][13] - LDLRAP1,[14] - MAGI1,[15] - MAPK8IP1,[9][12] - MAPK8IP2,[9][12] - NOS1AP,[9] and - SYNJ2BP.[9]

https://www.wikidoc.org/index.php/LRP2

329deb8280bbfe62d7a3fafb37334b3e83cd00f4

wikidoc

LRP5

LRP5 Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis-pseudoglioma (decrease in bone mass), while a gain-of-function mutation causes drastic increases in bone mass. # Structure LRP5 is a transmembrane low-density lipoprotein receptor that shares a similar structure with LRP6. In each protein, about 85% of its 1600-amino-acid length is extracellular. Each has four β-propeller motifs at the amino terminal end that alternate with four epidermal growth factor (EGF)-like repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid segment that crosses the cell membrane and a 207-amino-acid segment that is internal to the cell. # Function LRP5 acts as a co-receptor with LRP6 and the Frizzled protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway. This protein plays a key role in skeletal homeostasis. # Transcription The LRP5 promoter contains binding sites for KLF15 and SP1. In addition, 5' region region of the LRP5 gene contains four RUNX2 binding sites. LRP5 has been shown in mice and humans to inhibit expression of TPH1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum and that excess plasma serotonin leads to inhibition in bone. On the other hand, one study in mouse has shown a direct effect of Lrp5 on bone. # Interactions LRP5 has been shown to interact with AXIN1. Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation. Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation. # Clinical Significance The Wnt signaling pathway was first linked to bone development when a loss-of-function mutation in LRP5 was found to cause osteoporosis-pseudoglioma syndrome. Shortly thereafter, two studies reported that gain-of-function mutations in LRP5 caused high bone mass. Many bone density related diseases are caused by mutations in the LRP5 gene. There is controversy whether bone grows through Lrp5 through bone or the intestine. The majority of the current data supports the concept that bone mass is controlled by LRP5 through the osteocytes. Mice with the same Lrp5 gain-of-function mutations as also have high bone mass. The high bone mass is maintained when the mutation only occurs in limbs or in cells of the osteoblastic lineage. Bone mechanotransduction occurs through Lrp5 and is suppressed if Lrp5 is removed in only osteocytes. There are promising osteoporosis clinical trials targeting sclerostin, an osteocyte-specific protein which inhibits Wnt signaling by binding to Lrp5. An alternative model that has been verified in mice and in humans is that Lrp5 controls bone formation by inhibiting expression of TPH1, the rate-limiting biosynthetic enzyme for serotonin, a molecule that regulates bone formation, in enterochromaffin cells of the duodenum and that excess plasma serotonin leads to inhibition in bone. Another study found that a different Tph1-inhibitor decreased serotonin levels in the blood and intestine, but did not affect bone mass or markers of bone formation. LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation. Mutations in this gene also cause familial exudative vitreoretinopathy. A glial-derived extracellular ligand, Norrin, acts on a transmembrane receptor, Frizzled4, a coreceptor, Lrp5, and an auxiliary membrane protein, TSPAN12, on the surface of developing endothelial cells to control a transcriptional program that regulates endothelial growth and maturation. LRP5 knockout in mice led to increased plasma cholesterol levels on a high-fat diet because of the decreased hepatic clearance of chylomicron remnants. When fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance with marked reduction in intracellular ATP and Ca2+ in response to glucose, and impairment in glucose-induced insulin secretion. IP3 production in response to glucose was also reduced in LRP5—islets possibly caused by a marked reduction of various transcripts for genes involved in glucose sensing in LRP5—islets. LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets. In osteoarthritic chondrocytes the Wnt/beta-catenin pathway is activated with a significant up-regulation of beta-catenin mRNA expression. LRP5 mRNA and protein expression are also significantly up-regulated in osteoarthritic cartilage compared to normal cartilage, and LRP5 mRNA expression was further increased by vitamin D. Blocking LRP5 expression using siRNA against LRP5 resulted in a significant decrease in MMP13 mRNA and protein expressions. The catabolic role of LRP5 appears to be mediated by the Wnt/beta-catenin pathway in human osteoarthritis. The polyphenol curcumin increases the mRNA expression of LRP5. Mutations in LRP5 cause polycystic liver disease .

LRP5 Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene.[1][2][3] LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis-pseudoglioma (decrease in bone mass), while a gain-of-function mutation causes drastic increases in bone mass. # Structure LRP5 is a transmembrane low-density lipoprotein receptor that shares a similar structure with LRP6. In each protein, about 85% of its 1600-amino-acid length is extracellular. Each has four β-propeller motifs at the amino terminal end that alternate with four epidermal growth factor (EGF)-like repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid segment that crosses the cell membrane and a 207-amino-acid segment that is internal to the cell.[4] # Function LRP5 acts as a co-receptor with LRP6 and the Frizzled protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway.[4] This protein plays a key role in skeletal homeostasis.[3] # Transcription The LRP5 promoter contains binding sites for KLF15 and SP1.[5] In addition, 5' region region of the LRP5 gene contains four RUNX2 binding sites.[6] LRP5 has been shown in mice and humans to inhibit expression of TPH1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum[7][8][9][10][11][12] and that excess plasma serotonin leads to inhibition in bone. On the other hand, one study in mouse has shown a direct effect of Lrp5 on bone.[13] # Interactions LRP5 has been shown to interact with AXIN1.[14][15] Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation.[16] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.[17] # Clinical Significance The Wnt signaling pathway was first linked to bone development when a loss-of-function mutation in LRP5 was found to cause osteoporosis-pseudoglioma syndrome.[18] Shortly thereafter, two studies reported that gain-of-function mutations in LRP5 caused high bone mass.[19][20] Many bone density related diseases are caused by mutations in the LRP5 gene. There is controversy whether bone grows through Lrp5 through bone or the intestine.[21] The majority of the current data supports the concept that bone mass is controlled by LRP5 through the osteocytes.[22] Mice with the same Lrp5 gain-of-function mutations as also have high bone mass.[23] The high bone mass is maintained when the mutation only occurs in limbs or in cells of the osteoblastic lineage.[13] Bone mechanotransduction occurs through Lrp5[24] and is suppressed if Lrp5 is removed in only osteocytes.[25] There are promising osteoporosis clinical trials targeting sclerostin, an osteocyte-specific protein which inhibits Wnt signaling by binding to Lrp5.[22][26] An alternative model that has been verified in mice and in humans is that Lrp5 controls bone formation by inhibiting expression of TPH1, the rate-limiting biosynthetic enzyme for serotonin, a molecule that regulates bone formation, in enterochromaffin cells of the duodenum[7][8][9][10][11][12] and that excess plasma serotonin leads to inhibition in bone. Another study found that a different Tph1-inhibitor decreased serotonin levels in the blood and intestine, but did not affect bone mass or markers of bone formation.[13] LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation.[27] Mutations in this gene also cause familial exudative vitreoretinopathy.[3] A glial-derived extracellular ligand, Norrin, acts on a transmembrane receptor, Frizzled4, a coreceptor, Lrp5, and an auxiliary membrane protein, TSPAN12, on the surface of developing endothelial cells to control a transcriptional program that regulates endothelial growth and maturation.[28] LRP5 knockout in mice led to increased plasma cholesterol levels on a high-fat diet because of the decreased hepatic clearance of chylomicron remnants. When fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance with marked reduction in intracellular ATP and Ca2+ in response to glucose, and impairment in glucose-induced insulin secretion. IP3 production in response to glucose was also reduced in LRP5—islets possibly caused by a marked reduction of various transcripts for genes involved in glucose sensing in LRP5—islets. LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets.[29] In osteoarthritic chondrocytes the Wnt/beta-catenin pathway is activated with a significant up-regulation of beta-catenin mRNA expression. LRP5 mRNA and protein expression are also significantly up-regulated in osteoarthritic cartilage compared to normal cartilage, and LRP5 mRNA expression was further increased by vitamin D. Blocking LRP5 expression using siRNA against LRP5 resulted in a significant decrease in MMP13 mRNA and protein expressions. The catabolic role of LRP5 appears to be mediated by the Wnt/beta-catenin pathway in human osteoarthritis.[30] The polyphenol curcumin increases the mRNA expression of LRP5.[31] Mutations in LRP5 cause polycystic liver disease .[32]

https://www.wikidoc.org/index.php/LRP5

482da908e09e66327fc21aa1c9314b24451b4a12

wikidoc

LRP6

LRP6 Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. # Structure LRP6 is a transmembrane low-density lipoprotein receptor that shares a similar structure with LRP5. In each protein, about 85% of its 1600-amino-acid length is extracellular. Each has four β-propeller motifs at the amino terminal end that alternate with four epidermal growth factor (EGF)-like repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid segment that crosses the cell membrane and a 207-amino-acid segment that is internal to the cell. # Function LRP6 acts as a co-receptor with LRP5 and the Frizzled protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway. # Interactions Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation. Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation. LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like DKK1), sclerostin, R-spondins and members of the cysteine-knot-type protein family. # Clinical significance Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis. Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass. LRP6 is critical in bone's anabolic response to parathyroid hormone (PTH) treatment, whereas LRP5 is not involved. On the other hand, LRP6 does not appear active in mechanotransduction (bone's response to forces), while LRP5 is critical in that role. Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.

LRP6 Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene.[1][2] LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. # Structure LRP6 is a transmembrane low-density lipoprotein receptor that shares a similar structure with LRP5. In each protein, about 85% of its 1600-amino-acid length is extracellular. Each has four β-propeller motifs at the amino terminal end that alternate with four epidermal growth factor (EGF)-like repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid segment that crosses the cell membrane and a 207-amino-acid segment that is internal to the cell.[3] # Function LRP6 acts as a co-receptor with LRP5 and the Frizzled protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway.[3] # Interactions Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation.[4] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.[5] LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like DKK1[6]), sclerostin, R-spondins and members of the cysteine-knot-type protein family.[3] # Clinical significance Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis.[3] Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass.[7] LRP6 is critical in bone's anabolic response to parathyroid hormone (PTH) treatment, whereas LRP5 is not involved.[7] On the other hand, LRP6 does not appear active in mechanotransduction (bone's response to forces), while LRP5 is critical in that role.[7] Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.[8][9]

https://www.wikidoc.org/index.php/LRP6

343ad3340d48f97c612865332cc6320a0f10de66

wikidoc

LSM2

LSM2 U6 snRNA-associated Sm-like protein LSm2 is a protein that in humans is encoded by the LSM2 gene. # Function Sm-like proteins were identified in a variety of organisms based on sequence homology with the Sm protein family (see SNRPD2; MIM 601061). Sm-like proteins contain the Sm sequence motif, which consists of 2 regions separated by a linker of variable length that folds as a loop. The Sm-like proteins are thought to form a stable heteromer present in tri-snRNP particles, which are important for pre-mRNA splicing. # Interactions LSM2 has been shown to interact with DDX20, LSM3, LSM8 and LSM7.

LSM2 U6 snRNA-associated Sm-like protein LSm2 is a protein that in humans is encoded by the LSM2 gene.[1][2][3] # Function Sm-like proteins were identified in a variety of organisms based on sequence homology with the Sm protein family (see SNRPD2; MIM 601061). Sm-like proteins contain the Sm sequence motif, which consists of 2 regions separated by a linker of variable length that folds as a loop. The Sm-like proteins are thought to form a stable heteromer present in tri-snRNP particles, which are important for pre-mRNA splicing.[supplied by OMIM][3] # Interactions LSM2 has been shown to interact with DDX20,[4] LSM3,[5][6][7][8] LSM8[5][6] and LSM7.[5][6]

https://www.wikidoc.org/index.php/LSM2

754ed6ae8615d21f2465407f23461bf3f0036a7b

wikidoc

LYK5

LYK5 Protein kinase LYK5, also known as LYK5 or STRADα, is a human protein and also denotes the gene encoding it. # Function Endogenous LKB1 and STRADα form a complex in which STRADα activates LKB1, resulting in phosphorylation of both partners. Removal of endogenous LYK5 by small interfering RNA abrogates LKB1-induced G1 phase arrest. STRADα stabilizes LKB1 protein both in vivo and in vitro, and is capable of eliciting multiple axons in mouse embryonic cortical cultured neurons when overexpressed with LKB1. STRADα is highly spliced in vivo, and this is both developmentally regulated and tissue-specific, but the unique functions of the splice variants are not yet understood. # Disease linkage Mutations in the LYK5/STRADα gene are associated with polyhydramnios, megalencephaly and symptomatic epilepsy (collectively known as the PMSE syndrome). # Interactions STRADα has been shown to interact with LKB1 and MO25.

LYK5 Protein kinase LYK5, also known as LYK5 or STRADα, is a human protein and also denotes the gene encoding it.[1][2] # Function Endogenous LKB1 and STRADα form a complex in which STRADα activates LKB1, resulting in phosphorylation of both partners. Removal of endogenous LYK5 by small interfering RNA abrogates LKB1-induced G1 phase arrest.[2] STRADα stabilizes LKB1 protein both in vivo and in vitro, and is capable of eliciting multiple axons in mouse embryonic cortical cultured neurons when overexpressed with LKB1. STRADα is highly spliced in vivo, and this is both developmentally regulated and tissue-specific, but the unique functions of the splice variants are not yet understood.[3] # Disease linkage Mutations in the LYK5/STRADα gene are associated with polyhydramnios, megalencephaly and symptomatic epilepsy (collectively known as the PMSE syndrome).[4] # Interactions STRADα has been shown to interact with LKB1 and MO25.[2][5]

https://www.wikidoc.org/index.php/LYK5

170a18bd50846616a7216a3a3f7c95bba303f688

wikidoc

Leaf

Leaf In botany, a leaf is an above-ground plant organ specialized for photosynthesis. For this purpose, a leaf is typically flat (laminar) and thin, to expose the cells containing chloroplast to light over a broad area, and to allow light to penetrate fully into the tissues. Leaves are also the sites in most plants where transpiration and guttation take place. Leaves can store food and water, and are modified in some plants for other purposes. The comparable structures of ferns are correctly referred to as fronds. Furthermore, leaves are prominent in the human diet as leaf vegetables. # Leaf anatomy A structurally complete leaf of an angiosperm consists of a petiole (leaf stem), a lamina (leaf blade), and stipules (small processes located to either side of the base of the petiole). The petiole attaches to the stem at a point called the "leaf axil". Not every species produces leaves with all of the aforementioned structural components. In some species, paired stipules are not obvious or are absent altogether. A petiole may be absent, or the blade may not be laminar (flattened). The tremendous variety shown in leaf structure (anatomy) from species to species is presented in detail below under Leaf morphology. After a period of time (i.e. seasonally, during the autumn), deciduous trees shed their leaves. These leaves then decompose into the soil. A leaf is considered a plant organ and typically consists of the following tissues: - An epidermis that covers the upper and lower surfaces - An interior chlorenchyma called the mesophyll - An arrangement of veins (the vascular tissue). ## Epidermis The epidermis is the outer multi-layered group of cells covering the leaf. It forms the boundary separating the plant's inner cells from the external world. The epidermis serves several functions: protection against water loss, regulation of gas exchange, secretion of metabolic compounds, and (in some species) absorption of water. Most leaves show dorsoventral anatomy: the upper (adaxial) and lower (abaxial) surfaces have somewhat different construction and may serve different functions. The epidermis is usually transparent (epidermal cells lack chloroplasts) and coated on the outer side with a waxy cuticle that prevents water loss. The cuticle is in some cases thinner on the lower epidermis than on the upper epidermis, and is thicker on leaves from dry climates as compared with those from wet climates. The epidermis tissue includes several differentiated cell types: epidermal cells, guard cells, subsidiary cells, and epidermal hairs (trichomes). The epidermal cells are the most numerous, largest, and least specialized. These are typically more elongated in the leaves of monocots than in those of dicots. The epidermis is covered with pores called stomata, part of a stoma complex consisting of a pore surrounded on each side by chloroplast-containing guard cells, and two to four subsidiary cells that lack chloroplasts. The stoma complex regulates the exchange of gases and water vapor between the outside air and the interior of the leaf. Typically, the stomata are more numerous over the abaxial (lower) epidermis than the adaxial (upper) epidermis. ## Mesophyll Most of the interior of the leaf between the upper and lower layers of epidermis is a parenchyma (ground tissue) or chlorenchyma tissue called the mesophyll (Greek for "middle leaf"). This assimilation tissue is the primary location of photosynthesis in the plant. The products of photosynthesis are called "assimilates". In ferns and most flowering plants the mesophyll is divided into two layers: - An upper palisade layer of tightly packed, vertically elongated cells, one to two cells thick, directly beneath the adaxial epidermis. Its cells contain many more chloroplasts than the spongy layer. These long cylindrical cells are regularly arranged in one to five rows. Cylindrical cells, with the chloroplasts close to the walls of the cell, can take optimal advantage of light. The slight separation of the cells provides maximum absorption of carbon dioxide. This separation must be minimal to afford capillary action for water distribution. In order to adapt to their different environment (such as sun or shade), plants had to adapt this structure to obtain optimal result. Sun leaves have a multi-layered palisade layer, while shade leaves or older leaves closer to the soil, are single-layered. - Beneath the palisade layer is the spongy layer. The cells of the spongy layer are more rounded and not so tightly packed. There are large intercellular air spaces. These cells contain fewer chloroplasts than those of the palisade layer. The pores or stomata of the epidermis open into substomatal chambers, connecting to air spaces between the spongy layer cells. These two different layers of the mesophyll are absent in many aquatic and marsh plants. Even an epidermis and a mesophyll may be lacking. Instead for their gaseous exchanges they use a homogeneous aerenchyma (thin-walled cells separated by large gas-filled spaces). Their stomata are situated at the upper surface. Leaves are normally green in color, which comes from chlorophyll found in plastids in the chlorenchyma cells. Plants that lack chlorophyll cannot photosynthesize. Leaves in temperate, boreal, and seasonally dry zones may be seasonally deciduous (falling off or dying for the inclement season). This mechanism to shed leaves is called abscission. After the leaf is shed, a leaf scar develops on the twig. In cold autumns they sometimes change color, and turn yellow, bright orange or red as various accessory pigments (carotenoids and xanthophylls) are revealed when the tree responds to cold and reduced sunlight by curtailing chlorophyll production. Red anthocyanin pigments are now thought to be produced in the leaf as it dies. ## Veins The veins are the vascular tissue of the leaf and are located in the spongy layer of the mesophyll. They are typical examples of pattern formation through ramification. The pattern of the veins is called venation. The veins are made up of: - xylem, tubes that brings water and minerals from the roots into the leaf. - phloem, tubes that usually moves sap, with dissolved sucrose, produced by photosynthesis in the leaf, out of the leaf. The xylem typically lies over the phloem. Both are embedded in a dense parenchyma tissue, called "pith", with usually some structural collenchyma tissue present. # Leaf morphology External leaf characteristics (such as shape, margin, hairs, etc.) are important for identifying plant species, and botanists have developed a rich terminology for describing leaf characteristics. These structures are a part of what makes leaves determinant; they grow and achieve a specific pattern and shape, then stop. Other plant parts like stems or roots are non-determinant, and will usually continue to grow as long as they have the resources to do so. Classification of leaves can occur through many different designative schema, and the type of leaf is usually characteristic of a species, although some species produce more than one type of leaf. The longest type of leaf is a leaf from palm trees, measuring at nine feet long. The terminology associated with the description of leaf morphology is presented, in illustrated form, at Wikibooks. ## Basic leaf types - Ferns have fronds. - Conifer leaves are typically needle-, awl-, or scale-shaped - Angiosperm (flowering plant) leaves: the standard form includes stipules, a petiole, and a lamina. - Lycophytes have microphyll leaves. - Sheath leaves (type found in most grasses). - Other specialized leaves (such as those of Nepenthes) ## Arrangement on the stem Different terms are usually used to describe leaf placement (phyllotaxis): - Alternate — leaf attachments are singular at nodes, and leaves alternate direction, to a greater or lesser degree, along the stem. - Opposite — leaf attachments are paired at each node; decussate if, as typical, each successive pair is rotated 90° progressing along the stem; or distichous if not rotated, but two-ranked (in the same geometric flat-plane). - Whorled — three or more leaves attach at each point or node on the stem. As with opposite leaves, successive whorls may or may not be decussate, rotated by half the angle between the leaves in the whorl (i.e., successive whorls of three rotated 60°, whorls of four rotated 45°, etc). Opposite leaves may appear whorled near the tip of the stem. - Rosulate — leaves form a rosette As a stem grows, leaves tend to appear arranged around the stem in a way that optimizes yield of light. In essence, leaves form a helix pattern centred around the stem, either clockwise or counterclockwise, with (depending upon the species) the same angle of divergence. There is a regularity in these angles and they follow the numbers in a Fibonacci sequence: 1/2, 2/3, 3/5, 5/8, 8/13, 13/21, 21/34, 34/55, 55/89. This series tends to a limit of 360° x 34/89 = 137.52 or 137° 30', an angle known mathematically as the golden angle. In the series, the numerator indicates the number of complete turns or "gyres" until a leaf arrives at the initial position. The denominator indicates the number of leaves in the arrangement. This can be demonstrated by the following: - alternate leaves have an angle of 180° (or 1/2) - 120° (or 1/3) : three leaves in one circle - 144° (or 2/5) : five leaves in two gyres - 135° (or 3/8) : eight leaves in three gyres. The fact that an arrangement of anything in nature can be described by a mathematical formula is not in itself mysterious. Mathematics are the science of discovering numerical relationships and applying formulae to these relationships. The formulae themselves can provide clues to the underlying physiological processes that, in this case, determine where the next leaf bud will form in the elongating stem. ## Divisions of the lamina (blade) Two basic forms of leaves can be described considering the way the blade is divided. A simple leaf has an undivided blade. However, the leaf shape may be formed of lobes, but the gaps between lobes do not reach to the main vein. A compound leaf has a fully subdivided blade, each leaflet of the blade separated along a main or secondary vein. Because each leaflet can appear to be a simple leaf, it is important to recognize where the petiole occurs to identify a compound leaf. Compound leaves are a characteristic of some families of higher plants, such as the Fabaceae. The middle vein of a compound leaf or a frond, when it is present, is called a rachis. - Palmately compound leaves have the leaflets radiating from the end of the petiole, like fingers off the palm of a hand, e.g. Cannabis (hemp) and Aesculus (buckeyes). - Pinnately compound leaves have the leaflets arranged along the main or mid-vein. -dd pinnate: with a terminal leaflet, e.g. Fraxinus (ash). even pinnate: lacking a terminal leaflet, e.g. Swietenia (mahogany). - odd pinnate: with a terminal leaflet, e.g. Fraxinus (ash). - even pinnate: lacking a terminal leaflet, e.g. Swietenia (mahogany). - Bipinnately compound leaves are twice divided: the leaflets are arranged along a secondary vein that is one of several branching off the rachis. Each leaflet is called a "pinnule". The pinnules on one secondary vein are called "pinna"; e.g. Albizia (silk tree). - trifoliate: a pinnate leaf with just three leaflets, e.g. Trifolium (clover), Laburnum (laburnum). - pinnatifid: pinnately dissected to the midrib, but with the leaflets not entirely separate, e.g. Polypodium, some Sorbus (whitebeams). ## Characteristics of the petiole Petiolated leaves have a petiole. Sessile leaves do not: the blade attaches directly to the stem. In clasping or decurrent leaves, the blade partially or wholly surrounds the stem, often giving the impression that the shoot grows through the leaf. When this is actually the case, the leaves are called "perfoliate", such as in Claytonia perfoliata. In peltate leaves, the petiole attaches to the blade inside from the blade margin. In some Acacia species, such as the Koa Tree (Acacia koa), the petioles are expanded or broadened and function like leaf blades; these are called phyllodes. There may or may not be normal pinnate leaves at the tip of the phyllode. A stipule, present on the leaves of many dicotyledons, is an appendage on each side at the base of the petiole resembling a small leaf. Stipules may be lasting and not be shed (a stipulate leaf, such as in roses and beans), or be shed as the leaf expands, leaving a stipule scar on the twig (an exstipulate leaf). - The situation, arrangement, and structure of the stipules is called the "stipulation". free adnate : fused to the petiole base -chreate : provided with ochrea, or sheath-formed stipules, e.g. rhubarb, encircling the petiole base interpetiolar : between the petioles of two opposite leaves. intrapetiolar : between the petiole and the subtending stem - free - adnate : fused to the petiole base - ochreate : provided with ochrea, or sheath-formed stipules, e.g. rhubarb, - encircling the petiole base - interpetiolar : between the petioles of two opposite leaves. - intrapetiolar : between the petiole and the subtending stem ## Venation (arrangement of the veins) There are two subtypes of venation, namely, craspedodromous, where the major veins stretch up to the margin of the leaf, and camptodromous, when major veins extend close to the margin, but bend before they intersect with the margin. - Feather-veined, reticulate — the veins arise pinnately from a single mid-vein and subdivide into veinlets. These, in turn, form a complicated network. This type of venation is typical for (but by no means limited to) dicotyledons. Pinnate-netted, penniribbed, penninerved, penniveined; the leaf has usually one main vein (called the mid-vein), with veinlets, smaller veins branching off laterally, usually somewhat parallel to each other; eg Malus (apples). Three main veins branch at the base of the lamina and run essentially parallel subsequently, as in Ceanothus. A similar pattern (with 3-7 veins) is especially conspicuous in Melastomataceae. Palmate-netted, palmate-veined, fan-veined; several main veins diverge from near the leaf base where the petiole attaches, and radiate toward the edge of the leaf; e.g. most Acer (maples). - Pinnate-netted, penniribbed, penninerved, penniveined; the leaf has usually one main vein (called the mid-vein), with veinlets, smaller veins branching off laterally, usually somewhat parallel to each other; eg Malus (apples). - Three main veins branch at the base of the lamina and run essentially parallel subsequently, as in Ceanothus. A similar pattern (with 3-7 veins) is especially conspicuous in Melastomataceae. - Palmate-netted, palmate-veined, fan-veined; several main veins diverge from near the leaf base where the petiole attaches, and radiate toward the edge of the leaf; e.g. most Acer (maples). - Parallel-veined, parallel-ribbed, parallel-nerved, penniparallel — veins run parallel for the length of the leaf, from the base to the apex. Commissural veins (small veins) connect the major parallel veins. Typical for most monocotyledons, such as grasses. - Dichotomous — There are no dominant bundles, with the veins forking regularly by pairs; found in Ginkgo and some pteridophytes. Note that although it is the more complex pattern, branching veins appear to be plesiomorphic and in some form were present in ancient seed plants as long as 250 million years ago. A pseudo-reticulate venation that is actually a highly modified penniparallel one is an autapomorphy of some Melanthiaceae which are monocots, e.g. Paris quadrifolia (True-lover's Knot). ## Leaf morphology changes within a single plant - Homoblasty - Characteristic in which a plant has small changes in leaf size, shape, and growth habit between juvenile and adult stages. - Heteroblasty - Charactistic in which a plant has marked changes in leaf size, shape, and growth habit between juvenile and adult stages. # Leaf terminology ## Shape ## Margins (edge) The leaf margin is characteristic for a genus and aids in determining the species. - entire: even; with a smooth margin; without toothing - ciliate: fringed with hairs - crenate: wavy-toothed; dentate with rounded teeth, such as Fagus (beech) - dentate: toothed, such as Castanea (chestnut) coarse-toothed: with large teeth glandular toothed: with teeth that bear glands. - coarse-toothed: with large teeth - glandular toothed: with teeth that bear glands. - denticulate: finely toothed - doubly toothed: each tooth bearing smaller teeth, such as Ulmus (elm) - lobate: indented, with the indentations not reaching to the center, such as many Quercus (oaks) palmately lobed: indented with the indentations reaching to the center, such as Humulus (hop). - palmately lobed: indented with the indentations reaching to the center, such as Humulus (hop). - serrate: saw-toothed with asymmetrical teeth pointing forward, such as Urtica (nettle) - serrulate: finely serrate - sinuate: with deep, wave-like indentations; coarsely crenate, such as many Rumex (docks) - spiny: with stiff, sharp points, such as some Ilex (hollies) and Cirsium (thistles). ## Tip of the leaf - acuminate: long-pointed, prolonged into a narrow, tapering point in a concave manner. - acute: ending in a sharp, but not prolonged point - cuspidate: with a sharp, elongated, rigid tip; tipped with a cusp. - emarginate: indented, with a shallow notch at the tip. - mucronate: abruptly tipped with a small short point, as a continuation of the midrib; tipped with a mucro. - mucronulate: mucronate, but with a smaller spine. - obcordate: inversely heart-shaped, deeply notched at the top. - obtuse: rounded or blunt - truncate: ending abruptly with a flat end, that looks cut off. ## Base of the leaf - acuminate: coming to a sharp, narrow, prolonged point. - acute: coming to a sharp, but not prolonged point. - auriculate: ear-shaped - cordate: heart-shaped with the notch towards the stalk. - cuneate: wedge-shaped. - hastate: shaped like an halberd and with the basal lobes pointing outward. - oblique: slanting. - reniform: kidney-shaped but rounder and broader than long. - rounded: curving shape. - sagittate: shaped like an arrowhead and with the acute basal lobes pointing downward. - truncate: ending abruptly with a flat end, that looks cut off. ## Surface of the leaf The surface of a leaf can be described by several botanical terms: - farinose: bearing farina; mealy, covered with a waxy, whitish powder. - glabrous: smooth, not hairy. - glaucous: with a whitish bloom; covered with a very fine, bluish-white powder. - glutinous: sticky, viscid. - papillate, papillose: bearing papillae (minute, nipple-shaped protuberances). - pubescent: covered with erect hairs (especially soft and short ones) - punctate: marked with dots; dotted with depressions or with translucent glands or colored dots. - rugose: deeply wrinkled; with veins clearly visible. - scurfy: covered with tiny, broad scalelike particles. - tuberculate: covered with tubercles; covered with warty prominences. - verrucose: warted, with warty outgrowths. - viscid, viscous: covered with thick, sticky secretions. The leaf surface is also host to a large variety of microorganisms; in this context it is referred to as the phyllosphere. ## Hairiness (trichomes) "Hairs" on plants are properly called trichomes. Leaves can show several degrees of hairiness. The meaning of several of the following terms can overlap. - glabrous: no hairs of any kind present. - arachnoid, arachnose: with many fine, entangled hairs giving a cobwebby appearance. - barbellate: with finely barbed hairs (barbellae). - bearded: with long, stiff hairs. - bristly: with stiff hair-like prickles. - canescent: hoary with dense grayish-white pubescence. - ciliate: marginally fringed with short hairs (cilia). - ciliolate: minutely ciliate. - floccose: with flocks of soft, woolly hairs, which tend to rub off. - glandular: with a gland at the tip of the hair. - hirsute: with rather rough or stiff hairs. - hispid: with rigid, bristly hairs. - hispidulous: minutely hispid. - hoary: with a fine, close grayish-white pubescence. - lanate, lanose: with woolly hairs. - pilose: with soft, clearly separated hairs. - puberulent, puberulous: with fine, minute hairs. - pubescent: with soft, short and erect hairs. - scabrous, scabrid: rough to the touch - sericeous: silky appearance through fine, straight and appressed (lying close and flat) hairs. - silky: with adpressed, soft and straight pubescence. - stellate, stelliform: with star-shaped hairs. - strigose: with appressed, sharp, straight and stiff hairs. - tomentose: densely pubescent with matted, soft white woolly hairs. cano-tomentose: between canescent and tomentose felted-tomentose: woolly and matted with curly hairs. - cano-tomentose: between canescent and tomentose - felted-tomentose: woolly and matted with curly hairs. - villous: with long and soft hairs, usually curved. - woolly: with long, soft and tortuous or matted hairs. # Adaptations In the course of evolution, leaves adapted to different environments in the following ways: - A certain surface structure avoids moistening by rain and contaminations (Lotus effect). - Sliced leaves reduce wind resistance. - Hairs on the leaf surface trap humidity in dry climates and creates a large boundary layer and reduces water loss. - Waxy leaf surfaces reduce water loss. - Shiny leaves deflect the sun's rays. - Reductions of leaf sizes accompanied by a transfer of the photosynthetic functions to the stems reduces water loss. - In more or less opaque or buried in the soil leaves translucent windows filter the light before the photosynthetis takes place at the inner leaf surfaces (e.g. Fenestraria). - Thicker leaves store water (leaf succulents). - Aromatic oils, poisons or pheromones produced by leaf borne glands deter herbivores (e.g. eucalypts). - Inclusions of crystalline minerals deters herbivores. - A transformation into petals attracts pollinators. - A transformation into spines protects the plants (e.g. cactus). - A transformation into insect traps helps feeding the plants (carnivorous plants). - A transformation into bulbs helps storing food and water (e.g. onion). - A transformation into tendrils allow the plant to climb (e.g. pea). - A transformation into bracts and pseudanthia (false flowers) replaces normal flower structures if the true flowers are extremely reduced (e.g. Spurges). # Interactions with other organisms Although not as nutritious as other organs such as fruit, leaves provide a food source for many organisms. Animals which eat leaves are known as folivores. The leaf is one of the most vital parts of the plant, and plants have evolved protection against folivores such as tannins, chemicals which hinder the digestion of proteins and have an unpleasant taste. Some animals have cryptic adaptations to avoid their own predators, for example some caterpillars will create a small home in the leaf by folding it over themselves, while other herbivores and their prey mimic the appearance of the leaf. Some insects, such as the katydid, take this even further, moving from side to side much like a leaf does in the wind. # Bibliography - Leaves: The formation, charactistics and uses of hundred of leaves in all parts of the world by Ghillean Tolmie Prance. 324 photographic plates in black and white, and colour by Kjell B Sandved 256 pages # Footnotes - ↑ Published by Thames and Hudson (London) with an ISBN 0 500 54104 3

Leaf Template:Pp-semi In botany, a leaf is an above-ground plant organ specialized for photosynthesis. For this purpose, a leaf is typically flat (laminar) and thin, to expose the cells containing chloroplast to light over a broad area, and to allow light to penetrate fully into the tissues. Leaves are also the sites in most plants where transpiration and guttation take place. Leaves can store food and water, and are modified in some plants for other purposes. The comparable structures of ferns are correctly referred to as fronds. Furthermore, leaves are prominent in the human diet as leaf vegetables. # Leaf anatomy A structurally complete leaf of an angiosperm consists of a petiole (leaf stem), a lamina (leaf blade), and stipules (small processes located to either side of the base of the petiole). The petiole attaches to the stem at a point called the "leaf axil". Not every species produces leaves with all of the aforementioned structural components. In some species, paired stipules are not obvious or are absent altogether. A petiole may be absent, or the blade may not be laminar (flattened). The tremendous variety shown in leaf structure (anatomy) from species to species is presented in detail below under Leaf morphology. After a period of time (i.e. seasonally, during the autumn), deciduous trees shed their leaves. These leaves then decompose into the soil. A leaf is considered a plant organ and typically consists of the following tissues: - An epidermis that covers the upper and lower surfaces - An interior chlorenchyma called the mesophyll - An arrangement of veins (the vascular tissue). ## Epidermis The epidermis is the outer multi-layered group of cells covering the leaf. It forms the boundary separating the plant's inner cells from the external world. The epidermis serves several functions: protection against water loss, regulation of gas exchange, secretion of metabolic compounds, and (in some species) absorption of water. Most leaves show dorsoventral anatomy: the upper (adaxial) and lower (abaxial) surfaces have somewhat different construction and may serve different functions. The epidermis is usually transparent (epidermal cells lack chloroplasts) and coated on the outer side with a waxy cuticle that prevents water loss. The cuticle is in some cases thinner on the lower epidermis than on the upper epidermis, and is thicker on leaves from dry climates as compared with those from wet climates. The epidermis tissue includes several differentiated cell types: epidermal cells, guard cells, subsidiary cells, and epidermal hairs (trichomes). The epidermal cells are the most numerous, largest, and least specialized. These are typically more elongated in the leaves of monocots than in those of dicots. The epidermis is covered with pores called stomata, part of a stoma complex consisting of a pore surrounded on each side by chloroplast-containing guard cells, and two to four subsidiary cells that lack chloroplasts. The stoma complex regulates the exchange of gases and water vapor between the outside air and the interior of the leaf. Typically, the stomata are more numerous over the abaxial (lower) epidermis than the adaxial (upper) epidermis. ## Mesophyll Most of the interior of the leaf between the upper and lower layers of epidermis is a parenchyma (ground tissue) or chlorenchyma tissue called the mesophyll (Greek for "middle leaf"). This assimilation tissue is the primary location of photosynthesis in the plant. The products of photosynthesis are called "assimilates". In ferns and most flowering plants the mesophyll is divided into two layers: - An upper palisade layer of tightly packed, vertically elongated cells, one to two cells thick, directly beneath the adaxial epidermis. Its cells contain many more chloroplasts than the spongy layer. These long cylindrical cells are regularly arranged in one to five rows. Cylindrical cells, with the chloroplasts close to the walls of the cell, can take optimal advantage of light. The slight separation of the cells provides maximum absorption of carbon dioxide. This separation must be minimal to afford capillary action for water distribution. In order to adapt to their different environment (such as sun or shade), plants had to adapt this structure to obtain optimal result. Sun leaves have a multi-layered palisade layer, while shade leaves or older leaves closer to the soil, are single-layered. - Beneath the palisade layer is the spongy layer. The cells of the spongy layer are more rounded and not so tightly packed. There are large intercellular air spaces. These cells contain fewer chloroplasts than those of the palisade layer. The pores or stomata of the epidermis open into substomatal chambers, connecting to air spaces between the spongy layer cells. These two different layers of the mesophyll are absent in many aquatic and marsh plants. Even an epidermis and a mesophyll may be lacking. Instead for their gaseous exchanges they use a homogeneous aerenchyma (thin-walled cells separated by large gas-filled spaces). Their stomata are situated at the upper surface. Leaves are normally green in color, which comes from chlorophyll found in plastids in the chlorenchyma cells. Plants that lack chlorophyll cannot photosynthesize. Leaves in temperate, boreal, and seasonally dry zones may be seasonally deciduous (falling off or dying for the inclement season). This mechanism to shed leaves is called abscission. After the leaf is shed, a leaf scar develops on the twig. In cold autumns they sometimes change color, and turn yellow, bright orange or red as various accessory pigments (carotenoids and xanthophylls) are revealed when the tree responds to cold and reduced sunlight by curtailing chlorophyll production. Red anthocyanin pigments are now thought to be produced in the leaf as it dies. ## Veins The veins are the vascular tissue of the leaf and are located in the spongy layer of the mesophyll. They are typical examples of pattern formation through ramification. The pattern of the veins is called venation. The veins are made up of: - xylem, tubes that brings water and minerals from the roots into the leaf. - phloem, tubes that usually moves sap, with dissolved sucrose, produced by photosynthesis in the leaf, out of the leaf. The xylem typically lies over the phloem. Both are embedded in a dense parenchyma tissue, called "pith", with usually some structural collenchyma tissue present. # Leaf morphology External leaf characteristics (such as shape, margin, hairs, etc.) are important for identifying plant species, and botanists have developed a rich terminology for describing leaf characteristics. These structures are a part of what makes leaves determinant; they grow and achieve a specific pattern and shape, then stop. Other plant parts like stems or roots are non-determinant, and will usually continue to grow as long as they have the resources to do so. Classification of leaves can occur through many different designative schema, and the type of leaf is usually characteristic of a species, although some species produce more than one type of leaf. The longest type of leaf is a leaf from palm trees, measuring at nine feet long. The terminology associated with the description of leaf morphology is presented, in illustrated form, at Wikibooks. ## Basic leaf types - Ferns have fronds. - Conifer leaves are typically needle-, awl-, or scale-shaped - Angiosperm (flowering plant) leaves: the standard form includes stipules, a petiole, and a lamina. - Lycophytes have microphyll leaves. - Sheath leaves (type found in most grasses). - Other specialized leaves (such as those of Nepenthes) ## Arrangement on the stem Different terms are usually used to describe leaf placement (phyllotaxis): - Alternate — leaf attachments are singular at nodes, and leaves alternate direction, to a greater or lesser degree, along the stem. - Opposite — leaf attachments are paired at each node; decussate if, as typical, each successive pair is rotated 90° progressing along the stem; or distichous if not rotated, but two-ranked (in the same geometric flat-plane). - Whorled — three or more leaves attach at each point or node on the stem. As with opposite leaves, successive whorls may or may not be decussate, rotated by half the angle between the leaves in the whorl (i.e., successive whorls of three rotated 60°, whorls of four rotated 45°, etc). Opposite leaves may appear whorled near the tip of the stem. - Rosulate — leaves form a rosette As a stem grows, leaves tend to appear arranged around the stem in a way that optimizes yield of light. In essence, leaves form a helix pattern centred around the stem, either clockwise or counterclockwise, with (depending upon the species) the same angle of divergence. There is a regularity in these angles and they follow the numbers in a Fibonacci sequence: 1/2, 2/3, 3/5, 5/8, 8/13, 13/21, 21/34, 34/55, 55/89. This series tends to a limit of 360° x 34/89 = 137.52 or 137° 30', an angle known mathematically as the golden angle. In the series, the numerator indicates the number of complete turns or "gyres" until a leaf arrives at the initial position. The denominator indicates the number of leaves in the arrangement. This can be demonstrated by the following: - alternate leaves have an angle of 180° (or 1/2) - 120° (or 1/3) : three leaves in one circle - 144° (or 2/5) : five leaves in two gyres - 135° (or 3/8) : eight leaves in three gyres. The fact that an arrangement of anything in nature can be described by a mathematical formula is not in itself mysterious. Mathematics are the science of discovering numerical relationships and applying formulae to these relationships. The formulae themselves can provide clues to the underlying physiological processes that, in this case, determine where the next leaf bud will form in the elongating stem. ## Divisions of the lamina (blade) Two basic forms of leaves can be described considering the way the blade is divided. A simple leaf has an undivided blade. However, the leaf shape may be formed of lobes, but the gaps between lobes do not reach to the main vein. A compound leaf has a fully subdivided blade, each leaflet of the blade separated along a main or secondary vein. Because each leaflet can appear to be a simple leaf, it is important to recognize where the petiole occurs to identify a compound leaf. Compound leaves are a characteristic of some families of higher plants, such as the Fabaceae. The middle vein of a compound leaf or a frond, when it is present, is called a rachis. - Palmately compound leaves have the leaflets radiating from the end of the petiole, like fingers off the palm of a hand, e.g. Cannabis (hemp) and Aesculus (buckeyes). - Pinnately compound leaves have the leaflets arranged along the main or mid-vein. odd pinnate: with a terminal leaflet, e.g. Fraxinus (ash). even pinnate: lacking a terminal leaflet, e.g. Swietenia (mahogany). - odd pinnate: with a terminal leaflet, e.g. Fraxinus (ash). - even pinnate: lacking a terminal leaflet, e.g. Swietenia (mahogany). - Bipinnately compound leaves are twice divided: the leaflets are arranged along a secondary vein that is one of several branching off the rachis. Each leaflet is called a "pinnule". The pinnules on one secondary vein are called "pinna"; e.g. Albizia (silk tree). - trifoliate: a pinnate leaf with just three leaflets, e.g. Trifolium (clover), Laburnum (laburnum). - pinnatifid: pinnately dissected to the midrib, but with the leaflets not entirely separate, e.g. Polypodium, some Sorbus (whitebeams). ## Characteristics of the petiole Petiolated leaves have a petiole. Sessile leaves do not: the blade attaches directly to the stem. In clasping or decurrent leaves, the blade partially or wholly surrounds the stem, often giving the impression that the shoot grows through the leaf. When this is actually the case, the leaves are called "perfoliate", such as in Claytonia perfoliata. In peltate leaves, the petiole attaches to the blade inside from the blade margin. In some Acacia species, such as the Koa Tree (Acacia koa), the petioles are expanded or broadened and function like leaf blades; these are called phyllodes. There may or may not be normal pinnate leaves at the tip of the phyllode. A stipule, present on the leaves of many dicotyledons, is an appendage on each side at the base of the petiole resembling a small leaf. Stipules may be lasting and not be shed (a stipulate leaf, such as in roses and beans), or be shed as the leaf expands, leaving a stipule scar on the twig (an exstipulate leaf). - The situation, arrangement, and structure of the stipules is called the "stipulation". free adnate : fused to the petiole base ochreate : provided with ochrea, or sheath-formed stipules, e.g. rhubarb, encircling the petiole base interpetiolar : between the petioles of two opposite leaves. intrapetiolar : between the petiole and the subtending stem - free - adnate : fused to the petiole base - ochreate : provided with ochrea, or sheath-formed stipules, e.g. rhubarb, - encircling the petiole base - interpetiolar : between the petioles of two opposite leaves. - intrapetiolar : between the petiole and the subtending stem ## Venation (arrangement of the veins) There are two subtypes of venation, namely, craspedodromous, where the major veins stretch up to the margin of the leaf, and camptodromous, when major veins extend close to the margin, but bend before they intersect with the margin. - Feather-veined, reticulate — the veins arise pinnately from a single mid-vein and subdivide into veinlets. These, in turn, form a complicated network. This type of venation is typical for (but by no means limited to) dicotyledons. Pinnate-netted, penniribbed, penninerved, penniveined; the leaf has usually one main vein (called the mid-vein), with veinlets, smaller veins branching off laterally, usually somewhat parallel to each other; eg Malus (apples). Three main veins branch at the base of the lamina and run essentially parallel subsequently, as in Ceanothus. A similar pattern (with 3-7 veins) is especially conspicuous in Melastomataceae. Palmate-netted, palmate-veined, fan-veined; several main veins diverge from near the leaf base where the petiole attaches, and radiate toward the edge of the leaf; e.g. most Acer (maples). - Pinnate-netted, penniribbed, penninerved, penniveined; the leaf has usually one main vein (called the mid-vein), with veinlets, smaller veins branching off laterally, usually somewhat parallel to each other; eg Malus (apples). - Three main veins branch at the base of the lamina and run essentially parallel subsequently, as in Ceanothus. A similar pattern (with 3-7 veins) is especially conspicuous in Melastomataceae. - Palmate-netted, palmate-veined, fan-veined; several main veins diverge from near the leaf base where the petiole attaches, and radiate toward the edge of the leaf; e.g. most Acer (maples). - Parallel-veined, parallel-ribbed, parallel-nerved, penniparallel — veins run parallel for the length of the leaf, from the base to the apex. Commissural veins (small veins) connect the major parallel veins. Typical for most monocotyledons, such as grasses. - Dichotomous — There are no dominant bundles, with the veins forking regularly by pairs; found in Ginkgo and some pteridophytes. Note that although it is the more complex pattern, branching veins appear to be plesiomorphic and in some form were present in ancient seed plants as long as 250 million years ago. A pseudo-reticulate venation that is actually a highly modified penniparallel one is an autapomorphy of some Melanthiaceae which are monocots, e.g. Paris quadrifolia (True-lover's Knot). ## Leaf morphology changes within a single plant - Homoblasty - Characteristic in which a plant has small changes in leaf size, shape, and growth habit between juvenile and adult stages. - Heteroblasty - Charactistic in which a plant has marked changes in leaf size, shape, and growth habit between juvenile and adult stages. # Leaf terminology ## Shape ## Margins (edge) The leaf margin is characteristic for a genus and aids in determining the species. - entire: even; with a smooth margin; without toothing - ciliate: fringed with hairs - crenate: wavy-toothed; dentate with rounded teeth, such as Fagus (beech) - dentate: toothed, such as Castanea (chestnut) coarse-toothed: with large teeth glandular toothed: with teeth that bear glands. - coarse-toothed: with large teeth - glandular toothed: with teeth that bear glands. - denticulate: finely toothed - doubly toothed: each tooth bearing smaller teeth, such as Ulmus (elm) - lobate: indented, with the indentations not reaching to the center, such as many Quercus (oaks) palmately lobed: indented with the indentations reaching to the center, such as Humulus (hop). - palmately lobed: indented with the indentations reaching to the center, such as Humulus (hop). - serrate: saw-toothed with asymmetrical teeth pointing forward, such as Urtica (nettle) - serrulate: finely serrate - sinuate: with deep, wave-like indentations; coarsely crenate, such as many Rumex (docks) - spiny: with stiff, sharp points, such as some Ilex (hollies) and Cirsium (thistles). ## Tip of the leaf - acuminate: long-pointed, prolonged into a narrow, tapering point in a concave manner. - acute: ending in a sharp, but not prolonged point - cuspidate: with a sharp, elongated, rigid tip; tipped with a cusp. - emarginate: indented, with a shallow notch at the tip. - mucronate: abruptly tipped with a small short point, as a continuation of the midrib; tipped with a mucro. - mucronulate: mucronate, but with a smaller spine. - obcordate: inversely heart-shaped, deeply notched at the top. - obtuse: rounded or blunt - truncate: ending abruptly with a flat end, that looks cut off. ## Base of the leaf - acuminate: coming to a sharp, narrow, prolonged point. - acute: coming to a sharp, but not prolonged point. - auriculate: ear-shaped - cordate: heart-shaped with the notch towards the stalk. - cuneate: wedge-shaped. - hastate: shaped like an halberd and with the basal lobes pointing outward. - oblique: slanting. - reniform: kidney-shaped but rounder and broader than long. - rounded: curving shape. - sagittate: shaped like an arrowhead and with the acute basal lobes pointing downward. - truncate: ending abruptly with a flat end, that looks cut off. ## Surface of the leaf The surface of a leaf can be described by several botanical terms: - farinose: bearing farina; mealy, covered with a waxy, whitish powder. - glabrous: smooth, not hairy. - glaucous: with a whitish bloom; covered with a very fine, bluish-white powder. - glutinous: sticky, viscid. - papillate, papillose: bearing papillae (minute, nipple-shaped protuberances). - pubescent: covered with erect hairs (especially soft and short ones) - punctate: marked with dots; dotted with depressions or with translucent glands or colored dots. - rugose: deeply wrinkled; with veins clearly visible. - scurfy: covered with tiny, broad scalelike particles. - tuberculate: covered with tubercles; covered with warty prominences. - verrucose: warted, with warty outgrowths. - viscid, viscous: covered with thick, sticky secretions. The leaf surface is also host to a large variety of microorganisms; in this context it is referred to as the phyllosphere. ## Hairiness (trichomes) "Hairs" on plants are properly called trichomes. Leaves can show several degrees of hairiness. The meaning of several of the following terms can overlap. - glabrous: no hairs of any kind present. - arachnoid, arachnose: with many fine, entangled hairs giving a cobwebby appearance. - barbellate: with finely barbed hairs (barbellae). - bearded: with long, stiff hairs. - bristly: with stiff hair-like prickles. - canescent: hoary with dense grayish-white pubescence. - ciliate: marginally fringed with short hairs (cilia). - ciliolate: minutely ciliate. - floccose: with flocks of soft, woolly hairs, which tend to rub off. - glandular: with a gland at the tip of the hair. - hirsute: with rather rough or stiff hairs. - hispid: with rigid, bristly hairs. - hispidulous: minutely hispid. - hoary: with a fine, close grayish-white pubescence. - lanate, lanose: with woolly hairs. - pilose: with soft, clearly separated hairs. - puberulent, puberulous: with fine, minute hairs. - pubescent: with soft, short and erect hairs. - scabrous, scabrid: rough to the touch - sericeous: silky appearance through fine, straight and appressed (lying close and flat) hairs. - silky: with adpressed, soft and straight pubescence. - stellate, stelliform: with star-shaped hairs. - strigose: with appressed, sharp, straight and stiff hairs. - tomentose: densely pubescent with matted, soft white woolly hairs. cano-tomentose: between canescent and tomentose felted-tomentose: woolly and matted with curly hairs. - cano-tomentose: between canescent and tomentose - felted-tomentose: woolly and matted with curly hairs. - villous: with long and soft hairs, usually curved. - woolly: with long, soft and tortuous or matted hairs. # Adaptations Template:Cleanup-laundry In the course of evolution, leaves adapted to different environments in the following ways: - A certain surface structure avoids moistening by rain and contaminations (Lotus effect). - Sliced leaves reduce wind resistance. - Hairs on the leaf surface trap humidity in dry climates and creates a large boundary layer and reduces water loss. - Waxy leaf surfaces reduce water loss. - Shiny leaves deflect the sun's rays. - Reductions of leaf sizes accompanied by a transfer of the photosynthetic functions to the stems reduces water loss. - In more or less opaque or buried in the soil leaves translucent windows filter the light before the photosynthetis takes place at the inner leaf surfaces (e.g. Fenestraria). - Thicker leaves store water (leaf succulents). - Aromatic oils, poisons or pheromones produced by leaf borne glands deter herbivores (e.g. eucalypts). - Inclusions of crystalline minerals deters herbivores. - A transformation into petals attracts pollinators. - A transformation into spines protects the plants (e.g. cactus). - A transformation into insect traps helps feeding the plants (carnivorous plants). - A transformation into bulbs helps storing food and water (e.g. onion). - A transformation into tendrils allow the plant to climb (e.g. pea). - A transformation into bracts and pseudanthia (false flowers) replaces normal flower structures if the true flowers are extremely reduced (e.g. Spurges). # Interactions with other organisms Although not as nutritious as other organs such as fruit, leaves provide a food source for many organisms. Animals which eat leaves are known as folivores. The leaf is one of the most vital parts of the plant, and plants have evolved protection against folivores such as tannins, chemicals which hinder the digestion of proteins and have an unpleasant taste. Some animals have cryptic adaptations to avoid their own predators, for example some caterpillars will create a small home in the leaf by folding it over themselves, while other herbivores and their prey mimic the appearance of the leaf. Some insects, such as the katydid, take this even further, moving from side to side much like a leaf does in the wind. # Bibliography - Leaves: The formation, charactistics and uses of hundred of leaves in all parts of the world by Ghillean Tolmie Prance. 324 photographic plates in black and white, and colour by Kjell B Sandved 256 pages[1] # Footnotes - ↑ Published by Thames and Hudson (London) with an ISBN 0 500 54104 3

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ff14e2acc3c3d0cca9b3ecd02e4b6342f0a81e17

wikidoc

Lisp

Lisp # Background A lisp (O E wlisp, stammering) is a speech impediment, historically also known as sigmatism. Stereotypically, people with a lisp are unable to pronounce sibilants (like the sound ]), and replace them with interdentals (like the sound ]), though there are actually several kinds of lisp. The result is that the speech is unclear. - "Interdental" lisping is produced when the tip of the tongue protrudes between the front teeth and "dentalised" lisping is produced when the tip of the tongue just touches the front teeth. - The "lateral" lisp, where the Template:IPA and Template:IPA sounds are produced with air escaping over the sides of the tongue, is also called 'slushy ess' or a 'slushy lisp' due to the wet, spitty sound. The symbols for these lateralized sounds are in the Extended International Phonetic Alphabet for speech disorders, Template:IPA and Template:IPA. - Finally there is the "palatal lisp" where the speaker attempts to make the sounds with the tongue in contact with the palate.

Lisp Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background A lisp (O E wlisp, stammering)[1] is a speech impediment, historically also known as sigmatism.[2] Stereotypically, people with a lisp are unable to pronounce sibilants (like the sound [[Voiceless alveolar fricative|Template:IPA]]), and replace them with interdentals (like the sound [[Voiceless dental fricative|Template:IPA]]), though there are actually several kinds of lisp. The result is that the speech is unclear. - "Interdental" lisping is produced when the tip of the tongue protrudes between the front teeth and "dentalised" lisping is produced when the tip of the tongue just touches the front teeth. - The "lateral" lisp, where the Template:IPA and Template:IPA sounds are produced with air escaping over the sides of the tongue, is also called 'slushy ess' or a 'slushy lisp' due to the wet, spitty sound. The symbols for these lateralized sounds are in the Extended International Phonetic Alphabet for speech disorders, Template:IPA and Template:IPA. - Finally there is the "palatal lisp" where the speaker attempts to make the sounds with the tongue in contact with the palate.[2]

https://www.wikidoc.org/index.php/Lisp

4f65189be8b679a660ead6be24f621f41a706463

wikidoc

Luck

Luck Luck (also called fortuity) is a chance happening, or that which happens beyond a person's control. Luck can be good or bad. # Luck as lack of control Luck refers to that which happens beyond a person's control. This view incorporates phenomena that are chance happenings, a person's place of birth for example, but where there is no uncertainty involved, or where the uncertainty is irrelevant. Within this framework one can differentiate between three different types of luck: - Constitutional luck, that is, luck with factors that cannot be changed. Place of birth and genetic constitution are typical examples. - Circumstantial luck, that is, luck with factors that are haphazardly brought on. Accidents and epidemics are typical examples. - Ignorance luck, that is, luck with factors one does not know about. Examples can be identified only in hindsight. # Luck as a fallacy Another view holds that "luck is probability taken personally". A rationalist approach to luck includes the application of the rules of probability, and an avoidance of unscientific beliefs. The rationalist feels the belief in luck is a result of poor reasoning or wishful thinking. To a rationalist, a believer in luck commits the "post hoc, ergo propter hoc" logical fallacy, which argues that because two events are connected sequentially, they are connected causally as well: A happens (luck-attracting event or action) and then B happens; Therefore, A caused B. In this particular perspective, probability is only affected by confirmed causal connections. A brick falling on a person walking below, therefore, is not a function of that person's luck, but is instead the result of a collection of understood (or explainable) occurrences. Statistically, every person walking near the building was just as likely to have the brick fall on them. The gambler's fallacy and inverse gambler's fallacy both explain some reasoning problems in common beliefs in luck. They involve denying the unpredictability of random events: "I haven't rolled a seven all week, so I'll definitely roll one tonight". Luck is merely an expression noting an extended period of noted outcomes, completely consistent with random walk probability theory. Wishing one "good luck" will not cause such an extended period, but it expresses positive feelings toward the one -- not necessarily wholly undesirable. # Luck as an essence There is also a series of spiritual, or supernatural beliefs regarding fortune. These beliefs vary widely from one to another, but most agree that luck can be influenced through spiritual means by performing certain rituals or by avoiding certain circumstances. One such activity is prayer, a religious practice in which this belief is particularly strong. Many cultures and religions worldwide place a strong emphasis on a person's ability to influence their fortune by ritualistic means, sometimes involving sacrifice, omens or spells. Others associate luck with a strong sense of superstition, that is, a belief that certain taboo or blessed actions will influence how fortune favors them for the future. Luck can also be a belief in an organization of fortunate and unfortunate events. Luck is a form of superstition which is interpreted differently by different individuals. Carl Jung described synchronicity: the "temporally coincident occurrences of acausal events". He described coincidences as an effect of a collective unconscious. Christian and Islamic religions believe in the will of a supreme being rather than luck as the primary influence in future events. The degrees of this Divine Providence vary greatly from one person to another; however, most acknowledge providence as at least a partial, if not complete influence on luck. These religions, in their early development, accommodated many traditional practices. Each, at different times, accepted omens and practiced forms of ritual sacrifice in order to divine the will of their supreme being or to influence divine favoritism. The concept of "Divine Grace" as it is described by believers closely resembles what is referred to as "luck" by others. Mesoamerican religions, such as the Aztecs, Mayans and Incas, had particularly strong beliefs regarding the relationship between rituals and luck. In these cultures, human sacrifice (both of willing volunteers and captured enemies) was seen as a way to please the gods and earn favor for the city offering the sacrifice. The Mayans also believed in blood offerings, where men or women wanting to earn favor with the gods, to bring about good luck, would cut themselves and bleed on the gods' altar. Many traditional African practices, such as voodoo and hoodoo, have a strong belief in superstition. Some of these religions include a belief that third parties can influence an individual's luck. Shamans and witches are both respected yet feared, based on their ability to cause good or bad fortune for those in villages near them. # Luck as a placebo Some encourage the belief in luck as a false idea, but which may produce positive thinking, and alter one's responses for the better. Others, like Jean Paul Sartre and Sigmund Freud, feel a belief in luck has more to do with a locus of control for events in one's life, and the subsequent escape from personal responsibility. According to this theory, one who ascribes their travails to "bad luck" will be found upon close examination to be living risky lifestyles. If "good" and "bad" events occur at random to everyone, believers in good luck will experience a net gain in their fortunes, and vice versa for believers in bad luck. This is clearly likely to be self-reinforcing. Thus, although untrue, a belief in good luck may actually be an adaptive meme. # Numerology Most cultures consider some numbers to be lucky or unlucky. This is found to be particularly strong in Asian cultures, where the obtaining of "lucky" telephone numbers, automobile license plate numbers, and household addresses are actively sought, sometimes at great monetary expense. Numerology, as it relates to luck, is closer to an art than to a science, yet numerologists, astrologists or psychics may disagree. It is interrelated to astrology, and to some degree to parapsychology and spirituality and is based on converting virtually anything material into a pure number, using that number in an attempt to detect something meaningful about reality, and trying to predict or calculate the future based on lucky numbers. Numerology is folkloric by nature and started when humans first learned to count. Through human history it was, and still is, practiced by many cultures of the world from traditional fortunetelling to on-line psychic reading. There are many variations of numerology - most are based on the Chaldean System or the Pythagorean System. Latest modern methods such as Formalogy also are in use. Most are contemporary systems of advanced numerology and rely on leading principals of numerology and related mystical traditions observed by Ancestral Armenians, Mesopotamians, Egyptians, Assyrians, Phoenicians, Persians, Hebrews, Greeks and Romans. # Luck in Religion ## Judaism and Christianity - But you who forsake Yahweh, who forget my holy mountain, who prepare a table for Fortune, and who fill up mixed wine to Destiny (Isaiah 65:11 - The bearing that this has on beliefs concerning luck is a matter of controversy) - The lot is cast into the lap, but its every decision is from the Lord (Book of Proverbs 16:33 NIV) - I have seen something else under the sun: The race is not to the swift or the battle to the strong, nor does food come to the wise or wealth to the brilliant or favor to the learned; but time and chance happen to them all. (Ecclesiastes 9:11 NIV)

Luck Luck (also called fortuity) is a chance happening, or that which happens beyond a person's control. Luck can be good or bad. # Luck as lack of control Luck refers to that which happens beyond a person's control. This view incorporates phenomena that are chance happenings, a person's place of birth for example, but where there is no uncertainty involved, or where the uncertainty is irrelevant. Within this framework one can differentiate between three different types of luck: - Constitutional luck, that is, luck with factors that cannot be changed. Place of birth and genetic constitution are typical examples. - Circumstantial luck, that is, luck with factors that are haphazardly brought on. Accidents and epidemics are typical examples. - Ignorance luck, that is, luck with factors one does not know about. Examples can be identified only in hindsight. # Luck as a fallacy Another view holds that "luck is probability taken personally". A rationalist approach to luck includes the application of the rules of probability, and an avoidance of unscientific beliefs. The rationalist feels the belief in luck is a result of poor reasoning or wishful thinking. To a rationalist, a believer in luck commits the "post hoc, ergo propter hoc" logical fallacy, which argues that because two events are connected sequentially, they are connected causally as well: A happens (luck-attracting event or action) and then B happens; Therefore, A caused B. In this particular perspective, probability is only affected by confirmed causal connections. A brick falling on a person walking below, therefore, is not a function of that person's luck, but is instead the result of a collection of understood (or explainable) occurrences. Statistically, every person walking near the building was just as likely to have the brick fall on them. The gambler's fallacy and inverse gambler's fallacy both explain some reasoning problems in common beliefs in luck. They involve denying the unpredictability of random events: "I haven't rolled a seven all week, so I'll definitely roll one tonight". Luck is merely an expression noting an extended period of noted outcomes, completely consistent with random walk probability theory. Wishing one "good luck" will not cause such an extended period, but it expresses positive feelings toward the one -- not necessarily wholly undesirable. # Luck as an essence There is also a series of spiritual, or supernatural beliefs regarding fortune. These beliefs vary widely from one to another, but most agree that luck can be influenced through spiritual means by performing certain rituals or by avoiding certain circumstances. One such activity is prayer, a religious practice in which this belief is particularly strong. Many cultures and religions worldwide place a strong emphasis on a person's ability to influence their fortune by ritualistic means, sometimes involving sacrifice, omens or spells. Others associate luck with a strong sense of superstition, that is, a belief that certain taboo or blessed actions will influence how fortune favors them for the future. Luck can also be a belief in an organization of fortunate and unfortunate events. Luck is a form of superstition which is interpreted differently by different individuals. Carl Jung described synchronicity: the "temporally coincident occurrences of acausal events". He described coincidences as an effect of a collective unconscious. Christian and Islamic religions believe in the will of a supreme being rather than luck as the primary influence in future events. The degrees of this Divine Providence vary greatly from one person to another; however, most acknowledge providence as at least a partial, if not complete influence on luck. These religions, in their early development, accommodated many traditional practices. Each, at different times, accepted omens and practiced forms of ritual sacrifice in order to divine the will of their supreme being or to influence divine favoritism. The concept of "Divine Grace" as it is described by believers closely resembles what is referred to as "luck" by others. Mesoamerican religions, such as the Aztecs, Mayans and Incas, had particularly strong beliefs regarding the relationship between rituals and luck. In these cultures, human sacrifice (both of willing volunteers and captured enemies) was seen as a way to please the gods and earn favor for the city offering the sacrifice. The Mayans also believed in blood offerings, where men or women wanting to earn favor with the gods, to bring about good luck, would cut themselves and bleed on the gods' altar. Many traditional African practices, such as voodoo and hoodoo, have a strong belief in superstition. Some of these religions include a belief that third parties can influence an individual's luck. Shamans and witches are both respected yet feared, based on their ability to cause good or bad fortune for those in villages near them. # Luck as a placebo Some encourage the belief in luck as a false idea, but which may produce positive thinking, and alter one's responses for the better. Others, like Jean Paul Sartre and Sigmund Freud, feel a belief in luck has more to do with a locus of control for events in one's life, and the subsequent escape from personal responsibility. According to this theory, one who ascribes their travails to "bad luck" will be found upon close examination to be living risky lifestyles. If "good" and "bad" events occur at random to everyone, believers in good luck will experience a net gain in their fortunes, and vice versa for believers in bad luck. This is clearly likely to be self-reinforcing. Thus, although untrue, a belief in good luck may actually be an adaptive meme. # Numerology Most cultures consider some numbers to be lucky or unlucky. This is found to be particularly strong in Asian cultures, where the obtaining of "lucky" telephone numbers, automobile license plate numbers, and household addresses are actively sought, sometimes at great monetary expense. Numerology, as it relates to luck, is closer to an art than to a science, yet numerologists, astrologists or psychics may disagree. It is interrelated to astrology, and to some degree to parapsychology and spirituality and is based on converting virtually anything material into a pure number, using that number in an attempt to detect something meaningful about reality, and trying to predict or calculate the future based on lucky numbers. Numerology is folkloric by nature and started when humans first learned to count. Through human history it was, and still is, practiced by many cultures of the world from traditional fortunetelling to on-line psychic reading. There are many variations of numerology - most are based on the Chaldean System or the Pythagorean System. Latest modern methods such as Formalogy also are in use. Most are contemporary systems of advanced numerology and rely on leading principals of numerology and related mystical traditions observed by Ancestral Armenians, Mesopotamians, Egyptians, Assyrians, Phoenicians, Persians, Hebrews, Greeks and Romans. # Luck in Religion ## Judaism and Christianity - But you who forsake Yahweh, who forget my holy mountain, who prepare a table for Fortune, and who fill up mixed wine to Destiny (Isaiah 65:11 - The bearing that this has on beliefs concerning luck is a matter of controversy) - The lot is cast into the lap, but its every decision is from the Lord (Book of Proverbs 16:33 NIV) - I have seen something else under the sun: The race is not to the swift or the battle to the strong, nor does food come to the wise or wealth to the brilliant or favor to the learned; but time and chance happen to them all. (Ecclesiastes 9:11 NIV) # External links - Luck, Destiny, Fate, Karma, or Self-Made? with psychologist Richard Wiseman - Lucky charms and superstition - Diligent Media Corp. - Personalized Lucky Numbers - "Lucky": Documentary with Richard Wiseman transcript with link to 10 minute video. eo:Bonŝanco io:Fortuno he:מזל lv:Veiksme nl:Geluk (kans) no:Flaks qu:Sami simple:Luck fi:Onni sv:Tur Template:WS

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c4b3da298dddc9122083cef20a34f25589ae822f

wikidoc

Lung

Lung The lung is the essential respiration organ in air-breathing vertebrates, the most primitive being the lungfish. Its principal function is to transport oxygen from the atmosphere into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere. This exchange of gases is accomplished in the mosaic of specialized cells that form millions of tiny, exceptionally thin-walled air sacs called alveoli. The lungs also have non respiratory functions. Medical terms related to the lung often begin with pulmo-, from the Latin pulmonarius ("of the lungs"), or with pneumo- (from Greek πνεύμω "lung") # Respiratory function Energy production from aerobic respiration requires oxygen and glucose and produces carbon dioxide as a waste product, creating a need for an efficient means of oxygen delivery to cells and excretion of carbon dioxide from cells. In small organisms, such as single-celled bacteria, this process of gas exchange can take place entirely by simple diffusion. In larger organisms, this is not possible; only a small proportion of cells are close enough to the surface for oxygen from the atmosphere to enter them through diffusion. Two major adaptations made it possible for organisms to attain great multicellularity: an efficient circulatory system that conveyed gases to and from the deepest tissues in the body, and a large, internalized respiratory system that centralized the task of obtaining oxygen from the atmosphere and bringing it into the body, whence it could rapidly be distributed to all the circulatory system. In air-breathing vertebrates, respiration occurs in a series of steps. Air is brought into the animal via the airways — in reptiles, birds and mammals this often consists of the nose; the pharynx; the larynx; the trachea (also called the windpipe); the bronchi and bronchioles; and the terminal branches of the respiratory tree. The lungs of mammals are a rich lattice of alveoli, which provide an enormous surface area for gas exchange. A network of fine capillaries allows transport of blood over the surface of alveoli. Oxygen from the air inside the alveoli diffuses into the bloodstream, and carbon dioxide diffuses from the blood to the alveoli, both across thin alveolar membranes. The drawing and expulsion of air is driven by muscular action; in early tetrapods, air was driven into the lungs by the pharyngeal muscles, whereas in reptiles, birds and mammals a more complicated musculoskeletal system is used. In the mammal, a large muscle, the diaphragm (in addition to the internal intercostal muscles), drive ventilation by periodically altering the intra-thoracic volume and pressure; by increasing volume and thus decreasing pressure, air flows into the airways down a pressure gradient, and by reducing volume and increasing pressure, the reverse occurs. During normal breathing, expiration is passive and no muscles are contracted (the diaphragm relaxes). Another name for this inspiration and expulsion of air is ventilation. Vital capacity is the maximum volume of air that a person can exhale after maximum inhalation. A person's vital capacity can be measured by a spirometer (spirometry). In combination with other physiological measurements, the vital capacity can help make a diagnosis of underlying lung disease. # Non respiratory functions In addition to respiratory functions such as gas exchange and regulation of hydrogen ion concentration, the lungs also: - influence the concentration of biologically active substances and drugs used in medicine in arterial blood - filter out small blood clots formed in veins - serve as a physical layer of soft, shock-absorbent protection for the heart, which the lungs flank and nearly enclose. - filter out gas micro-bubbles occurring in the venous blood stream during SCUBA diving decompression. # Mammalian lungs The lungs of mammals have a spongy texture and are honeycombed with epithelium having a much larger surface area in total than the outer surface area of the lung itself. The lungs of humans are typical of this type of lung. Breathing is largely driven by the muscular diaphragm at the bottom of the thorax. Contraction of the diaphragm pulls the bottom of the cavity in which the lung is enclosed downward. Air enters through the oral and nasal cavities; it flows through the larynx and into the trachea, which branches out into bronchi. Relaxation of the diaphragm has the opposite effect, passively recoiling during normal breathing. During exercise, the diaphragm contracts, forcing the air out more quickly and forcefully. The rib cage itself is also able to expand and contract to some degree, through the action of other respiratory and accessory respiratory muscles. As a result, air is sucked into or expelled out of the lungs, always moving down its pressure gradient. This type of lung is known as a bellows lung as it resembles a blacksmith's bellows. # Anatomy In humans, the trachea divides into the two main bronchi that enter the roots of the lungs. The bronchi continue to divide within the lung, and after multiple divisions, give rise to bronchioles. The bronchial tree continues branching until it reaches the level of terminal bronchioles, which lead to alveolar sacks. Alveolar sacs are made up of clusters of alveoli, like individual grapes within a bunch. The individual alveoli are tightly wrapped in blood vessels, and it is here that gas exchange actually occurs. Deoxygenated blood from the heart is pumped through the pulmonary artery to the lungs, where oxygen diffuses into blood and is exchanged for carbon dioxide in the hemoglobin of the erythrocytes. The oxygen-rich blood returns to the heart via the pulmonary veins to be pumped back into systemic circulation. Human lungs are located in two cavities on either side of the heart. Though similar in appearance, the two are not identical. Both are separated into lobes, with three lobes on the right and two on the left. The lobes are further divided into lobules, hexagonal divisions of the lungs that are the smallest subdivision visible to the naked eye. The connective tissue that divides lobules is often blackened in smokers and city dwellers. The medial border of the right lung is nearly vertical, while the left lung contains a cardiac notch. The cardiac notch is a concave impression molded to accommodate the shape of the heart. Lungs are to a certain extent 'overbuilt' and have a tremendous reserve volume as compared to the oxygen exchange requirements when at rest. This is the reason that individuals can smoke for years without having a noticeable decrease in lung function while still or moving slowly; in situations like these only a small portion of the lungs are actually perfused with blood for gas exchange. As oxygen requirements increase due to exercise, a greater volume of the lungs is perfused, allowing the body to match its CO2/O2 exchange requirements. The environment of the lung is very moist, which makes it hospitable for bacteria. Many respiratory illnesses are the result of bacterial or viral infection of the lungs. # Avian lungs Avian lungs do not have alveoli, as mammalian lungs do, but instead contain millions of tiny passages known as para-bronchi, connected at both ends by the dorsobronchi and ventrobronchi. Air flows through the honeycombed walls of the para-bronchi and into air capillaries, where oxygen and carbon dioxide are traded with cross-flowing blood capillaries by diffusion, a process of crosscurrent exchange. Avian lungs contain two sets of air sacs, one towards the front, and a second towards the back. Upon inspiration, air travels backwards into the rear (caudal) sac, and a small portion travels forward past the para-bronchi and oxygenating the blood into the cranial air sac. On expiration, deoxygenated air held in the cranial air sack is exhaled, and the still-oxygenated air stored in the caudal sack moves over the parabronchi and is exhaled, with some remaining in the cranial sac. The complex system of air sacs ensures that the airflow through the avian lung always travels in the same direction - posterior to anterior. This is in contrast to the mammalian system, in which the direction of airflow in the lung is tidal, reversing between inhalation and exhalation. By utilizing a unidirectional flow of air, avian lungs are able to extract a greater concentration of oxygen from inhaled air. Birds are thus equipped to fly at altitudes at which mammals would succumb to hypoxia, and this also allows them to sustain a higher metabolic rate than an equivalent weight mammal. Because of the complexity of the system, misunderstanding is common and it is incorrectly believed that that it takes two breathing cycles for air to pass entirely through a bird's respiratory system. A bird's lungs do not store air in either of the sacs between respiration cycles, air moves continuously from the posterior to anterior air sacs throughout respiration. This type of lung construction is called circulatory lungs as distinct from the bellows lung possessed by most other animals. # Reptilian lungs Reptilian lungs are typically ventilated by a combination of expansion and contraction of the ribs via axial muscles and buccal pumping. Crocodilians also rely on the hepatic piston method, in which the liver is pulled back by a muscle anchored to the pubic bone (part of the pelvis), which in turn pulls the bottom of the lungs backward, expanding them. # Amphibian lungs The lungs of most frogs and other amphibians are simple balloon-like structures, with gas exchange limited to the outer surface area of the lung. This is not a very efficient arrangement, but amphibians have low metabolic demands and also frequently supplement their oxygen supply by diffusion across the moist outer skin of their bodies. Unlike mammals, which use a breathing system driven by negative pressure, amphibians employ positive pressure. Note that the majority of salamander species are lung-less salamanders and conduct respiration through their skin and the tissues lining their mouth. # Invertebrate lungs Some invertebrates have "lungs" that serve a similar respiratory purpose, but are not evolutionarily related to, vertebrate lungs. Some arachnids have structures called "book lungs" used for atmospheric gas exchange. The Coconut crab uses structures called branchiostegal lungs to breathe air and indeed will drown in water, hence it breathes on land and holds its breath underwater. The Pulmonata are an order of snails and slugs that have developed "lungs". # Origins The lungs of today's terrestrial vertebrates and the gas bladders of today's fish have evolved from simple sacs (outpocketings) of the esophagus that allowed the organism to gulp air under oxygen-poor conditions. Thus the lungs of vertebrates are homologous to the gas bladders of fish (but not to their gills). This is reflected by the fact that the lungs of a fetus also develop from an outpocketing of the esophagus and in the case of gas bladders, this connection to the gut continues to exist as the pneumatic duct in more "primitive" teleosts, and is lost in the higher orders. (This is an instance of correlation between ontogeny and phylogeny.) There are currently no known animals which have both a gas bladder and lungs.

Lung Template:WikiDoc Cardiology News Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The lung is the essential respiration organ in air-breathing vertebrates, the most primitive being the lungfish. Its principal function is to transport oxygen from the atmosphere into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere. This exchange of gases is accomplished in the mosaic of specialized cells that form millions of tiny, exceptionally thin-walled air sacs called alveoli. The lungs also have non respiratory functions. Medical terms related to the lung often begin with pulmo-, from the Latin pulmonarius ("of the lungs"), or with pneumo- (from Greek πνεύμω "lung")[2][3] # Respiratory function Energy production from aerobic respiration requires oxygen and glucose and produces carbon dioxide as a waste product, creating a need for an efficient means of oxygen delivery to cells and excretion of carbon dioxide from cells. In small organisms, such as single-celled bacteria, this process of gas exchange can take place entirely by simple diffusion. In larger organisms, this is not possible; only a small proportion of cells are close enough to the surface for oxygen from the atmosphere to enter them through diffusion. Two major adaptations made it possible for organisms to attain great multicellularity: an efficient circulatory system that conveyed gases to and from the deepest tissues in the body, and a large, internalized respiratory system that centralized the task of obtaining oxygen from the atmosphere and bringing it into the body, whence it could rapidly be distributed to all the circulatory system. In air-breathing vertebrates, respiration occurs in a series of steps. Air is brought into the animal via the airways — in reptiles, birds and mammals this often consists of the nose; the pharynx; the larynx; the trachea (also called the windpipe); the bronchi and bronchioles; and the terminal branches of the respiratory tree. The lungs of mammals are a rich lattice of alveoli, which provide an enormous surface area for gas exchange. A network of fine capillaries allows transport of blood over the surface of alveoli. Oxygen from the air inside the alveoli diffuses into the bloodstream, and carbon dioxide diffuses from the blood to the alveoli, both across thin alveolar membranes. The drawing and expulsion of air is driven by muscular action; in early tetrapods, air was driven into the lungs by the pharyngeal muscles, whereas in reptiles, birds and mammals a more complicated musculoskeletal system is used. In the mammal, a large muscle, the diaphragm (in addition to the internal intercostal muscles), drive ventilation by periodically altering the intra-thoracic volume and pressure; by increasing volume and thus decreasing pressure, air flows into the airways down a pressure gradient, and by reducing volume and increasing pressure, the reverse occurs. During normal breathing, expiration is passive and no muscles are contracted (the diaphragm relaxes). Another name for this inspiration and expulsion of air is ventilation. Vital capacity is the maximum volume of air that a person can exhale after maximum inhalation. A person's vital capacity can be measured by a spirometer (spirometry). In combination with other physiological measurements, the vital capacity can help make a diagnosis of underlying lung disease. # Non respiratory functions In addition to respiratory functions such as gas exchange and regulation of hydrogen ion concentration, the lungs also: - influence the concentration of biologically active substances and drugs used in medicine in arterial blood - filter out small blood clots formed in veins - serve as a physical layer of soft, shock-absorbent protection for the heart, which the lungs flank and nearly enclose. - filter out gas micro-bubbles occurring in the venous blood stream during SCUBA diving decompression.[4] # Mammalian lungs The lungs of mammals have a spongy texture and are honeycombed with epithelium having a much larger surface area in total than the outer surface area of the lung itself. The lungs of humans are typical of this type of lung. Breathing is largely driven by the muscular diaphragm at the bottom of the thorax. Contraction of the diaphragm pulls the bottom of the cavity in which the lung is enclosed downward. Air enters through the oral and nasal cavities; it flows through the larynx and into the trachea, which branches out into bronchi. Relaxation of the diaphragm has the opposite effect, passively recoiling during normal breathing. During exercise, the diaphragm contracts, forcing the air out more quickly and forcefully. The rib cage itself is also able to expand and contract to some degree, through the action of other respiratory and accessory respiratory muscles. As a result, air is sucked into or expelled out of the lungs, always moving down its pressure gradient. This type of lung is known as a bellows lung as it resembles a blacksmith's bellows. # Anatomy In humans, the trachea divides into the two main bronchi that enter the roots of the lungs. The bronchi continue to divide within the lung, and after multiple divisions, give rise to bronchioles. The bronchial tree continues branching until it reaches the level of terminal bronchioles, which lead to alveolar sacks. Alveolar sacs are made up of clusters of alveoli, like individual grapes within a bunch. The individual alveoli are tightly wrapped in blood vessels, and it is here that gas exchange actually occurs. Deoxygenated blood from the heart is pumped through the pulmonary artery to the lungs, where oxygen diffuses into blood and is exchanged for carbon dioxide in the hemoglobin of the erythrocytes. The oxygen-rich blood returns to the heart via the pulmonary veins to be pumped back into systemic circulation. Human lungs are located in two cavities on either side of the heart. Though similar in appearance, the two are not identical. Both are separated into lobes, with three lobes on the right and two on the left. The lobes are further divided into lobules, hexagonal divisions of the lungs that are the smallest subdivision visible to the naked eye. The connective tissue that divides lobules is often blackened in smokers and city dwellers. The medial border of the right lung is nearly vertical, while the left lung contains a cardiac notch. The cardiac notch is a concave impression molded to accommodate the shape of the heart. Lungs are to a certain extent 'overbuilt' and have a tremendous reserve volume as compared to the oxygen exchange requirements when at rest. This is the reason that individuals can smoke for years without having a noticeable decrease in lung function while still or moving slowly; in situations like these only a small portion of the lungs are actually perfused with blood for gas exchange. As oxygen requirements increase due to exercise, a greater volume of the lungs is perfused, allowing the body to match its CO2/O2 exchange requirements. The environment of the lung is very moist, which makes it hospitable for bacteria. Many respiratory illnesses are the result of bacterial or viral infection of the lungs. # Avian lungs Avian lungs do not have alveoli, as mammalian lungs do, but instead contain millions of tiny passages known as para-bronchi, connected at both ends by the dorsobronchi and ventrobronchi. Air flows through the honeycombed walls of the para-bronchi and into air capillaries, where oxygen and carbon dioxide are traded with cross-flowing blood capillaries by diffusion, a process of crosscurrent exchange. Avian lungs contain two sets of air sacs, one towards the front, and a second towards the back. Upon inspiration, air travels backwards into the rear (caudal) sac, and a small portion travels forward past the para-bronchi and oxygenating the blood into the cranial air sac. On expiration, deoxygenated air held in the cranial air sack is exhaled, and the still-oxygenated air stored in the caudal sack moves over the parabronchi and is exhaled, with some remaining in the cranial sac. The complex system of air sacs ensures that the airflow through the avian lung always travels in the same direction - posterior to anterior. This is in contrast to the mammalian system, in which the direction of airflow in the lung is tidal, reversing between inhalation and exhalation. By utilizing a unidirectional flow of air, avian lungs are able to extract a greater concentration of oxygen from inhaled air. Birds are thus equipped to fly at altitudes at which mammals would succumb to hypoxia, and this also allows them to sustain a higher metabolic rate than an equivalent weight mammal. Because of the complexity of the system, misunderstanding is common and it is incorrectly believed that that it takes two breathing cycles for air to pass entirely through a bird's respiratory system. A bird's lungs do not store air in either of the sacs between respiration cycles, air moves continuously from the posterior to anterior air sacs throughout respiration. This type of lung construction is called circulatory lungs as distinct from the bellows lung possessed by most other animals. # Reptilian lungs Reptilian lungs are typically ventilated by a combination of expansion and contraction of the ribs via axial muscles and buccal pumping. Crocodilians also rely on the hepatic piston method, in which the liver is pulled back by a muscle anchored to the pubic bone (part of the pelvis), which in turn pulls the bottom of the lungs backward, expanding them. # Amphibian lungs The lungs of most frogs and other amphibians are simple balloon-like structures, with gas exchange limited to the outer surface area of the lung. This is not a very efficient arrangement, but amphibians have low metabolic demands and also frequently supplement their oxygen supply by diffusion across the moist outer skin of their bodies. Unlike mammals, which use a breathing system driven by negative pressure, amphibians employ positive pressure. Note that the majority of salamander species are lung-less salamanders and conduct respiration through their skin and the tissues lining their mouth. # Invertebrate lungs Some invertebrates have "lungs" that serve a similar respiratory purpose, but are not evolutionarily related to, vertebrate lungs. Some arachnids have structures called "book lungs" used for atmospheric gas exchange. The Coconut crab uses structures called branchiostegal lungs to breathe air and indeed will drown in water, hence it breathes on land and holds its breath underwater. The Pulmonata are an order of snails and slugs that have developed "lungs". # Origins The lungs of today's terrestrial vertebrates and the gas bladders of today's fish have evolved from simple sacs (outpocketings) of the esophagus that allowed the organism to gulp air under oxygen-poor conditions. Thus the lungs of vertebrates are homologous to the gas bladders of fish (but not to their gills). This is reflected by the fact that the lungs of a fetus also develop from an outpocketing of the esophagus and in the case of gas bladders, this connection to the gut continues to exist as the pneumatic duct in more "primitive" teleosts, and is lost in the higher orders. (This is an instance of correlation between ontogeny and phylogeny.) There are currently no known animals which have both a gas bladder and lungs.

https://www.wikidoc.org/index.php/Lung

94d930976fb433ce81078362863300e788544909

wikidoc

Lust

Lust Lust is any intense desire or craving for gratification and excitement. Lust can mean strictly sexual lust, although it is also common to speak of a "lust for men", "lust for blood (bloodlust for short)" or a "lust for power", or other goals and to "lust for love". The Greek word which translates as lust is epithymia (επιθυμια), which also is translated into English as "to covet". # Lust in the context of religion ## Christianity—General Catholic tradition considers lust to be one of the main sins or vices. In the Old Testament, adultery was punishable by stoning. In the New Testament, Jesus included looking "lustfully at a woman" as adultery. (Matthew 5:28) The "woman" is a "Married" woman. ## Christianity—Protestantism Protestants hold that all sins, including lust, can be forgiven only by God through the death and resurrection of Jesus Christ. If a person believes in Jesus as his only Savior, then that person, regardless of what he has done, will receive Jesus' righteousness and will be able to enter heaven. But to enter the heaven of God , One must receive the Spirit of God . The Holy Bible tells of this in Luke 7:36-50, where the Lord Jesus Christ forgives a sinful woman. ## Punishment in the afterlife According to some Christian sources , reprobates whose chief unforgiven sin is lust are punished in Hell by being "smothered in fire and brimstone." However, while most Christian traditions agree that at some point after death the damned individuals find themselves in a hell where they suffer punishment for their sins, most traditions also agree that one can only speculate regarding the precise nature of any punishment above and beyond the principal torment, which comes simply from being totally separated from God. In Dante's Inferno, the first Canticle of the Divine Comedy, the lustful are punished by being continuously swept around in a whirlwind, which symbolizes their passions. ## Repentance in Purgatory According to The Divine Comedy, penitents who are guilty of lust cleanse their soul of the sin by walking through flames, thereby purging their minds of all lustful thoughts. ## Judaism According to traditional Judaism, nothing on Earth was created without a purpose. This includes basic human drives. Lust is only sinful when it is after another man's possessions or wife. Lust is not only not sinful, but a mitzvah, when one lusts after their spouse. ## Symbolic representations A frequent visual symbol for the sin of lust is the color blue, as with the cover of the book Lust in The Seven Deadly Sins series published by the Oxford University Press. Another symbol of lust is the animal cow (or bull). An example of this appears in the engraving Shamelessness by the 16th century artist Georg Pencz. Also, lust can be seen in the eponymous Eighth ATU in the Thoth Tarot card of Aleister Crowley.

Lust Lust is any intense desire or craving for gratification and excitement. Lust can mean strictly sexual lust, although it is also common to speak of a "lust for men", "lust for blood (bloodlust for short)" or a "lust for power", or other goals and to "lust for love". The Greek word which translates as lust is epithymia (επιθυμια), which also is translated into English as "to covet". # Lust in the context of religion ## Christianity—General Catholic tradition considers lust to be one of the main sins or vices. In the Old Testament, adultery was punishable by stoning. In the New Testament, Jesus included looking "lustfully at a woman" as adultery. (Matthew 5:28) The "woman" is a "Married" woman. ## Christianity—Protestantism Protestants hold that all sins, including lust, can be forgiven only by God through the death and resurrection of Jesus Christ. If a person believes in Jesus as his only Savior, then that person, regardless of what he has done, will receive Jesus' righteousness and will be able to enter heaven. But to enter the heaven of God , One must receive the Spirit of God . The Holy Bible tells of this in Luke 7:36-50, where the Lord Jesus Christ forgives a sinful woman. ## Punishment in the afterlife According to some Christian sources [1], reprobates whose chief unforgiven sin is lust are punished in Hell by being "smothered in fire and brimstone." However, while most Christian traditions agree that at some point after death the damned individuals find themselves in a hell where they suffer punishment for their sins, most traditions also agree that one can only speculate regarding the precise nature of any punishment above and beyond the principal torment, which comes simply from being totally separated from God.[citation needed] In Dante's Inferno, the first Canticle of the Divine Comedy, the lustful are punished by being continuously swept around in a whirlwind, which symbolizes their passions. ## Repentance in Purgatory According to The Divine Comedy, penitents who are guilty of lust cleanse their soul of the sin by walking through flames, thereby purging their minds of all lustful thoughts.[citation needed] ## Judaism According to traditional Judaism, nothing on Earth was created without a purpose. This includes basic human drives. Lust is only sinful when it is after another man's possessions or wife. Lust is not only not sinful, but a mitzvah, when one lusts after their spouse. ## Symbolic representations A frequent visual symbol for the sin of lust is the color blue, as with the cover of the book Lust in The Seven Deadly Sins series published by the Oxford University Press. Another symbol of lust is the animal cow (or bull). An example of this appears in the engraving Shamelessness [1] by the 16th century artist Georg Pencz.[citation needed] Also, lust can be seen in the eponymous Eighth ATU in the Thoth Tarot card of Aleister Crowley.

https://www.wikidoc.org/index.php/Lust

e10d1cf588a9dc80df8543f886fbbb1ad9bf1ecb

wikidoc

MAFG

MAFG Transcription factor MafG is a bZip Maf transcription factor protein that in humans is encoded by the MAFG gene. MafG is one of the small Maf proteins, which are basic region and basic leucine zipper (bZIP)-type transcription factors. The HUGO Gene Nomenclature Committee-approved gene name of MAFG is “v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G”. # Discovery MafG was first cloned and identified in chicken in 1995 as a new member of the small Maf (sMaf) genes. MAFG has been identified in many vertebrates, including humans. There are three functionally redundant sMaf proteins in vertebrates, MafF, MafG, and MafK. # Structure MafG has a bZIP structure that consists of a basic region for DNA binding and a leucine zipper structure for dimer formation. Similar to other sMafs, MafG lacks any canonical transcriptional activation domains. # Expression MAFG is broadly but differentially expressed in various tissues. MAFG expression was detected in all 16 tissues examined by the human BodyMap Project, but relatively abundant in lung, lymph node, skeletal muscle and thyroid tissues. MafG gene expression is induced by oxidative stresses, such as hydrogen peroxide and electrophilic compounds. Mouse Mafg gene is induced by Nrf2-sMaf heterodimers through an antioxidant response element (ARE) at the promoter proximal region. In response to bile acids, mouse Mafg gene is induced by the nuclear receptor, FXR (Farnesoid X receptor). # Function Because of sequence similarity, no functional differences have been observed among the sMafs in terms of their bZIP structures. sMafs form homodimers by themselves and heterodimers with other specific bZIP transcription factors, such as CNC (cap 'n' collar) proteins and Bach proteins (BACH1 and BACH2). sMaf homodimers bind to a palindromic DNA sequence called the Maf recognition element (MARE: TGCTGACTCAGCA) and its related sequences. Structural analyses have demonstrated that the basic region of a Maf factor recognizes the flanking GC sequences. By contrast, CNC-sMaf or Bach-sMaf heterodimers preferentially bind to DNA sequences (RTGA(C/G)NNNGC: R=A or G) that are slightly different from MARE. The latter DNA sequences have been recognized as antioxidant/electrophile response elements or NF-E2-binding motifs to which Nrf2-sMaf heterodimers and p45 NF-E2-sMaf heterodimer bind, respectively. It has been proposed that the latter sequences should be classified as CNC-sMaf-binding elements (CsMBEs). It has also been reported that sMafs form heterodimers with other bZIP transcription factors, such as c-Jun and c-Fos. # Target genes sMafs regulate different target genes depending on their partners. For instance, the p45-NF-E2-sMaf heterodimer regulate genes responsible for platelet production. Nrf2-sMaf heterodimer regulates a battery of cytoprotective genes, such as antioxidant/xenobiotic metabolizing enzyme genes. The Bach1-sMaf heterodimer regulates the heme oxygenase-1 gene. In particular, it has been reported that Bach1-MafG heterodimers participate in the hypermethylation of genes with CpG island promoters in certain types of cancers. The contribution of individual sMafs to the transcriptional regulation of their target genes has not yet been well examined. # Disease linkage Loss of sMafs results in disease-like phenotypes as summarized in table below. Mice lacking MafG exhibit mild neuronal phenotype and mild thrombocytopenia. However, mice lacking Mafg and one allele of Mafk (Mafg−/−::Mafk+/−) exhibit more severe neuronal phenotypes, severe thrombocytopenia and cataracts. Mice lacking MafG and MafK (Mafg−/−::Mafk−/− ) die in the perinatal stage. Finally, mice lacking MafF, MafG and MafK are embryonic lethal. Embryonic fibroblasts that are derived from Maff−/−::Mafg−/−::Mafk−/− mice fail to activate Nrf2-dependent cytoprotective genes in response to stress. In addition, accumulating evidence suggests that as partners of CNC and Bach proteins, sMafs are involved in the onset and progression of various human diseases, including neurodegeneration, arteriosclerosis and cancer. # Notes

MAFG Transcription factor MafG is a bZip Maf transcription factor protein that in humans is encoded by the MAFG gene.[1][2] MafG is one of the small Maf proteins, which are basic region and basic leucine zipper (bZIP)-type transcription factors. The HUGO Gene Nomenclature Committee-approved gene name of MAFG is “v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G”. # Discovery MafG was first cloned and identified in chicken in 1995 as a new member of the small Maf (sMaf) genes.[1] MAFG has been identified in many vertebrates, including humans. There are three functionally redundant sMaf proteins in vertebrates, MafF, MafG, and MafK.[2][3] # Structure MafG has a bZIP structure that consists of a basic region for DNA binding and a leucine zipper structure for dimer formation.[1] Similar to other sMafs, MafG lacks any canonical transcriptional activation domains.[1] # Expression MAFG is broadly but differentially expressed in various tissues. MAFG expression was detected in all 16 tissues examined by the human BodyMap Project, but relatively abundant in lung, lymph node, skeletal muscle and thyroid tissues.[4] MafG gene expression is induced by oxidative stresses, such as hydrogen peroxide and electrophilic compounds.[5][6] Mouse Mafg gene is induced by Nrf2-sMaf heterodimers through an antioxidant response element (ARE) at the promoter proximal region.[6] In response to bile acids, mouse Mafg gene is induced by the nuclear receptor, FXR (Farnesoid X receptor).[7] # Function Because of sequence similarity, no functional differences have been observed among the sMafs in terms of their bZIP structures. sMafs form homodimers by themselves and heterodimers with other specific bZIP transcription factors, such as CNC (cap 'n' collar) proteins [p45 NF-E2 (NFE2), Nrf1 (NFE2L1), Nrf2 (NFE2L2), and Nrf3 (NFE2L3)][8][9][10][11] and Bach proteins (BACH1 and BACH2).[12] sMaf homodimers bind to a palindromic DNA sequence called the Maf recognition element (MARE: TGCTGACTCAGCA) and its related sequences.[3][13] Structural analyses have demonstrated that the basic region of a Maf factor recognizes the flanking GC sequences.[14] By contrast, CNC-sMaf or Bach-sMaf heterodimers preferentially bind to DNA sequences (RTGA(C/G)NNNGC: R=A or G) that are slightly different from MARE.[15] The latter DNA sequences have been recognized as antioxidant/electrophile response elements[16][17] or NF-E2-binding motifs[18][19] to which Nrf2-sMaf heterodimers and p45 NF-E2-sMaf heterodimer bind, respectively. It has been proposed that the latter sequences should be classified as CNC-sMaf-binding elements (CsMBEs).[15] It has also been reported that sMafs form heterodimers with other bZIP transcription factors, such as c-Jun and c-Fos.[20] # Target genes sMafs regulate different target genes depending on their partners. For instance, the p45-NF-E2-sMaf heterodimer regulate genes responsible for platelet production.[8][21][22] Nrf2-sMaf heterodimer regulates a battery of cytoprotective genes, such as antioxidant/xenobiotic metabolizing enzyme genes.[10][23] The Bach1-sMaf heterodimer regulates the heme oxygenase-1 gene.[12] In particular, it has been reported that Bach1-MafG heterodimers participate in the hypermethylation of genes with CpG island promoters in certain types of cancers.[24] The contribution of individual sMafs to the transcriptional regulation of their target genes has not yet been well examined. # Disease linkage Loss of sMafs results in disease-like phenotypes as summarized in table below. Mice lacking MafG exhibit mild neuronal phenotype and mild thrombocytopenia.[21] However, mice lacking Mafg and one allele of Mafk (Mafg−/−::Mafk+/−) exhibit more severe neuronal phenotypes, severe thrombocytopenia and cataracts.[25][26] Mice lacking MafG and MafK (Mafg−/−::Mafk−/− ) die in the perinatal stage.[27] Finally, mice lacking MafF, MafG and MafK are embryonic lethal.[28] Embryonic fibroblasts that are derived from Maff−/−::Mafg−/−::Mafk−/− mice fail to activate Nrf2-dependent cytoprotective genes in response to stress.[23] In addition, accumulating evidence suggests that as partners of CNC and Bach proteins, sMafs are involved in the onset and progression of various human diseases, including neurodegeneration, arteriosclerosis and cancer. # Notes

https://www.wikidoc.org/index.php/MAFG

f2a541937b3f08c35d511a3a90aa6b81767d706e

wikidoc

MAFK

MAFK Transcription factor MafK is a bZip Maf transcription factor protein that in humans is encoded by the MAFK gene. MafK is one of the small Maf proteins, which are basic region and basic leucine zipper (bZIP)-type transcription factors. The HUGO Gene Nomenclature Committee-approved gene name of MAFK is “v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog K”. # Discovery MafK was first cloned and identified in chicken in 1993 as a member of the small Maf (sMaf) genes. MafK was also identified as p18 NF-E2, a component of NF-E2 complex binding to a specific motif (NF-E2) in the regulatory regions of β-globin and other erythroid-related genes. MAFK has been identified in many vertebrates, including humans. There are three functionally redundant sMaf proteins in vertebrates, MafF, MafG, and MafK. # Structure MafK has a bZIP structure that consists of a basic region for DNA binding and a leucine zipper structure for dimer formation. Similar to other sMafs, MafK lacks any canonical transcriptional activation domains. # Expression MAFK is broadly but differentially expressed in various tissues. MAFK expression was detected in all 16 tissues examined by the human BodyMap Project, but relatively abundant in adipose, lung and skeletal muscle tissues. Mouse Mafk is regulated by different GATA factors in both hematopoietic and cardiac tissues. MAFK expression is influenced by TGF-β and Wnt signaling, and rat Mafk expression is influenced by NGF and AKT in neuronal cells. # Function Because of sequence similarity, no functional differences have been observed among the sMafs in terms of their bZIP structures. sMafs form homodimers by themselves and heterodimers with other specific bZIP transcription factors, such as CNC (cap 'n' collar) proteins and Bach proteins (BACH1 and BACH2). sMaf homodimers bind to a palindromic DNA sequence called the Maf recognition element (MARE: TGCTGACTCAGCA) and its related sequences. Structural analyses have demonstrated that the basic region of a Maf factor recognizes the flanking GC sequences. By contrast, CNC-sMaf or Bach-sMaf heterodimers preferentially bind to DNA sequences (RTGA(C/G)NNNGC: R=A or G) that are slightly different from MARE. The latter DNA sequences have been recognized as antioxidant/electrophile response elements or NF-E2-binding motifs to which Nrf2-sMaf heterodimers and p45 NF-E2-sMaf heterodimer bind, respectively. It has been proposed that the latter sequences should be classified as CNC-sMaf-binding elements (CsMBEs). It has also been reported that sMafs form heterodimers with other bZIP transcription factors, such as c-Jun and c-Fos. # Target genes sMafs regulate different target genes depending on their partners. For instance, the p45-NF-E2-sMaf heterodimer regulates genes responsible for platelet production. Although it has not been confirmed by mouse genetic studies, many studies suggest that p45-NFE2-sMaf heterodimer is involved in the regulation of β-globin and other erythroid-related genes. Nrf2-sMaf heterodimer regulates a battery of cytoprotective genes, such as antioxidant/xenobiotic metabolizing enzyme genes. The Bach1-sMaf heterodimer regulates the heme oxygenase-1 gene. The contribution of individual sMafs to the transcriptional regulation of their target genes has not yet been well examined. # Disease linkage Loss of sMafs results in disease-like phenotypes as summarized in table below. Mice lacking MafK are seemingly healthy under laboratory conditions, while mice lacking MafG exhibit mild neuronal phenotype and mild thrombocytopenia. However, mice lacking Mafg and one allele of Mafk (Mafg−/−::Mafk+/−) exhibit progressive neuronal degeneration, thrombocytopenia and cataract, and mice lacking MafG and MafK (Mafg−/−::Mafk−/−) exhibit more severe neuronal degeneration and die in the perinatal stage. Mice lacking MafF, MafG and MafK are embryonic lethal. Embryonic fibroblasts that are derived from Maff−/−::Mafg−/−::Mafk−/− mice fail to activate Nrf2-dependent cytoprotective genes in response to stress. In addition, accumulating evidence suggests that as partners of CNC and Bach proteins, sMafs are involved in the onset and progression of various human diseases, including neurodegeneration, arteriosclerosis and cancer. # Notes

MAFK Transcription factor MafK is a bZip Maf transcription factor protein that in humans is encoded by the MAFK gene.[1][2] MafK is one of the small Maf proteins, which are basic region and basic leucine zipper (bZIP)-type transcription factors. The HUGO Gene Nomenclature Committee-approved gene name of MAFK is “v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog K”. # Discovery MafK was first cloned and identified in chicken in 1993 as a member of the small Maf (sMaf) genes. MafK was also identified as p18 NF-E2, a component of NF-E2 complex binding to a specific motif (NF-E2) in the regulatory regions of β-globin and other erythroid-related genes.[3] MAFK has been identified in many vertebrates, including humans. There are three functionally redundant sMaf proteins in vertebrates, MafF, MafG, and MafK.[2] # Structure MafK has a bZIP structure that consists of a basic region for DNA binding and a leucine zipper structure for dimer formation.[1] Similar to other sMafs, MafK lacks any canonical transcriptional activation domains.[1] # Expression MAFK is broadly but differentially expressed in various tissues. MAFK expression was detected in all 16 tissues examined by the human BodyMap Project, but relatively abundant in adipose, lung and skeletal muscle tissues.[4] Mouse Mafk is regulated by different GATA factors in both hematopoietic and cardiac tissues.[5] MAFK expression is influenced by TGF-β[6] and Wnt signaling,[7] and rat Mafk expression is influenced by NGF[8] and AKT[9] in neuronal cells. # Function Because of sequence similarity, no functional differences have been observed among the sMafs in terms of their bZIP structures. sMafs form homodimers by themselves and heterodimers with other specific bZIP transcription factors, such as CNC (cap 'n' collar) proteins [p45 NF-E2 (NFE2), Nrf1 (NFE2L1), Nrf2 (NFE2L2), and Nrf3 (NFE2L3)][10][11][12][13] and Bach proteins (BACH1 and BACH2).[14] sMaf homodimers bind to a palindromic DNA sequence called the Maf recognition element (MARE: TGCTGACTCAGCA) and its related sequences.[1][15] Structural analyses have demonstrated that the basic region of a Maf factor recognizes the flanking GC sequences.[16] By contrast, CNC-sMaf or Bach-sMaf heterodimers preferentially bind to DNA sequences (RTGA(C/G)NNNGC: R=A or G) that are slightly different from MARE.[17] The latter DNA sequences have been recognized as antioxidant/electrophile response elements[18][19] or NF-E2-binding motifs[20][21] to which Nrf2-sMaf heterodimers and p45 NF-E2-sMaf heterodimer bind, respectively. It has been proposed that the latter sequences should be classified as CNC-sMaf-binding elements (CsMBEs).[17] It has also been reported that sMafs form heterodimers with other bZIP transcription factors, such as c-Jun and c-Fos.[22] # Target genes sMafs regulate different target genes depending on their partners. For instance, the p45-NF-E2-sMaf heterodimer regulates genes responsible for platelet production.[10][23][24] Although it has not been confirmed by mouse genetic studies, many studies suggest that p45-NFE2-sMaf heterodimer is involved in the regulation of β-globin and other erythroid-related genes.[3][10] Nrf2-sMaf heterodimer regulates a battery of cytoprotective genes, such as antioxidant/xenobiotic metabolizing enzyme genes.[12][25] The Bach1-sMaf heterodimer regulates the heme oxygenase-1 gene.[14] The contribution of individual sMafs to the transcriptional regulation of their target genes has not yet been well examined. # Disease linkage Loss of sMafs results in disease-like phenotypes as summarized in table below. Mice lacking MafK are seemingly healthy under laboratory conditions,[23] while mice lacking MafG exhibit mild neuronal phenotype and mild thrombocytopenia.[23] However, mice lacking Mafg and one allele of Mafk (Mafg−/−::Mafk+/−) exhibit progressive neuronal degeneration, thrombocytopenia and cataract,[26][27] and mice lacking MafG and MafK (Mafg−/−::Mafk−/−) exhibit more severe neuronal degeneration and die in the perinatal stage.[28] Mice lacking MafF, MafG and MafK are embryonic lethal.[29] Embryonic fibroblasts that are derived from Maff−/−::Mafg−/−::Mafk−/− mice fail to activate Nrf2-dependent cytoprotective genes in response to stress.[25] In addition, accumulating evidence suggests that as partners of CNC and Bach proteins, sMafs are involved in the onset and progression of various human diseases, including neurodegeneration, arteriosclerosis and cancer. # Notes

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MAP4

MAP4 Microtubule-associated protein 4 is a protein that in humans is encoded by the MAP4 gene. The protein encoded by this gene is a major non-neuronal microtubule-associated protein. This protein contains a domain similar to the microtubule-binding domains of neuronal microtubule-associated protein (MAP2) and microtubule-associated protein tau (MAPT/TAU). This protein promotes microtubule assembly, and has been shown to counteract destabilization of interphase microtubule catastrophe promotion. Cyclin B was found to interact with this protein, which targets cell division cycle 2 (CDC2) kinase to microtubules. The phosphorylation of this protein affects microtubule properties and cell cycle progression. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed, the full-length nature of three of which are supported. uMAP4, the ubiquitous isoform of MAP4, functions in the architecture and positioning of the mitotic spindle in human cells. oMAP4 is predominantly expressed in brain and muscle and has been shown to organise microtubules into antiparallel bundles. mMAP4 is a muscle-specific isoform.

MAP4 Microtubule-associated protein 4 is a protein that in humans is encoded by the MAP4 gene.[1] The protein encoded by this gene is a major non-neuronal microtubule-associated protein. This protein contains a domain similar to the microtubule-binding domains of neuronal microtubule-associated protein (MAP2) and microtubule-associated protein tau (MAPT/TAU). This protein promotes microtubule assembly, and has been shown to counteract destabilization of interphase microtubule catastrophe promotion. Cyclin B was found to interact with this protein, which targets cell division cycle 2 (CDC2) kinase to microtubules. The phosphorylation of this protein affects microtubule properties and cell cycle progression. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed, the full-length nature of three of which are supported.[2] uMAP4, the ubiquitous isoform of MAP4, functions in the architecture and positioning of the mitotic spindle in human cells.[3] oMAP4 is predominantly expressed in brain and muscle and has been shown to organise microtubules into antiparallel bundles.[4] mMAP4 is a muscle-specific isoform.[4][5]

https://www.wikidoc.org/index.php/MAP4

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MAS1

MAS1 MAS proto-oncogene, or MAS1 proto-oncogene, G protein-coupled receptor (MRGA,MAS,MGRA""), is a protein that in humans is encoded by the MAS1 gene. The structure of the MAS1 product indicates that it belongs to the class of receptors that are coupled to GTP-binding proteins and share a conserved structural motif, which is described as a '7-transmembrane segment' following the prediction that these hydrophobic segments form membrane-spanning alpha-helices. The MAS1 protein may be a receptor that, when activated, modulates a critical component in a growth-regulating pathway to bring about oncogenic effects. Agonists of the receptor include angiotensin-(1-7). Antagonist include A-779 (angiotensin-1-7 with c-terminal proline substituted for D-Ala), or D-Pro (angiotensin-1-7 with c-terminal proline submitted for D-proline). Mas1 proto-oncogene (MAS1, MGRA) is not to be confused with the MAS-related G-protein coupled receptor, a recently believed to be activated by the ligand alamandine (generated by catalysis of Ang A via ACE2 or directly from Ang-(1-7)).

MAS1 MAS proto-oncogene, or MAS1 proto-oncogene, G protein-coupled receptor (MRGA,MAS,MGRA""), is a protein that in humans is encoded by the MAS1 gene.[1] The structure of the MAS1 product indicates that it belongs to the class of receptors that are coupled to GTP-binding proteins and share a conserved structural motif, which is described as a '7-transmembrane segment' following the prediction that these hydrophobic segments form membrane-spanning alpha-helices. The MAS1 protein may be a receptor that, when activated, modulates a critical component in a growth-regulating pathway to bring about oncogenic effects.[1] Agonists of the receptor include angiotensin-(1-7). Antagonist include A-779 (angiotensin-1-7 with c-terminal proline substituted for D-Ala), or D-Pro (angiotensin-1-7 with c-terminal proline submitted for D-proline). Mas1 proto-oncogene (MAS1, MGRA) is not to be confused with the MAS-related G-protein coupled receptor, a recently believed to be activated by the ligand alamandine (generated by catalysis of Ang A via ACE2 or directly from Ang-(1-7)).

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MBD1

MBD1 Methyl-CpG-binding domain protein 1 is a protein that in humans is encoded by the MBD1 gene. The protein encoded by MBD1 binds to methylated sequences in DNA, and thereby influences transcription. It binds to a variety of methylated sequences, and appears to mediate repression of gene expression. It has been shown to play a role in chromatin modification through interaction with the histone H3K9 methyltransferase SETDB1. H3K9me3 is a repressive modification. # Function DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. Five transcript variants of the MBD1 are generated by alternative splicing resulting in protein isoforms that contain one MBD domain, two to three cysteine-rich (CXXC) domains, and some differences in the COOH terminus. All five transcript variants repress transcription from methylated promoters; in addition, variants with three CXXC domains also repress unmethylated promoter activity. MBD1 and MBD2 map very close to each other on chromosome 18q21. # Interactions MBD1 has been shown to interact with ATF7IP, CBX5, CHAF1A and SUV39H1.

MBD1 Methyl-CpG-binding domain protein 1 is a protein that in humans is encoded by the MBD1 gene.[1][2][3] The protein encoded by MBD1 binds to methylated sequences in DNA, and thereby influences transcription. It binds to a variety of methylated sequences, and appears to mediate repression of gene expression. It has been shown to play a role in chromatin modification through interaction with the histone H3K9 methyltransferase SETDB1. H3K9me3 is a repressive modification. # Function DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. Five transcript variants of the MBD1 are generated by alternative splicing resulting in protein isoforms that contain one MBD domain, two to three cysteine-rich (CXXC) domains, and some differences in the COOH terminus. All five transcript variants repress transcription from methylated promoters; in addition, variants with three CXXC domains also repress unmethylated promoter activity. MBD1 and MBD2 map very close to each other on chromosome 18q21.[3] # Interactions MBD1 has been shown to interact with ATF7IP,[4] CBX5,[5][6] CHAF1A[6] and SUV39H1.[5]

https://www.wikidoc.org/index.php/MBD1

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MBD3

MBD3 Methyl-CpG-binding domain protein 3 is a protein that in humans is encoded by the MBD3 gene. # Function DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). However, unlike the other family members, MBD3 is not capable of binding to methylated DNA but instead binds to hydroxymethylated DNA. The predicted MBD3 protein shares 71% and 94% identity with MBD2 (isoform 1) and mouse Mbd3. MBD3 is a subunit of the NuRD, a multisubunit complex containing nucleosome remodeling and histone deacetylase activities. MBD3 mediates the association of metastasis-associated protein 2 (MTA2) with the core histone deacetylase complex. MBD3 also contains the coiled‐coil domain common to all three MBD3 isoforms. The coiled‐coil domain, but not the MBD domain, helps to maintain pluripotency of embryonic stem cells via the recruitment of polycomb repressive complex 2 to a subset of genes linked to development and organogenesis, thus establishing stable transcriptional repression. # Interactions MBD3 has been shown to interact with: - AURKA, - GATAD2B, - HDAC1, - MTA2, and - MBD2.

MBD3 Methyl-CpG-binding domain protein 3 is a protein that in humans is encoded by the MBD3 gene.[1][2][3] # Function DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). However, unlike the other family members, MBD3 is not capable of binding to methylated DNA but instead binds to hydroxymethylated DNA.[4] The predicted MBD3 protein shares 71% and 94% identity with MBD2 (isoform 1) and mouse Mbd3. MBD3 is a subunit of the NuRD, a multisubunit complex containing nucleosome remodeling and histone deacetylase activities. MBD3 mediates the association of metastasis-associated protein 2 (MTA2) with the core histone deacetylase complex.[3] MBD3 also contains the coiled‐coil domain common to all three MBD3 isoforms. The coiled‐coil domain, but not the MBD domain, helps to maintain pluripotency of embryonic stem cells via the recruitment of polycomb repressive complex 2 to a subset of genes linked to development and organogenesis, thus establishing stable transcriptional repression.[5] # Interactions MBD3 has been shown to interact with: - AURKA,[6] - GATAD2B,[7][8] - HDAC1,[6][9][10] - MTA2,[6][9][10] and - MBD2.[9][11]

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MBD4

MBD4 Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene. # Structure Human MBD4 protein has 580 amino acids with a methyl-CpG-binding domain at amino acids 82–147 and a C-terminal DNA glycosylase domain at amino acids 426–580. These domains are separated by an intervening region that interacts with UHRF1, an E3 ubiquitin ligase, and USP7, a de-ubiquinating enzyme. # Function DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 (this gene) comprise a family of nuclear proteins related by the presence in each of a methyl-CpG-binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MBD4 may function to mediate the biological consequences of the methylation signal. In addition, MBD4 has protein sequence similarity to bacterial DNA repair enzymes and thus may have some function in DNA repair. Further, MBD4 gene mutations are detected in tumors with primary microsatellite instability (MSI), a form of genomic instability associated with defective DNA mismatch repair, and MBD4 gene meets 4 of 5 criteria of a bona fide MIS target gene. ## Deaminated bases as targets Bases in DNA decay spontaneously, and this decay includes hydrolytic deamination of purines and pyrimidines that contain an exocyclic amino group (see image). Hypoxanthine and xanthine are generated at a relatively slow rate by deamination of adenine and guanine, respectively. However, deamination of pyrimidines occurs at a 50-fold higher rate of approximately 200–300 events per cell per day, and is potentially highly mutagenic. Deamination of cytosine (C) to uracil (U) and 5-methylcytosine (5mC) to thymine (T) generates G:U and G:T mismatches, respectively. Upon DNA replication, these mismatches cause C to T transition mutations. Notably, for 5mC deamination, these mutations arise predominantly in the context of CpG sites. The deamination rate of 5mC is approximately three times that of C. MBD4 protein binds preferentially to fully methylated CpG sites and to their deamination derivatives G:U and G:T base pairs. MBD4, which is employed in an initial step of base excision repair, specifically catalyzes the removal of T and U paired with guanine (G) within CpG sites. ## Mutational importance of targets G:U and G:T mismatches, upon DNA replication, give rise to C to T transition mutations. The mismatched U or T is usually removed by MBD4 before replication, thus avoiding mutation. Alternatively, for G:T mismatches, the T may be removed by thymine-DNA glycosylase. Mutations in the MBD4 gene (especially expansions/deletions in the polyadenine regions of the MBD4 gene) increase the genomic instability phenotype of a subset of MMR-defective tumors in mice, specifically contributing to elevated G:C to A:T transitions. About 1/3 of all intragenic single base pair mutations in human cancers occur in CpG dinucleotides and are the result of C to T or G to A transitions. These transitions comprise the most frequent mutations in human cancer. For example, nearly 50% of somatic mutations of the tumor suppressor gene p53 in colorectal cancer are G:C to A:T transitions within CpG sites. # Clinical significance in cancer ## Germline mutations of MBD4 Germline mutations of MBD4 have been identified in acute myeloid leukemias, uveal melanomas, and glioblastomas. These cases presented an inactivation of the second allele of MBD4 in tumor and were associated with a subsequent very high mutation burden at CpG dinucleotides. ## Somatic mutations of MBD4 Mutation of MBD4 occurs in about 4% of colorectal cancers. MBD4 mutations also occur in tumor samples of melanoma, ovarian, lung, esophageal and prostate cancers at frequencies between 0.5% and 8%. MBD4 has a special relationship with DNA mismatch repair (MMR). MBD4 protein binds strongly to the MMR protein MLH1. A mutational deficiency in MBD4 causes down-regulation, at the protein level, of MMR proteins Mlh1, Msh2, Pms2, and Msh6 by 5.8-, 5.6-, 2.6-, and 2.7-fold, respectively. In colorectal cancers with mutations in MMR genes, co-occurrence of MBD4 mutations were found in 27% of cancers. ## Epigenetic silencing MBD4 mRNA expression is reduced in colorectal neoplasms due to methylation of the promoter region of MBD4. A majority of histologically normal fields surrounding the neoplastic growths also show reduced MBD4 mRNA expression (a field defect) compared to histologically normal tissue from individuals who never had a colonic neoplasm. This indicates that an epigenetic deficiency in MBD4 expression is a frequent early event in colorectal tumorigenesis. While other DNA repair genes, such as MGMT and MLH1, are often evaluated for epigenetic repression in many types of cancer, epigenetic deficiency of MBD4 is usually not evaluated, but might be of importance in such cancers as well. ## Response to checkpoint inhibitors MBD4-associated hypermutated profile was shown to be associated with a tumor regression when a uveal melanoma patient was treated with a checkpoint inhibitor making these mutations potential biomarkers to treat cancers. # Interactions MBD4 has been shown to interact with MLH1 and FADD.

MBD4 Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.[1][2][3] # Structure Human MBD4 protein has 580 amino acids with a methyl-CpG-binding domain at amino acids 82–147 and a C-terminal DNA glycosylase domain at amino acids 426–580.[4] These domains are separated by an intervening region that interacts with UHRF1, an E3 ubiquitin ligase, and USP7, a de-ubiquinating enzyme.[5] # Function DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 (this gene) comprise a family of nuclear proteins related by the presence in each of a methyl-CpG-binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MBD4 may function to mediate the biological consequences of the methylation signal. In addition, MBD4 has protein sequence similarity to bacterial DNA repair enzymes and thus may have some function in DNA repair. Further, MBD4 gene mutations are detected in tumors with primary microsatellite instability (MSI), a form of genomic instability associated with defective DNA mismatch repair, and MBD4 gene meets 4 of 5 criteria of a bona fide MIS target gene.[3] ## Deaminated bases as targets Bases in DNA decay spontaneously, and this decay includes hydrolytic deamination of purines and pyrimidines that contain an exocyclic amino group (see image). Hypoxanthine and xanthine are generated at a relatively slow rate by deamination of adenine and guanine, respectively. However, deamination of pyrimidines occurs at a 50-fold higher rate of approximately 200–300 events per cell per day,[4] and is potentially highly mutagenic. Deamination of cytosine (C) to uracil (U) and 5-methylcytosine (5mC) to thymine (T) generates G:U and G:T mismatches, respectively. Upon DNA replication, these mismatches cause C to T transition mutations. Notably, for 5mC deamination, these mutations arise predominantly in the context of CpG sites. The deamination rate of 5mC is approximately three times that of C. MBD4 protein binds preferentially to fully methylated CpG sites and to their deamination derivatives G:U and G:T base pairs.[4] MBD4, which is employed in an initial step of base excision repair, specifically catalyzes the removal of T and U paired with guanine (G) within CpG sites.[6] ## Mutational importance of targets G:U and G:T mismatches, upon DNA replication, give rise to C to T transition mutations.[6] The mismatched U or T is usually removed by MBD4 before replication, thus avoiding mutation. Alternatively, for G:T mismatches, the T may be removed by thymine-DNA glycosylase. Mutations in the MBD4 gene (especially expansions/deletions in the polyadenine regions of the MBD4 gene) increase the genomic instability phenotype of a subset of MMR-defective tumors in mice, specifically contributing to elevated G:C to A:T transitions.[7] About 1/3 of all intragenic single base pair mutations in human cancers occur in CpG dinucleotides and are the result of C to T or G to A transitions.[6][8] These transitions comprise the most frequent mutations in human cancer. For example, nearly 50% of somatic mutations of the tumor suppressor gene p53 in colorectal cancer are G:C to A:T transitions within CpG sites.[6] # Clinical significance in cancer ## Germline mutations of MBD4 Germline mutations of MBD4 have been identified in acute myeloid leukemias, uveal melanomas, and glioblastomas[9][10][11]. These cases presented an inactivation of the second allele of MBD4 in tumor and were associated with a subsequent very high mutation burden at CpG dinucleotides. ## Somatic mutations of MBD4 Mutation of MBD4 occurs in about 4% of colorectal cancers.[7] MBD4 mutations also occur in tumor samples of melanoma, ovarian, lung, esophageal and prostate cancers at frequencies between 0.5% and 8%.[7] MBD4 has a special relationship with DNA mismatch repair (MMR). MBD4 protein binds strongly to the MMR protein MLH1.[2] A mutational deficiency in MBD4 causes down-regulation, at the protein level, of MMR proteins Mlh1, Msh2, Pms2, and Msh6 by 5.8-, 5.6-, 2.6-, and 2.7-fold, respectively.[12] In colorectal cancers with mutations in MMR genes, co-occurrence of MBD4 mutations were found in 27% of cancers.[7] ## Epigenetic silencing MBD4 mRNA expression is reduced in colorectal neoplasms due to methylation of the promoter region of MBD4.[13] A majority of histologically normal fields surrounding the neoplastic growths also show reduced MBD4 mRNA expression (a field defect) compared to histologically normal tissue from individuals who never had a colonic neoplasm. This indicates that an epigenetic deficiency in MBD4 expression is a frequent early event in colorectal tumorigenesis. While other DNA repair genes, such as MGMT and MLH1, are often evaluated for epigenetic repression in many types of cancer,[14] epigenetic deficiency of MBD4 is usually not evaluated, but might be of importance in such cancers as well. ## Response to checkpoint inhibitors MBD4-associated hypermutated profile was shown to be associated with a tumor regression when a uveal melanoma patient was treated with a checkpoint inhibitor making these mutations potential biomarkers to treat cancers.[11] # Interactions MBD4 has been shown to interact with MLH1[2] and FADD.[15]

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MBDB

MBDB MBDB, or 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine, is a lesser-known hallucinogenic phenethylamine. It is also known as "EDEN" or "Methyl-J." It is the alpha-ethyl-N-methyl analog of MDMA (Esctasy). It was first synthesized by David E. Nichols, a leading pharmacologist and chemist, and later tested by Alexander Shulgin and written up in his book, PiHKAL (Phenethylamines I Have Known and Loved). MBDB's dosage, according to PiHKAL, is 180-210 mg; the proper dosage relative to body mass seems unknown. Its duration is 4-6 hours, with noticeable after-effects lasting for 1-3 hours. MBDB causes many mild, MDMA-like effects, such as lowering of social barriers and inhibitions, a pronounced sense of empathy and compassion, and mild happiness, euphoria, and enhanced emotions are all present. However, MBDB's effects are much less profound then those of MDMA. MBDM's effects tend to produce less euphoria, less psychedelia, and have less stimulative properties than MDMA does. Many users declare that MBDB is a "watered-down" version of MDMA as MBDB loses action much more quickly, due to the milder effects, lack of a "rush," and its sedative effects. As with MDMA, users are at risk for acute dehydration if participating in strenuous physical activity and forget to drink water, as the drug may mask one's normal sense of exhaustion and thirst. # Dangers - DO NOT take MBDB if you are on an MAOI. MAOIs (Monoamine oxidase inhibitors) are most common in antidepressants. Ask your pharmacist/doctor if your medication contains any MAOIs. The combination is dangerous and could be lethal.* - DO NOT Operate any machinery or anything else that can potentially harm you while under the influence of MBDB.

MBDB MBDB, or 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine, is a lesser-known hallucinogenic phenethylamine. It is also known as "EDEN" or "Methyl-J." It is the alpha-ethyl-N-methyl analog of MDMA (Esctasy). It was first synthesized by David E. Nichols, a leading pharmacologist and chemist, and later tested by Alexander Shulgin and written up in his book, PiHKAL (Phenethylamines I Have Known and Loved). MBDB's dosage, according to PiHKAL, is 180-210 mg; the proper dosage relative to body mass seems unknown. Its duration is 4-6 hours, with noticeable after-effects lasting for 1-3 hours. MBDB causes many mild, MDMA-like effects, such as lowering of social barriers and inhibitions, a pronounced sense of empathy and compassion, and mild happiness, euphoria, and enhanced emotions are all present. However, MBDB's effects are much less profound then those of MDMA. MBDM's effects tend to produce less euphoria, less psychedelia, and have less stimulative properties than MDMA does. Many users declare that MBDB is a "watered-down" version of MDMA as MBDB loses action much more quickly, due to the milder effects, lack of a "rush," and its sedative effects. As with MDMA, users are at risk for acute dehydration if participating in strenuous physical activity and forget to drink water, as the drug may mask one's normal sense of exhaustion and thirst. # Dangers - DO NOT take MBDB if you are on an MAOI. MAOIs (Monoamine oxidase inhibitors) are most common in antidepressants. Ask your pharmacist/doctor if your medication contains any MAOIs. The combination is dangerous and could be lethal.* - DO NOT Operate any machinery or anything else that can potentially harm you while under the influence of MBDB. # External links - PiHKAL entry - Erowid MBDB vault Template:Entactogens Template:Phenethylamines Template:PiHKAL Template:Hallucinogen-stub de:MBDB Template:WikiDoc Sources

https://www.wikidoc.org/index.php/MBDB

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wikidoc

MCEF

MCEF MCEF or Major Cdk9-interacting elongation factor is a transcription factor related to Af4. It is the fourth member of the Af4 family (AFF) of transcription factors, involved in numerous pathologies, including Acute Lymphoblastic Leukemia (ALL), abnormal CNS development, breast cancer and azoospermia. Because it apparently interacts with the species-specific human co-factor (P-TEFb) for HIV-1 transcription, and because it can repress HIV-1 replication, MCEF (also known as AFF4 or AF5q31) may have future therapeutic uses. MCEF was originally cloned and named by Mario Clemente Estable of Ryerson University, while he was a post-doctoral fellow in the laboratory of Robert G. Roeder, at the Rockefeller University.

MCEF MCEF or Major Cdk9-interacting elongation factor is a transcription factor related to Af4. It is the fourth member of the Af4 family (AFF) of transcription factors, involved in numerous pathologies, including Acute Lymphoblastic Leukemia (ALL), abnormal CNS development, breast cancer and azoospermia. Because it apparently interacts with the species-specific human co-factor (P-TEFb) for HIV-1 transcription, and because it can repress HIV-1 replication, MCEF (also known as AFF4 or AF5q31) may have future therapeutic uses.[1] MCEF was originally cloned and named by Mario Clemente Estable of Ryerson University, while he was a post-doctoral fellow in the laboratory of Robert G. Roeder, at the Rockefeller University.

https://www.wikidoc.org/index.php/MCEF

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wikidoc

MCL1

MCL1 Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the MCL1 gene. # Function The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. The longer gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene product (isoform 2) promotes apoptosis and is death-inducing. # Clinical significance Omacetaxine mepesuccinate (a drug approved for the treatment for chronic myelogenous leukemia (CML)) and Seliciclib (which is under investigation as a potential multiple myeloma treatment) both act in part by inhibiting synthesis of Mcl-1. # Interactions MCL1 has been shown to interact with: - BAK1, - BCL2L11, - BID, - BAD, - DAD1, - PMAIP1, - PCNA, - TCTP and - TNKS

MCL1 Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the MCL1 gene.[1][2] # Function The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. The longer gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene product (isoform 2) promotes apoptosis and is death-inducing.[3] # Clinical significance Omacetaxine mepesuccinate (a drug approved for the treatment for chronic myelogenous leukemia (CML)) and Seliciclib [4] (which is under investigation as a potential multiple myeloma treatment) both act in part by inhibiting synthesis of Mcl-1. # Interactions MCL1 has been shown to interact with: - BAK1,[5][6][7][8] - BCL2L11,[8][9][10] - BID,[7][9] - BAD,[9][11] - DAD1,[12] - PMAIP1,[6][9] - PCNA,[13] - TCTP[14] and - TNKS[15]

https://www.wikidoc.org/index.php/MCL1

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wikidoc

MCM6

MCM6 DNA replication licensing factor MCM6 is a protein that in humans is encoded by the MCM6 gene. MCM6 is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. # Function The MCM complex consisting of MCM6 (this protein) and MCM2, 4 and 7 possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre-RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The phosphorylation of the complex by CDC2 kinase reduces the helicase activity, suggesting a role in the regulation of DNA replication. Mcm 6 has recently been shown to interact strongly Cdt1 at defined residues, by mutating these target residues Wei et al. observed lack of Cdt1 recruitment of Mcm2-7 to the pre-RC. # Gene The MCM6 gene, MCM6, is expressed at very high level. MCM6 contains 18 introns. There are 2 non overlapping alternative last exons. The transcripts appear to differ by truncation of the 3' end, presence or absence of 2 cassette exons, common exons with different boundaries. MCM6 produces, by alternative splicing, 3 different transcripts, all with introns, putatively encoding 3 different protein isoforms. MCM6 contains two of the regulatory regions for LCT, the gene encoding the protein lactase, located in two of the MCM6 introns, approximately 14 kb (-13910) and 22 kb (-22018) upstream of LCT. The (-13910) region, in particular, has been shown to function in vitro as an enhancer element capable of differentially activating transcription of LCT promoter. Mutations in these regions are associated with lactose tolerance into adult life. # Interactions MCM6 has been shown to interact with: - CDC45-related protein, - MCM2, - MCM4, - MCM7, - ORC1L, - ORC2L, - ORC4L, and - Replication protein A1.

MCM6 DNA replication licensing factor MCM6 is a protein that in humans is encoded by the MCM6 gene.[1] MCM6 is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. # Function The MCM complex consisting of MCM6 (this protein) and MCM2, 4 and 7 possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre-RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The phosphorylation of the complex by CDC2 kinase reduces the helicase activity, suggesting a role in the regulation of DNA replication.[2] Mcm 6 has recently been shown to interact strongly Cdt1 at defined residues, by mutating these target residues Wei et al. observed lack of Cdt1 recruitment of Mcm2-7 to the pre-RC.[3] # Gene The MCM6 gene, MCM6, is expressed at very high level. MCM6 contains 18 introns. There are 2 non overlapping alternative last exons. The transcripts appear to differ by truncation of the 3' end, presence or absence of 2 cassette exons, common exons with different boundaries. MCM6 produces, by alternative splicing, 3 different transcripts, all with introns, putatively encoding 3 different protein isoforms. MCM6 contains two of the regulatory regions for LCT, the gene encoding the protein lactase, located in two of the MCM6 introns, approximately 14 kb (-13910) and 22 kb (-22018) upstream of LCT.[4] The (-13910) region, in particular, has been shown to function in vitro as an enhancer element capable of differentially activating transcription of LCT promoter.[5] Mutations in these regions are associated with lactose tolerance into adult life.[4][6] # Interactions MCM6 has been shown to interact with: - CDC45-related protein,[7] - MCM2,[7][8][9][10][11] - MCM4,[8][9][12] - MCM7,[9][13] - ORC1L,[7] - ORC2L,[7] - ORC4L,[7] and - Replication protein A1.[7]

https://www.wikidoc.org/index.php/MCM6

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wikidoc

MCM8

MCM8 DNA replication licensing factor MCM8 is a protein that in humans is encoded by the MCM8 gene. The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein contains the central domain that is conserved among the MCM proteins. This protein has been shown to co-immunoprecipitate with MCM4, 6 and 7, which suggests that it may interact with other MCM proteins and play a role in DNA replication. Alternatively spliced transcript variants encoding distinct isoforms have been described. # DNA repair MCM8-deficient mice are defective in gametogenesis and display genome instability due to impaired homologous recombination. Male MCM8 (-/-) mice are sterile because spermatocytes are blocked in meiotic prophase I. Female MCM8(-/-) mice have arrested primary follicles and frequently develop ovarian tumors. MCM8 protein forms a complex with MCM9. In the plant Arabidopsis thaliana, MCM8 is required for a pathway of meiotic DNA double-strand break repair. It was proposed that MCM8 is involved with RAD51 in a backup pathway that repairs meiotic double-strand breaks without yielding crossovers when the major recombination pathway, which relies on DMC1, fails. MCM8 forms a complex with MCM9 that is required for DNA resection by the MRN complex (MRE11-RAD50-NBS1) at double strand breaks to generate single-stranded DNA ends. The formation of single-strand ends is an early step in homologous recombination (see Figure). MCM8/MCM9 interacts with MRN and is required for the nuclease action and stable association of MRN with double-strand breaks. In humans, an MCM8 mutation can give rise to premature ovarian failure, as well as chromosomal instability.

MCM8 DNA replication licensing factor MCM8 is a protein that in humans is encoded by the MCM8 gene.[1][2] The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein contains the central domain that is conserved among the MCM proteins. This protein has been shown to co-immunoprecipitate with MCM4, 6 and 7, which suggests that it may interact with other MCM proteins and play a role in DNA replication. Alternatively spliced transcript variants encoding distinct isoforms have been described.[2] # DNA repair MCM8-deficient mice are defective in gametogenesis and display genome instability due to impaired homologous recombination.[3] Male MCM8 (-/-) mice are sterile because spermatocytes are blocked in meiotic prophase I. Female MCM8(-/-) mice have arrested primary follicles and frequently develop ovarian tumors.[3] MCM8 protein forms a complex with MCM9. In the plant Arabidopsis thaliana, MCM8 is required for a pathway of meiotic DNA double-strand break repair.[4] It was proposed that MCM8 is involved with RAD51 in a backup pathway that repairs meiotic double-strand breaks without yielding crossovers when the major recombination pathway, which relies on DMC1, fails.[4] MCM8 forms a complex with MCM9 that is required for DNA resection by the MRN complex (MRE11-RAD50-NBS1) at double strand breaks to generate single-stranded DNA ends.[5] The formation of single-strand ends is an early step in homologous recombination (see Figure). MCM8/MCM9 interacts with MRN and is required for the nuclease action and stable association of MRN with double-strand breaks.[5] In humans, an MCM8 mutation can give rise to premature ovarian failure, as well as chromosomal instability.[6]

https://www.wikidoc.org/index.php/MCM8

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wikidoc

MCMI

MCMI The Millon Clinical Multiaxial Inventory-III (MCMI-III) is a psychological assessment tool intended to provide information on psychopathology, including specific disorders outlined in the DSM-IV. It is intended for adults (18 and over) with at least an 8th grade reading level. It is composed of 175 true-false questions that reportedly takes 25-30 minutes to complete. It was created by Theodore Millon, Carrie Millon, Roger Davis, and Seth Grossman. The test is modeled on four scales - 14 Personality Disorder Scales - 10 Clinical Syndrome Scales - Correction Scales (which help detect inaccurate responding) - 42 Grossman Personality Facet Scales (based on Seth Grossman's theories of personality and psychopathology) The test was normed on a sample of 998 male and female adults with a wide variety of clinical disorders. # Scoring System The major scales are divided in four ranges: normal (0-60), tendency (61-75), trait (76-85), and personality disorder (86-115).

MCMI The Millon Clinical Multiaxial Inventory-III (MCMI-III) is a psychological assessment tool intended to provide information on psychopathology, including specific disorders outlined in the DSM-IV. It is intended for adults (18 and over) with at least an 8th grade reading level. It is composed of 175 true-false questions that reportedly takes 25-30 minutes to complete. It was created by Theodore Millon, Carrie Millon, Roger Davis, and Seth Grossman. The test is modeled on four scales - 14 Personality Disorder Scales - 10 Clinical Syndrome Scales - Correction Scales (which help detect inaccurate responding) - 42 Grossman Personality Facet Scales (based on Seth Grossman's theories of personality and psychopathology) The test was normed on a sample of 998 male and female adults with a wide variety of clinical disorders. # Scoring System The major scales are divided in four ranges: normal (0-60), tendency (61-75), trait (76-85), and personality disorder (86-115).

https://www.wikidoc.org/index.php/MCMI

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wikidoc

MCPA

MCPA MCPA (2-methyl-4-chlorophenoxy-acetic acid, IUPAC (4-chloro-2-methylphenoxy)acetic acid, C9H9ClO3) is a powerful and selective phenoxy herbicide. The pure compound is brown-colored powder. # History Synthesis of MCPA was first reported by Synerholme and Zimmerman in 1945 and by Templeman and Foster in 1946. Templeman and Foster were searching for a compounds with similar or greater selective activity than à-napthylacetic acid in inhibiting the growth of weeds while not adversely affecting the growth of cereal grains. They synthesized MCPA from the corresponding phenol by exposing it to chloroacetic acid and dilute base in a straightforward substitution reaction. # Chemical use Because it is inexpensive MCPA is used in various chemical applications. Its carboxylic acid group allows the formation of conjugated complexes with metals (see below). The acid functionality makes MCPA a versatile synthetic intermediate for more complex derivatives. # Commercial use MCPA is used as an herbicide, generally as its salt or esterified forms. Used thus, it controls broadleaf weeds, including thistle and dock, in cereal crops and pasture. It is selective for plants with broad leaves, and this includes most deciduous trees. Clovers are tolerant at moderate application levels. It is currently classified as a restricted use pesticide. Its toxicity and biodegradation are topics of current research. Though not extremely toxic, it has recently been determined that MCPA can form complexes with metal ions and thereby increase their bioavailability, though there is also work being done to utilize this ability. ## Brand names The following commercial products contain MCPA. - Agritox - Agroxone - Chiptox - Chwastox - Cornox - Methoxone - Rhonox - Tigrex - Verdone Extra (UK) - Weed-Rhap - Weed'n'Feed - Zero Bindii & Clover Weeder (Aus)

MCPA Template:Chembox new MCPA (2-methyl-4-chlorophenoxy-acetic acid, IUPAC (4-chloro-2-methylphenoxy)acetic acid, C9H9ClO3) is a powerful and selective phenoxy herbicide. The pure compound is brown-colored powder. # History Synthesis of MCPA was first reported by Synerholme and Zimmerman in 1945 and by Templeman and Foster in 1946.[1] Templeman and Foster were searching for a compounds with similar or greater selective activity than à-napthylacetic acid in inhibiting the growth of weeds while not adversely affecting the growth of cereal grains. They synthesized MCPA from the corresponding phenol by exposing it to chloroacetic acid and dilute base in a straightforward substitution reaction.[2] # Chemical use Because it is inexpensive MCPA is used in various chemical applications. Its carboxylic acid group allows the formation of conjugated complexes with metals (see below). The acid functionality makes MCPA a versatile synthetic intermediate for more complex derivatives.[3] # Commercial use MCPA is used as an herbicide, generally as its salt or esterified forms. Used thus, it controls broadleaf weeds, including thistle and dock, in cereal crops and pasture. It is selective for plants with broad leaves, and this includes most deciduous trees. Clovers are tolerant at moderate application levels. It is currently classified as a restricted use pesticide. Its toxicity and biodegradation are topics of current research. Though not extremely toxic[4], it has recently been determined that MCPA can form complexes with metal ions and thereby increase their bioavailability,[5] though there is also work being done to utilize this ability.[6] ## Brand names The following commercial products contain MCPA.[4] - Agritox - Agroxone - Chiptox - Chwastox - Cornox - Methoxone - Rhonox - Tigrex - Verdone Extra (UK) - Weed-Rhap - Weed'n'Feed[7] - Zero Bindii & Clover Weeder (Aus)

https://www.wikidoc.org/index.php/MCPA

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wikidoc

MDA5

MDA5 MDA5 (Melanoma Differentiation-Associated protein 5) is a RIG-I-like receptor dsRNA helicase enzyme that in humans is encoded by the IFIH1 gene. MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2, and functions as a pattern recognition receptor (recognizing dsRNA) that is a sensor for viruses. MDA5 typically recognizes dsRNA that is over 2000nts in length. For many viruses, effective MDA5-mediated antiviral responses are dependent on functionally active LGP2. The signaling cascades in MDA5 is initiated via CARD domain. # Function DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein that is upregulated in response to treatment with beta-interferon (IFNB) and a protein kinase C-activating compound, mezerein (MEZ). Irreversible reprogramming of melanomas can be achieved by treatment with both these agents; treatment with either agent alone only achieves reversible differentiation. # Clinical significance Mutations in IFIH1/MDA5 are associated to Singleton-Merten Syndrome and to Aicardi–Goutières syndrome. Antibodies against MDA5 are associated to amyopathic dermatomyositis with rapidly progressive interstitial lung disease.

MDA5 MDA5 (Melanoma Differentiation-Associated protein 5) is a RIG-I-like receptor dsRNA helicase enzyme that in humans is encoded by the IFIH1 gene.[1] MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2, and functions as a pattern recognition receptor (recognizing dsRNA) that is a sensor for viruses. MDA5 typically recognizes dsRNA that is over 2000nts in length.[2] For many viruses, effective MDA5-mediated antiviral responses are dependent on functionally active LGP2.[3] The signaling cascades in MDA5 is initiated via CARD domain.[4] # Function DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein that is upregulated in response to treatment with beta-interferon (IFNB) and a protein kinase C-activating compound, mezerein (MEZ). Irreversible reprogramming of melanomas can be achieved by treatment with both these agents; treatment with either agent alone only achieves reversible differentiation.[1] # Clinical significance Mutations in IFIH1/MDA5 are associated to Singleton-Merten Syndrome [5] and to Aicardi–Goutières syndrome. Antibodies against MDA5 are associated to amyopathic dermatomyositis with rapidly progressive interstitial lung disease.

https://www.wikidoc.org/index.php/MDA5

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wikidoc

MDC1

MDC1 Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the MDC1 gene located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle checkpoints and recruits repair proteins to the site of DNA damage. It is involved in determining cell survival fate in association with tumor suppressor protein p53. This protein also goes by the name Nuclear Factor with BRCT Domain 1 (NFBD1). # Function ## Role in DNA damage response The MDC1 gene encodes the MDC1 nuclear protein which is part of the DNA damage response (DDR) pathway, the mechanism through which eukaryotic cells respond to damaged DNA, specifically DNA double-strand breaks (DSB) that are caused by ionizing radiation or chemical clastogens. The DDR of mammalian cells is made up of kinases, and mediator/adaptors factors. In mammalian cells the DRR is a network of pathways made up of proteins that function as either kinases, or and mediator/adaptors that recruit the kinases to their phosphorylation targets, these factors work together to detect DNA damage, and signal the repair mechanism as well as activating cell cycle checkpoints. The MDC1s role in DDR is to function both as a mediator/adaptor protein mediating a complex of other DDR proteins at the site of DNA damage and repairing DNA damage through its PST domain. When a cell is exposed to ionizing radiation, its chromatin can be damaged with DSB, triggering the DDR which starts with the MRN complex recruiting ATM kinase to the exposed H2AX histones on the damaged DNA. ATM phosphorylates the C-terminus of the H2AX histone (phosphorylated H2AX histones are commonly noted as γH2AX), and they become an epigenetic flag that highlights the site of DNA damage . The SDT domain of the MDC1 protein is phosphorylated by caseine kinase 2 (CK2) which allows it to bind another MRN complex, the MDC1 protein can sense the DNA damage by binding to the γH2AX flag through its BRCT domain and brings the bound MRN complex to the site of damaged DNA and it facilitates the recruitment and retention of another ATM kinase. The second ATM kinase phosphorylates the TQXF domain on MDC1 which allows it to recruit the E3 ubiquitin ligase RNF8, which will ubiquitinate the histones near the DSB which initiates further ubiquitination of the chromatin around the site of damage by other factors of the DDR. This aggregation of DDR factors and concentration of phosphorylated and ubiquitinated histones is called a DNA damage foci or ionizing radiation-induced foci and the main role of MDC1 is to coordinate the creation of DNA damage foci. This protein is required to activate the intra-S phase and G2/M phase cell cycle checkpoints in response to DNA damage. ## Role in apoptosis MDC1 has anti-apoptotic properties by directly inhibiting the apoptotic activity of the tumor suppressing protein p53. DNA damage can induce apoptosis when the ATM kinase and Chk2 phosphorylate p53 on its Ser-15 and Ser-20 residues which activates p53 and stabilizes it by allowing it to dissociate from the E3 ubiquitin protein ligase MDM2. MDC1 can execute its anti-apoptotic activity by inhibiting p53 in two ways. The MDC1 protein can bind to the n-terminus of p53 through its BRC1 domain which blocks p53 transactivation domain. MDC1 can also inactivate p53 by reducing the phosphorylation levels of p53 Ser-15 residues necessary to p53 apoptotic activity. Studies on lung cancer cell lines (A549 cells) showed an increase in apoptosis in response to genotoxic agents when MDC1 protein levels were reduced with siRNA. ## Loss of MDC1 protein Inhibition or loss of MDC1 protein through studies with siRNA on human cells or knockout studies in mice have shown several defects at both the cellular and organismal level. Mice lacking MDC1 are smaller, have infertile males, are radiosensitive, and are more susceptible to tumors. Knock out MDC1 mice cells and silenced human cells were radiosensitive, failed to initiate Intra-S phase and G2/M checkpoints, failed to produce ionizing radiation-induced foci had poor phosphorylation by the DRR kinases (ATM, CHK1, CHK2), defects in homologous recombination. Human cells with silenced MDC1 also displayed random plasmid integration, reduced apoptosis, and slowed mitosis. # Interactions MDC1 has been shown to interact with: - APC/C, - ATM, - CHEK2, - γH2AX, - H2AFX, - MRE11A, - NBS1, - RAD51, - RNF8, - TOPOα, - p53, and - MDM2 MDC1 also binds to mRNA or polyadenylated RNA in the nucleus. # Protein structure The MDC1 protein contains the following domains listed in order from N-terminal to C-terminal: - forkhead-associated domain (FHA), N-terminus domain lies between amino acid residues 54 and 105 - SDT (or SDTD) - This domain is located between amino acids 218 and 460. - TQXF- This domain is located between amino acids 699 and 768. - PST- This domain lies between amino acid residues 114 and 1662. - BRCA 1 C-terminus (BRCT) domain and lies between amino acids 1891 and 2082. # Regulation MDC1 is indirectly down regulated by the oncogene AKT1. AKT1 activates expression of the microRNA-22 (miR-22) which targets the 3’ end of MDC1 mRNA inhibiting translation. Aberrant overexpression of AKT1, which is observed in several cancers including breast, lung and prostate, results in reduced production of MDC1 and subsequently a destabilization of the genome and increased tumorigenicity. # Role in cancer MDC1 is a putative tumor suppressor. Knockout studies in mice have shown an increase in tumor development when MDC1 is lost. Reduction in MDC1 protein levels has been observed in a large number of breast and lung carcinomas. Several studies on various human cancer cell lines including the A549 cell human lung carcinoma line, multiple esophageal cancer cell lines (TE11, YES2 ,YES5), and cervical cancer cell lines (HeLa, SiHa, and CaSki) showed increased sensitivity to anti-cancer drugs (adriamycin and cisplatin), when endogenous MDC1 protein levels were knockdown with siRNA. Because of MDC1s involvement in several pathways that are often misappropriated by cancer cells including the cell cycle checkpoints, DDR, and p53 tumor suppression, cancer treatments that target MDC1 have the potential to be potent radiosensitizer and chemosensitizer.

MDC1 Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the MDC1 gene[1][2][3] located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle checkpoints and recruits repair proteins to the site of DNA damage. It is involved in determining cell survival fate in association with tumor suppressor protein p53. This protein also goes by the name Nuclear Factor with BRCT Domain 1 (NFBD1). # Function ## Role in DNA damage response The MDC1 gene encodes the MDC1 nuclear protein which is part of the DNA damage response (DDR) pathway, the mechanism through which eukaryotic cells respond to damaged DNA, specifically DNA double-strand breaks (DSB) that are caused by ionizing radiation or chemical clastogens.[4] The DDR of mammalian cells is made up of kinases, and mediator/adaptors factors.[5] In mammalian cells the DRR is a network of pathways made up of proteins that function as either kinases, or and mediator/adaptors that recruit the kinases to their phosphorylation targets, these factors work together to detect DNA damage, and signal the repair mechanism as well as activating cell cycle checkpoints.[5] The MDC1s role in DDR is to function both as a mediator/adaptor protein mediating a complex of other DDR proteins at the site of DNA damage[5] and repairing DNA damage through its PST domain.[6] When a cell is exposed to ionizing radiation, its chromatin can be damaged with DSB, triggering the DDR which starts with the MRN complex recruiting ATM kinase to the exposed H2AX histones on the damaged DNA. ATM phosphorylates the C-terminus of the H2AX histone (phosphorylated H2AX histones are commonly noted as γH2AX), and they become an epigenetic flag that highlights the site of DNA damage . The SDT domain of the MDC1 protein is phosphorylated by caseine kinase 2 (CK2) which allows it to bind another MRN complex, the MDC1 protein can sense the DNA damage by binding to the γH2AX flag through its BRCT domain and brings the bound MRN complex to the site of damaged DNA and it facilitates the recruitment and retention of another ATM kinase. The second ATM kinase phosphorylates the TQXF domain on MDC1 which allows it to recruit the E3 ubiquitin ligase RNF8, which will ubiquitinate the histones near the DSB which initiates further ubiquitination of the chromatin around the site of damage by other factors of the DDR. This aggregation of DDR factors and concentration of phosphorylated and ubiquitinated histones is called a DNA damage foci or ionizing radiation-induced foci[5] and the main role of MDC1 is to coordinate the creation of DNA damage foci. This protein is required to activate the intra-S phase and G2/M phase cell cycle checkpoints in response to DNA damage. ## Role in apoptosis MDC1 has anti-apoptotic properties by directly inhibiting the apoptotic activity of the tumor suppressing protein p53. DNA damage can induce apoptosis when the ATM kinase and Chk2 phosphorylate p53 on its Ser-15 and Ser-20 residues which activates p53 and stabilizes it by allowing it to dissociate from the E3 ubiquitin protein ligase MDM2.[7] MDC1 can execute its anti-apoptotic activity by inhibiting p53 in two ways. The MDC1 protein can bind to the n-terminus of p53 through its BRC1 domain which blocks p53 transactivation domain. MDC1 can also inactivate p53 by reducing the phosphorylation levels of p53 Ser-15 residues necessary to p53 apoptotic activity. Studies on lung cancer cell lines (A549 cells) showed an increase in apoptosis in response to genotoxic agents when MDC1 protein levels were reduced with siRNA.[7] ## Loss of MDC1 protein Inhibition or loss of MDC1 protein through studies with siRNA on human cells or knockout studies in mice have shown several defects at both the cellular and organismal level. Mice lacking MDC1 are smaller, have infertile males, are radiosensitive, and are more susceptible to tumors. Knock out MDC1 mice cells and silenced human cells were radiosensitive, failed to initiate Intra-S phase and G2/M checkpoints, failed to produce ionizing radiation-induced foci had poor phosphorylation by the DRR kinases (ATM, CHK1, CHK2), defects in homologous recombination. Human cells with silenced MDC1 also displayed random plasmid integration, reduced apoptosis, and slowed mitosis.[5] # Interactions MDC1 has been shown to interact with: - APC/C, - ATM, - CHEK2,[8] - γH2AX, - H2AFX,[2][9] - MRE11A,[9] - NBS1, - RAD51, - RNF8, - TOPOα, - p53, and - MDM2 MDC1 also binds to mRNA or polyadenylated RNA in the nucleus.[10] # Protein structure The MDC1 protein contains the following domains listed in order from N-terminal to C-terminal: - forkhead-associated domain (FHA), N-terminus domain lies between amino acid residues 54 and 105 - SDT (or SDTD) - This domain is located between amino acids 218 and 460. - TQXF- This domain is located between amino acids 699 and 768. - PST- This domain lies between amino acid residues 114 and 1662. - BRCA 1 C-terminus (BRCT) domain and lies between amino acids 1891 and 2082. # Regulation MDC1 is indirectly down regulated by the oncogene AKT1. AKT1 activates expression of the microRNA-22 (miR-22) which targets the 3’ end of MDC1 mRNA inhibiting translation. Aberrant overexpression of AKT1, which is observed in several cancers including breast, lung and prostate, results in reduced production of MDC1 and subsequently a destabilization of the genome and increased tumorigenicity.[18] # Role in cancer MDC1 is a putative tumor suppressor. Knockout studies in mice have shown an increase in tumor development when MDC1 is lost. Reduction in MDC1 protein levels has been observed in a large number of breast and lung carcinomas.[19][20] Several studies on various human cancer cell lines including the A549 cell human lung carcinoma line,[7] multiple esophageal cancer cell lines (TE11, YES2 ,YES5),[21] and cervical cancer cell lines (HeLa, SiHa, and CaSki)[22] showed increased sensitivity to anti-cancer drugs (adriamycin and cisplatin), when endogenous MDC1 protein levels were knockdown with siRNA. Because of MDC1s involvement in several pathways that are often misappropriated by cancer cells including the cell cycle checkpoints, DDR, and p53 tumor suppression, cancer treatments that target MDC1 have the potential to be potent radiosensitizer and chemosensitizer.

https://www.wikidoc.org/index.php/MDC1

e5d9938f7f4bcd97d5146c8d368865162a19269f

wikidoc

MDH1

MDH1 Malate dehydrogenase, cytoplasmic also known as malate dehydrogenase 1 is an enzyme that in humans is encoded by the MDH1 gene. # Function Malate dehydrogenase catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. The protein encoded by this gene is localized to the cytoplasm and may play pivotal roles in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria and clitera. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. # Regulation The acetylation of MDH1 activates its enzymatic activity and enhance intracellular levels of NADPH, which promotes adipogenic differentiation. Methylation on arginine 248 (R248) negatively regulates MDH1. Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates and inhibits MDH1 by disrupting its dimerization. Arginine methylation of MDH1 represses mitochondria respiration and inhibits glutamine utilization. CARM1-mediated MDH1 methylation reduces cellular NADPH level and sensitizes cells to oxidative stress. Besides, MDH1 methylation suppresses cell growth and clonogenic activity. R248 of MDH1 is hypomethylated in pancreatic ductal adenocarcinoma. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

MDH1 Malate dehydrogenase, cytoplasmic also known as malate dehydrogenase 1 is an enzyme that in humans is encoded by the MDH1 gene.[1] # Function Malate dehydrogenase catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. The protein encoded by this gene is localized to the cytoplasm and may play pivotal roles in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria and clitera. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[1] # Regulation The acetylation of MDH1 activates its enzymatic activity and enhance intracellular levels of NADPH, which promotes adipogenic differentiation.[2] Methylation on arginine 248 (R248) negatively regulates MDH1. Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates and inhibits MDH1 by disrupting its dimerization. Arginine methylation of MDH1 represses mitochondria respiration and inhibits glutamine utilization. CARM1-mediated MDH1 methylation reduces cellular NADPH level and sensitizes cells to oxidative stress. Besides, MDH1 methylation suppresses cell growth and clonogenic activity. R248 of MDH1 is hypomethylated in pancreatic ductal adenocarcinoma.[3] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/MDH1

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wikidoc

MDM4

MDM4 Protein Mdm4 is a protein that in humans is encoded by the MDM4 gene. # Function The human MDM4 gene, which plays a role in apoptosis, encodes a 490-amino acid protein containing a RING finger domain and a putative nuclear localization signal. The MDM4 putative nuclear localization signal, which all Mdm proteins contain, is located in the C-terminal region of the protein. The mRNA is expressed at a high level in thymus and at lower levels in all other tissues tested. MDM4 protein produced by in vitro translation interacts with p53 via a binding domain located in the N-terminal region of the MDM4 protein. MDM4 shows significant structural similarity to p53-binding protein MDM2 # Interactions MDM4 has been shown to interact with E2F1, Mdm2 and P53.

MDM4 Protein Mdm4 is a protein that in humans is encoded by the MDM4 gene.[1][2] # Function The human MDM4 gene, which plays a role in apoptosis, encodes a 490-amino acid protein containing a RING finger domain and a putative nuclear localization signal. The MDM4 putative nuclear localization signal, which all Mdm proteins contain, is located in the C-terminal region of the protein. The mRNA is expressed at a high level in thymus and at lower levels in all other tissues tested. MDM4 protein produced by in vitro translation interacts with p53 via a binding domain located in the N-terminal region of the MDM4 protein. MDM4 shows significant structural similarity to p53-binding protein MDM2[2] # Interactions MDM4 has been shown to interact with E2F1,[3] Mdm2[4][5][6][7] and P53.[1][6]

https://www.wikidoc.org/index.php/MDM4

fac00be98c1232abed7171ba3f6cb8055db12856

wikidoc

MDN1

MDN1 MDN1, midasin homolog (yeast) is a protein that in humans is encoded by the MDN1 gene. # Model organisms Model organisms have been used in the study of MDN1 function. A conditional knockout mouse line, called Mdn1tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; females had an increased susceptibility to bacterial infection.

MDN1 MDN1, midasin homolog (yeast) is a protein that in humans is encoded by the MDN1 gene.[1] # Model organisms Model organisms have been used in the study of MDN1 function. A conditional knockout mouse line, called Mdn1tm1a(KOMP)Wtsi[6][7] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[8][9][10] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty four tests were carried out on mutant mice and three significant abnormalities were observed.[4] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; females had an increased susceptibility to bacterial infection.[4]

https://www.wikidoc.org/index.php/MDN1

23dab689a18f993fe2bfb14b1d60c69d0ed70139

wikidoc

MDPV

MDPV # Overview Methylenedioxypyrovalerone, also known as MDPK or 1-(3,4-methylenedioxyphenyl)-2-pyrrolidinyl-pentan-1-one, is a stimulant drug which acts as a norepinephrine and dopamine reuptake inhibitor, reportedly with four times the potency of methylphenidate. This compound is reported to be used as a stimulant and an aphrodisiac. It has no history of medical use but has been sold as a "research chemical" (a.k.a. designer drug) for recreational use. # Appearance and effects The substance appears as an off-white to light-brown crumbly powder that is significantly hydrophilic, at least as has been available from the few online sellers who offered it. It appears to darken slightly in colour and take on a potato-tuber-like odor if exposed to air for any significant length of time. Early on, an impurity was identified and said to consist of pyrrolidine, and that could account for its earthy odour when left uncapped. It has also been observed to rapidly degrade and lose potency when in solution. Subjective effects include CNS stimulation, euphoria, hypersexuality, agitation/anxiety and insomnia, with a duration of three to six hours. High doses have been observed to cause intense, prolonged anxiety attacks in stimulant-intolerant users, and there are anecdotal reports of addiction at higher doses or more frequent dosing intervals. MDPV has been remarked about more than once for its powers as an aphrodisiac, which have been said to rival those of methamphetamine when dosed correctly . However, it is apparently not as powerful as meth as far as general effects go, and may be safer (there have been no reports of death or disability as a result of abuse posted on "research chemical" related internet forums, and these tend to surface rapidly when a substance poses immediate dangers). MDPV is the 3,4-methylenedioxy ring-substituted analogue of the appetite suppressant pyrovalerone, however despite its apparent structural similarity to the untrained eye, the effects of MDPV bear little resemblance to other methylenedioxyphenylalkylamine derivatives such as MDMA and methylone, instead producing purely stimulant effects with no empathogenic qualities. Extended binges on MDPV have also been reported to produce severe come-down syndrome similar to that of methamphetamine and characterised by depression, lethargy and headache. # Legality MDPV is not specifically listed as an illegal drug in any country, but its structural similarity to illegal drugs of abuse makes it likely that it would be considered a controlled substance analogue in several countries such as the USA, Australia and New Zealand. Other analogues derived from alpha-pyrrolidinopropiophenone include the 4-methyl analogue pyrovalerone, as well as analogues with no substitution on the aromatic ring, and analogues with between 3 and 6 carbons on the alkyl chain. These compounds have been reported as stimulants of abuse mainly in Germany and other european countries since the early 2000s, but they have remained little known and rarely used or encountered by law enforcement. MDPV was never sold online in large quantities, and as of October, 2007 has become virtually unobtainable.

MDPV # Overview Methylenedioxypyrovalerone, also known as MDPK or 1-(3,4-methylenedioxyphenyl)-2-pyrrolidinyl-pentan-1-one, is a stimulant drug which acts as a norepinephrine and dopamine reuptake inhibitor, reportedly with four times the potency of methylphenidate. [1] This compound is reported to be used as a stimulant and an aphrodisiac. It has no history of medical use but has been sold as a "research chemical" (a.k.a. designer drug) for recreational use. # Appearance and effects The substance appears as an off-white to light-brown crumbly powder that is significantly hydrophilic, at least as has been available from the few online sellers who offered it. It appears to darken slightly in colour and take on a potato-tuber-like odor if exposed to air for any significant length of time.[2] Early on, an impurity was identified and said to consist of pyrrolidine, and that could account for its earthy odour when left uncapped. It has also been observed to rapidly degrade and lose potency when in solution. Subjective effects include CNS stimulation, euphoria, hypersexuality, agitation/anxiety and insomnia, with a duration of three to six hours. High doses have been observed to cause intense, prolonged anxiety attacks in stimulant-intolerant users, and there are anecdotal reports of addiction at higher doses or more frequent dosing intervals. MDPV has been remarked about more than once for its powers as an aphrodisiac, which have been said to rival those of methamphetamine when dosed correctly [3]. However, it is apparently not as powerful as meth as far as general effects go, and may be safer (there have been no reports of death or disability as a result of abuse posted on "research chemical" related internet forums, and these tend to surface rapidly when a substance poses immediate dangers). MDPV is the 3,4-methylenedioxy ring-substituted analogue of the appetite suppressant pyrovalerone, however despite its apparent structural similarity to the untrained eye, the effects of MDPV bear little resemblance to other methylenedioxyphenylalkylamine derivatives such as MDMA and methylone, instead producing purely stimulant effects with no empathogenic qualities. Extended binges on MDPV have also been reported to produce severe come-down syndrome similar to that of methamphetamine and characterised by depression, lethargy and headache. [4] [5] [6] # Legality MDPV is not specifically listed as an illegal drug in any country, but its structural similarity to illegal drugs of abuse makes it likely that it would be considered a controlled substance analogue in several countries such as the USA, Australia and New Zealand. Other analogues derived from alpha-pyrrolidinopropiophenone include the 4-methyl analogue pyrovalerone, as well as analogues with no substitution on the aromatic ring, and analogues with between 3 and 6 carbons on the alkyl chain. [7] These compounds have been reported as stimulants of abuse mainly in Germany and other european countries since the early 2000s, but they have remained little known and rarely used or encountered by law enforcement. [8] MDPV was never sold online in large quantities, and as of October, 2007 has become virtually unobtainable. [9]

https://www.wikidoc.org/index.php/MDPV

4b2619bb66e9f8da8473f70d942794859c2e600e

wikidoc

MECR

MECR Trans-2-enoyl-CoA reductase, mitochondrial is an enzyme that in humans is encoded by the MECR gene. # Structure The MECR gene is located on the 1st chromosome, with its specific location being 1p35.3. The gene contains 15 exons. MECR encodes a 21.2 kDa protein that is composed of 189 amino acids; 10 peptides have been observed through mass spectrometry data. # Function mtFAS is a co-factor for several mitochondrial enzymes that synthesize lipoic acid that is essential for aerobic metabolism. A Purkinje cell specific knock out of the Mecr gene in mice leads to neurodegeneration. # Clinical significance Genetic mutations to MECR have been suggested to cause MEPAN Syndrome, a neurometabolic disorder in humans that involves disruptions in the pathway involved in mitochondrial fatty acid synthesis (mtFAS). MEPAN patients were found to harbor recessive mutations in MECR, and typically present with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI.

MECR Trans-2-enoyl-CoA reductase, mitochondrial is an enzyme that in humans is encoded by the MECR gene.[1][2][3] # Structure The MECR gene is located on the 1st chromosome, with its specific location being 1p35.3.[3] The gene contains 15 exons.[3] MECR encodes a 21.2 kDa protein that is composed of 189 amino acids; 10 peptides have been observed through mass spectrometry data.[4][5] # Function mtFAS is a co-factor for several mitochondrial enzymes that synthesize lipoic acid that is essential for aerobic metabolism.[6] A Purkinje cell specific knock out of the Mecr gene in mice leads to neurodegeneration.[7] # Clinical significance Genetic mutations to MECR have been suggested to cause MEPAN Syndrome, a neurometabolic disorder in humans that involves disruptions in the pathway involved in mitochondrial fatty acid synthesis (mtFAS). MEPAN patients were found to harbor recessive mutations in MECR, and typically present with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI.[8]

https://www.wikidoc.org/index.php/MECR

5086d64725e493625fe993eda3e9a8a1e2a2cc21

wikidoc

MED1

MED1 Mediator of RNA polymerase II transcription subunit 1 also known as DRIP205 or Trap220 is a subunit of the Mediator complex and is a protein that in humans is encoded by the MED1 gene. MED1 functions as a nuclear receptor coactivator. # Function The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The mediator of RNA polymerase II transcription subunit 1 protein is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes . It also regulates p53-dependent apoptosis and it is essential for adipogenesis. This protein is known to have the ability to self-oligomerize. # Interactions MED1 has been shown to interact with: - Androgen receptor, - BRCA1, - Calcitriol receptor, - Cyclin-dependent kinase 8, - Estrogen receptor alpha, - Glucocorticoid receptor, - Hepatocyte nuclear factor 4 alpha, - P53, - PPARGC1A, - PPARG, - TGS1, and - Thyroid hormone receptor alpha. # Protein family This entry represents subunit Med1 of the Mediator complex. The Med1 forms part of the Med9 submodule of the Srb/Med complex. It is one of three subunits essential for viability of the whole organism via its role in environmentally-directed cell-fate decisions.

MED1 Mediator of RNA polymerase II transcription subunit 1 also known as DRIP205 or Trap220 is a subunit of the Mediator complex and is a protein that in humans is encoded by the MED1 gene.[1][2][3] MED1 functions as a nuclear receptor coactivator. # Function The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The mediator of RNA polymerase II transcription subunit 1 protein is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes [e.g., thyroid hormone receptor-(TR-) associated proteins that interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors]. It also regulates p53-dependent apoptosis and it is essential for adipogenesis. This protein is known to have the ability to self-oligomerize.[3] # Interactions MED1 has been shown to interact with: - Androgen receptor,[4] - BRCA1,[5] - Calcitriol receptor,[6][7] - Cyclin-dependent kinase 8,[6][8] - Estrogen receptor alpha,[7][8] - Glucocorticoid receptor,[9][10] - Hepatocyte nuclear factor 4 alpha,[11][12] - P53,[13][14] - PPARGC1A,[15] - PPARG,[16] - TGS1,[17] and - Thyroid hormone receptor alpha.[18] # Protein family This entry represents subunit Med1 of the Mediator complex. The Med1 forms part of the Med9 submodule of the Srb/Med complex. It is one of three subunits essential for viability of the whole organism via its role in environmentally-directed cell-fate decisions.[19]

https://www.wikidoc.org/index.php/MED1

d98a1f688cfcc8738d85b1042f7a0baa1d203835

wikidoc

MEFV

MEFV MEFV (Mediterranean fever) is a human gene that provides instructions for making a protein called pyrin (also known as marenostrin). Pyrin is produced in certain white blood cells (neutrophils, eosinophils and monocytes) that play a role in inflammation and in fighting infection. Inside these white blood cells, pyrin is found with the cytoskeleton, the structural framework that helps to define the shape, size, and movement of a cell. Pyrin's protein structure also allows it to interact with other molecules involved in fighting infection and in the inflammatory response. Although pyrin's function is not fully understood, it likely assists in keeping the inflammation process under control. Research indicates that pyrin helps regulate inflammation by interacting with the cytoskeleton. Pyrin may direct the migration of white blood cells to sites of inflammation and stop or slow the inflammatory response when it is no longer needed. The MEFV gene is located on the short (p) arm of chromosome 16 at position 13.3, from base pair 3,292,027 to 3,306,626. # Related conditions More than 80 MEFV mutations that cause familial Mediterranean fever have been identified. A few mutations delete small amounts of DNA from the MEFV gene, which can lead to an abnormally small protein. Most MEFV mutations, however, change one of the protein building blocks (amino acids) used to make pyrin. The most common mutation replaces the amino acid methionine with the amino acid valine at protein position 694 (written as Met694Val or M694V). Among people with familial Mediterranean fever, this particular mutation is also associated with an increased risk of developing amyloidosis, a complication in which abnormal protein deposits can lead to kidney failure. Some evidence suggests that another gene, called SAA1, can further modify the risk of developing amyloidosis among people with the M694V mutation. MEFV mutations lead to reduced amounts of pyrin or a malformed pyrin protein that cannot function properly. As a result, pyrin cannot perform its presumed role in controlling inflammation, leading to an inappropriate or prolonged inflammatory response. Fever and inflammation in the abdomen, chest, joints, or skin are signs of familial Mediterranean fever.

MEFV MEFV (Mediterranean fever) is a human gene that provides instructions for making a protein called pyrin (also known as marenostrin). Pyrin is produced in certain white blood cells (neutrophils, eosinophils and monocytes) that play a role in inflammation and in fighting infection. Inside these white blood cells, pyrin is found with the cytoskeleton, the structural framework that helps to define the shape, size, and movement of a cell. Pyrin's protein structure also allows it to interact with other molecules involved in fighting infection and in the inflammatory response. Although pyrin's function is not fully understood, it likely assists in keeping the inflammation process under control. Research indicates that pyrin helps regulate inflammation by interacting with the cytoskeleton. Pyrin may direct the migration of white blood cells to sites of inflammation and stop or slow the inflammatory response when it is no longer needed. The MEFV gene is located on the short (p) arm of chromosome 16 at position 13.3, from base pair 3,292,027 to 3,306,626.[1] # Related conditions More than 80 MEFV mutations that cause familial Mediterranean fever have been identified. A few mutations delete small amounts of DNA from the MEFV gene, which can lead to an abnormally small protein. Most MEFV mutations, however, change one of the protein building blocks (amino acids) used to make pyrin. The most common mutation replaces the amino acid methionine with the amino acid valine at protein position 694 (written as Met694Val or M694V). Among people with familial Mediterranean fever, this particular mutation is also associated with an increased risk of developing amyloidosis, a complication in which abnormal protein deposits can lead to kidney failure. Some evidence suggests that another gene, called SAA1, can further modify the risk of developing amyloidosis among people with the M694V mutation. MEFV mutations lead to reduced amounts of pyrin or a malformed pyrin protein that cannot function properly. As a result, pyrin cannot perform its presumed role in controlling inflammation, leading to an inappropriate or prolonged inflammatory response. Fever and inflammation in the abdomen, chest, joints, or skin are signs of familial Mediterranean fever.

https://www.wikidoc.org/index.php/MEFV

4dd053e0f2448ae279fccd76caa00676b8fe8905

wikidoc

MEN1

MEN1 Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 (MEN-1 syndrome). In vitro studies have shown that menin is localized to the nucleus, possesses two functional nuclear localization signals, and inhibits transcriptional activation by JunD. However, the function of this protein is not known. Two messages have been detected on northern blots but the larger message has not been characterized. Two variants of the shorter transcript have been identified where alternative splicing affects the coding sequence. Five variants where alternative splicing takes place in the 5' UTR have also been identified. # History In 1988, researchers at Uppsala University Hospital and the Karolinska Institute in Stockholm mapped the MEN1 gene to the long arm of chromosome 11. The gene was finally cloned in 1997. # Genomics The gene is located on long arm of chromosome 11 (11q13) between base pairs 64,570,985 and 64,578,765. It has 10 exons and encodes a 610-amino acid protein. Over 1300 mutations have been reported to date (2010). The majority (>70%) of these are predicted to lead to truncated forms are scattered throughout the gene. Four - c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210-211) have been reported to occur in 4.5%, 2.7%, 2.6% and 2.5% of families. # Clinical implications The MEN1 phenotype is inherited via an autosomal-dominant pattern and is associated with neoplasms of the pituitary gland, the parathyroid gland, and the pancreas (the 3 "P"s). While these neoplasias are often benign (in contrast to tumours occurring in MEN2A), they are adenomas and, therefore, produce endocrine phenotypes. Pancreatic presentations of the MEN1 phenotype may manifest as Zollinger-Ellison syndrome. MEN1 pituitary tumours are adenomas of anterior cells, typically prolactinomas or growth hormone-secreting. Pancreatic tumours involve the islet cells, giving rise to gastrinomas or insulinomas. In rare cases, adrenal cortex tumours are also seen. # Role in cancer Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin resulting in the inability of MEN1 to act as a tumor suppressor gene. Such mutations in MEN1 have been associated with defective binding of encoded menin to proteins implicated in genetic and epigenetic mechanisms. Menin is a 621 amino acid protein associated with insulinomas which acts as an adapter while also interacting with partner proteins involved in vital cell activities such as transcriptional regulation, cell division, cell proliferation, and genome stability. Insulinomas are neuroendocrine tumors of the pancreas with an incidence of 0.4 % which usually are benign solitary tumors but 5-12 % of cases have distant metastasis at diagnosis. These familial MEN-1 and sporadic tumors may arise either due to loss of heterozygosity or the chromosome region 11q13 where MEN1 is located, or due to presence of mutations in the gene. MEN1 mutations comprise mostly frameshift deletions or insertions, followed by nonsense, missense, splice-site mutations and either part or complete gene deletions resulting in disease pathology. Frameshift and nonsense mutations result in a supposed inactive and truncated menin protein while splice-site mutations result in incorrectly spliced mRNA. Missense mutations of MEN1 are especially important as they result in a change to crucial amino acids needed in order to bind and interact with other proteins and molecules. As menin is located predominantly in the nucleus, these mutations can impact the stability of the cell and may further affect functional activity or expression levels of the protein. Studies have also shown that single amino acid changes in genes involved in oncogenic disorders may result in proteolytic degradation leading to loss of function and reduced stability of the mutant protein; a common mechanism for inactivating tumor suppressor gene products. MEN1 gene mutations and deletions also play a role in the development of hereditary and a subgroup of sporadic pituitary adenomas and were detected in approximately 5% of sporadic pituitary adenomas. Consequently, alterations of the gene represent a candidate pathogenetic mechanism of pituitary tumorigenesis especially when considered in terms of interactions with other proteins, growth factors, oncogenes play a rule in tumorigenesis. Although the exact function of MEN1 is not known, the Knudson "two-hit" hypothesis provides strong evidence that it is a tumor suppressor gene. Familial loss of one copy of MEN1 is seen In association with MEN-1 syndrome. Tumor suppressor carcinogenesis follows Knudson's "two-hit" model. The first hit is a heterozygous MEN1 germline mutation either developed in an early embryonic stage and consequently present in all cells at birth for the sporadic cases, or inherited from one parent in a familial case. The second hit is a MEN1 somatic mutation, oftentimes a large deletion occurring in the predisposed endocrine cell and providing cells with the survival advantaged needed for tumor development. The MEN-1 syndrome often exhibits tumors of parathyroid glands, anterior pituitary, endocrine pancreas, and endocrine duodenum. Less frequently, neuroendocrine tumors of lung, thymus, and stomach or non-endocrine tumors such as lipomas, angiofibromas, and ependymomas are observed neoplasms. In a study of 12 sporadic carcinoid tumors of the lung, five cases involved inactivation of both copies of the MEN1 gene. Of the five carcinoids, three were atypical and two were typical. The two typical carcinoids were characterized by a rapid proliferative rate with a higher mitotic index and stronger Ki67 positivity than the other typical carcinoids in the study. Consequently, the carcinoid tumors with MEN1 gene inactivation in the study were considered to be characterized by more aggressive molecular and histopathological features than those without MEN1 gene alterations. # Interactions MEN1 has been shown to interact with: - FANCD2, - GFAP, - JunD, - NFKB1, - MLL, - RPA2, and - VIM.

MEN1 Menin is a protein that in humans is encoded by the MEN1 gene.[1] Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 (MEN-1 syndrome).[2] In vitro studies have shown that menin is localized to the nucleus, possesses two functional nuclear localization signals, and inhibits transcriptional activation by JunD. However, the function of this protein is not known. Two messages have been detected on northern blots but the larger message has not been characterized. Two variants of the shorter transcript have been identified where alternative splicing affects the coding sequence. Five variants where alternative splicing takes place in the 5' UTR have also been identified.[1] # History In 1988, researchers at Uppsala University Hospital and the Karolinska Institute in Stockholm mapped the MEN1 gene to the long arm of chromosome 11.[3] The gene was finally cloned in 1997.[4] # Genomics The gene is located on long arm of chromosome 11 (11q13) between base pairs 64,570,985 and 64,578,765. It has 10 exons and encodes a 610-amino acid protein. Over 1300 mutations have been reported to date (2010). The majority (>70%) of these are predicted to lead to truncated forms are scattered throughout the gene. Four - c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210-211) have been reported to occur in 4.5%, 2.7%, 2.6% and 2.5% of families.[2] # Clinical implications The MEN1 phenotype is inherited via an autosomal-dominant pattern and is associated with neoplasms of the pituitary gland, the parathyroid gland, and the pancreas (the 3 "P"s). While these neoplasias are often benign (in contrast to tumours occurring in MEN2A), they are adenomas and, therefore, produce endocrine phenotypes. Pancreatic presentations of the MEN1 phenotype may manifest as Zollinger-Ellison syndrome. MEN1 pituitary tumours are adenomas of anterior cells, typically prolactinomas or growth hormone-secreting. Pancreatic tumours involve the islet cells, giving rise to gastrinomas or insulinomas. In rare cases, adrenal cortex tumours are also seen. # Role in cancer Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin resulting in the inability of MEN1 to act as a tumor suppressor gene.[5] Such mutations in MEN1 have been associated with defective binding of encoded menin to proteins implicated in genetic and epigenetic mechanisms.[6] Menin is a 621 amino acid protein associated with insulinomas[7] which acts as an adapter while also interacting with partner proteins involved in vital cell activities such as transcriptional regulation, cell division, cell proliferation, and genome stability. Insulinomas are neuroendocrine tumors of the pancreas with an incidence of 0.4 %[8] which usually are benign solitary tumors but 5-12 % of cases have distant metastasis at diagnosis.[9] These familial MEN-1 and sporadic tumors may arise either due to loss of heterozygosity or the chromosome region 11q13 where MEN1 is located, or due to presence of mutations in the gene.[10][11] MEN1 mutations comprise mostly frameshift deletions or insertions, followed by nonsense, missense, splice-site mutations and either part or complete gene deletions resulting in disease pathology.[12] Frameshift and nonsense mutations result in a supposed inactive and truncated menin protein while splice-site mutations result in incorrectly spliced mRNA. Missense mutations of MEN1 are especially important as they result in a change to crucial amino acids needed in order to bind and interact with other proteins and molecules. As menin is located predominantly in the nucleus,[13] these mutations can impact the stability of the cell and may further affect functional activity or expression levels of the protein. Studies have also shown that single amino acid changes in genes involved in oncogenic disorders may result in proteolytic degradation leading to loss of function and reduced stability of the mutant protein; a common mechanism for inactivating tumor suppressor gene products.[14][15] MEN1 gene mutations and deletions also play a role in the development of hereditary and a subgroup of sporadic pituitary adenomas and were detected in approximately 5% of sporadic pituitary adenomas.[16] Consequently, alterations of the gene represent a candidate pathogenetic mechanism of pituitary tumorigenesis especially when considered in terms of interactions with other proteins, growth factors, oncogenes play a rule in tumorigenesis. Although the exact function of MEN1 is not known, the Knudson "two-hit" hypothesis provides strong evidence that it is a tumor suppressor gene. Familial loss of one copy of MEN1 is seen In association with MEN-1 syndrome. Tumor suppressor carcinogenesis follows Knudson's "two-hit" model.[17] The first hit is a heterozygous MEN1 germline mutation either developed in an early embryonic stage and consequently present in all cells at birth for the sporadic cases, or inherited from one parent in a familial case. The second hit is a MEN1 somatic mutation, oftentimes a large deletion occurring in the predisposed endocrine cell and providing cells with the survival advantaged needed for tumor development.[18] The MEN-1 syndrome often exhibits tumors of parathyroid glands, anterior pituitary, endocrine pancreas, and endocrine duodenum. Less frequently, neuroendocrine tumors of lung, thymus, and stomach or non-endocrine tumors such as lipomas, angiofibromas, and ependymomas are observed neoplasms.[19] In a study of 12 sporadic carcinoid tumors of the lung, five cases involved inactivation of both copies of the MEN1 gene. Of the five carcinoids, three were atypical and two were typical. The two typical carcinoids were characterized by a rapid proliferative rate with a higher mitotic index and stronger Ki67 positivity than the other typical carcinoids in the study. Consequently, the carcinoid tumors with MEN1 gene inactivation in the study were considered to be characterized by more aggressive molecular and histopathological features than those without MEN1 gene alterations.[20] # Interactions MEN1 has been shown to interact with: - FANCD2,[21] - GFAP,[22] - JunD,[23] - NFKB1,[22] - MLL,[24] - RPA2,[25] and - VIM.[26]

https://www.wikidoc.org/index.php/MEN1

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wikidoc

MFN2

MFN2 Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission. # Function Mitofusin-2 is a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. Mitochondria function as a dynamic network constantly undergoing fusion and fission. The balance between fusion and fission is important in maintaining the integrity of the mitochondria and facilitates the mixing of the membranes and the exchange of DNA between mitochondria. MFN1 and MFN2 mediate outer membrane fusion while OPA1 is involved in inner membrane fusion. Mitochondrial fusion is essential for embryonic development. knockout mice for either MFN1 or MFN2 have fusion deficits and die midgestation. MFN2 knockout mice die at embryonic day 11.5 due to a defect in the giant cell layer of the placenta. Fusion is also important for mitochondrial transport and localization in neuronal processes. Conditional MFN2 knockout mice show degeneration in the Purkinje cells of the cerebellum, as well as improperly localized mitochondria in the dendrites. MFN2 also associates with the MIRO-Milton complex which links the mitochondria to the kinesin motor. # Clinical significance Mutations of the gene are implicated in Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by mutations in the MFN2 gene. While the symptoms of CMT2A are variable they are characterized by a sometimes early onset, severe phenotype, and optic atrophy. Mutations in OPA1 also cause optic atrophy, which suggests a common role of mitochondrial fusion in neuronal dysfunction. The exact mechanism of how mutations in MFN2 selectively cause the degeneration of long peripheral axons is not known. There is evidence suggesting that it could be due to defects in the axonal transport of mitochondria. The MFN2 protein may play a role in the pathophysiology of obesity. Mitochondria arrest fusion by downregulating Mfn2 in obesity and diabetes, which leads to a fragmented mitochondrial network. This fragmentation is obvious in the pancreatic beta-cells in the Islets of Langerhaans and can inhibit mitochondrial quality control mechanisms such as mitophagy and autophagy - leading to a defect in insulin secretion and eventual beta-cell failure. The expression of MFN2 in skeletal muscle is proportional to insulin sensitivity in this tissue, and its expression is reduced in high-fat diet fed mice and Zucker fatty rats. This protein is involved in the regulation of vascular smooth muscle cell proliferation.

MFN2 Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene.[1][2] Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion.[3] In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.[4] # Function Mitofusin-2 is a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network.[5] Mitochondria function as a dynamic network constantly undergoing fusion and fission. The balance between fusion and fission is important in maintaining the integrity of the mitochondria and facilitates the mixing of the membranes and the exchange of DNA between mitochondria. MFN1 and MFN2 mediate outer membrane fusion while OPA1 is involved in inner membrane fusion.[6] Mitochondrial fusion is essential for embryonic development. knockout mice for either MFN1 or MFN2 have fusion deficits and die midgestation. MFN2 knockout mice die at embryonic day 11.5 due to a defect in the giant cell layer of the placenta.[3] Fusion is also important for mitochondrial transport and localization in neuronal processes.[7] Conditional MFN2 knockout mice show degeneration in the Purkinje cells of the cerebellum, as well as improperly localized mitochondria in the dendrites.[8] MFN2 also associates with the MIRO-Milton complex which links the mitochondria to the kinesin motor.[7] # Clinical significance Mutations of the gene are implicated in Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by mutations in the MFN2 gene. While the symptoms of CMT2A are variable they are characterized by a sometimes early onset, severe phenotype, and optic atrophy. Mutations in OPA1 also cause optic atrophy, which suggests a common role of mitochondrial fusion in neuronal dysfunction.[8] The exact mechanism of how mutations in MFN2 selectively cause the degeneration of long peripheral axons is not known. There is evidence suggesting that it could be due to defects in the axonal transport of mitochondria.[8] The MFN2 protein may play a role in the pathophysiology of obesity.[9] Mitochondria arrest fusion by downregulating Mfn2 in obesity and diabetes, which leads to a fragmented mitochondrial network.[10] This fragmentation is obvious in the pancreatic beta-cells in the Islets of Langerhaans and can inhibit mitochondrial quality control mechanisms such as mitophagy and autophagy - leading to a defect in insulin secretion and eventual beta-cell failure.[11] The expression of MFN2 in skeletal muscle is proportional to insulin sensitivity in this tissue,[12] and its expression is reduced in high-fat diet fed mice[13] and Zucker fatty rats.[12] This protein is involved in the regulation of vascular smooth muscle cell proliferation.[5]

https://www.wikidoc.org/index.php/MFN2

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wikidoc

MFNG

MFNG Beta-1,3-N-acetylglucosaminyltransferase manic fringe is an enzyme that in humans is encoded by the MFNG gene, a member of the fringe gene family which also includes the radical fringe (RFNG) and lunatic fringe (LFNG). They all encode evolutionarily conserved proteins that act in the Notch receptor pathway to demarcate boundaries during embryonic development. While their genomic structure is distinct from other glycosyltransferases, fringe proteins have a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that leads to elongation of O-linked fucose residues on Notch, which alters Notch signaling.

MFNG Beta-1,3-N-acetylglucosaminyltransferase manic fringe is an enzyme that in humans is encoded by the MFNG gene,[1][2][3] a member of the fringe gene family which also includes the radical fringe (RFNG) and lunatic fringe (LFNG).[4][5] They all encode evolutionarily conserved proteins that act in the Notch receptor pathway to demarcate boundaries during embryonic development. While their genomic structure is distinct from other glycosyltransferases, fringe proteins have a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that leads to elongation of O-linked fucose residues on Notch, which alters Notch signaling.[3]

https://www.wikidoc.org/index.php/MFNG

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wikidoc

MKL1

MKL1 MKL/megakaryoblastic leukemia 1 (also termed MRTFA/myocardin related transcription factor A) is a protein that in humans is encoded by the MKL1 gene. # Function l The protein encoded by this gene interacts with the transcription factor serum response factor, a key regulator of smooth muscle cell differentiation. It is closely related to MKL2 and myocardin. The encoded protein can shuttle between the cytoplasm and the nucleus, and may help this way transduce signals from the cytoskeleton to the nucleus. # Clinical significance This gene is involved in a specific translocation event that creates a fusion of this gene and the RNA-binding motif protein-15 gene. This translocation has been associated with acute megakaryocytic leukemia.

MKL1 MKL/megakaryoblastic leukemia 1 (also termed MRTFA/myocardin related transcription factor A) is a protein that in humans is encoded by the MKL1 gene.[1][2][3][4] # Function l The protein encoded by this gene interacts with the transcription factor serum response factor,[5] a key regulator of smooth muscle cell differentiation. It is closely related to MKL2 and myocardin.[6] The encoded protein can shuttle between the cytoplasm and the nucleus, and may help this way transduce signals from the cytoskeleton to the nucleus.[7] # Clinical significance This gene is involved in a specific translocation event that creates a fusion of this gene and the RNA-binding motif protein-15 gene. This translocation has been associated with acute megakaryocytic leukemia.[4]

https://www.wikidoc.org/index.php/MKL1

99c53768e5a781be4a6014de08741bb7320f8877

wikidoc

MKS1

MKS1 Meckel syndrome, type 1 also known as MKS1 is a protein that in humans is encoded by the MKS1 gene. # Function The MKS1 protein along with meckelin are part of the flagellar apparatus basal body proteome and are required for cilium formation. # Clinical significance Mutations in the MKS1 are associated with Meckel syndrome or Bardet-Biedl syndrome. # Model organisms Model organisms have been used in the study of MKS1 function. A conditional knockout mouse line, called Mks1tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and two significant abnormalities were observed. The homozygous mutant embryos identified during gestation had polydactyly, oedema and eye or craniofacial defects. None survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no further abnormalities were observed.

MKS1 Meckel syndrome, type 1 also known as MKS1 is a protein that in humans is encoded by the MKS1 gene.[1] # Function The MKS1 protein along with meckelin are part of the flagellar apparatus basal body proteome and are required for cilium formation.[2] # Clinical significance Mutations in the MKS1 are associated with Meckel syndrome[1][3] or Bardet-Biedl syndrome.[4] # Model organisms Model organisms have been used in the study of MKS1 function. A conditional knockout mouse line, called Mks1tm1a(EUCOMM)Wtsi[9][10] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[11][12][13] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[7] The homozygous mutant embryos identified during gestation had polydactyly, oedema and eye or craniofacial defects. None survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no further abnormalities were observed.[7]

https://www.wikidoc.org/index.php/MKS1

90fbb707186a846295a55e17e0b01480c5b1c24b

wikidoc

MLC1

MLC1 Membrane protein MLC1 is a protein that in humans is encoded by the MLC1 gene. MLC1 (also called WKL1) is the only human gene currently associated with megalencephalic leukoencephalopathy with subcortical cysts (MLC). Evidence exists for at least one other gene for MLC, but it has not been mapped or identified. # Function The function of this gene product is not known; however, homology to other proteins suggests that it may be an integral membrane transport protein. Mutations in this gene have been associated with megalencephalic leukoencephalopathy with subcortical cysts, an autosomal recessive neurological disorder. The MLC1 protein contains six putative transmembrane domains (S1–S6) and a pore region (P) between S5 and S6. Furthermore, MLC1 has highest homology with the KCNA1 shaker-related voltage-gated potassium channel (Kv1.1). This analysis suggests that MLC1 may be a cation channel.

MLC1 Membrane protein MLC1 is a protein that in humans is encoded by the MLC1 gene.[1][2] MLC1 (also called WKL1[3][4]) is the only human gene currently associated with megalencephalic leukoencephalopathy with subcortical cysts (MLC).[5] Evidence exists for at least one other gene for MLC, but it has not been mapped or identified. # Function The function of this gene product is not known; however, homology to other proteins suggests that it may be an integral membrane transport protein.[3] Mutations in this gene have been associated with megalencephalic leukoencephalopathy with subcortical cysts, an autosomal recessive neurological disorder.[5] The MLC1 protein contains six putative transmembrane domains (S1–S6) and a pore region (P) between S5 and S6. Furthermore, MLC1 has highest homology with the KCNA1 shaker-related voltage-gated potassium channel (Kv1.1). This analysis suggests that MLC1 may be a cation channel.[3]

https://www.wikidoc.org/index.php/MLC1

168b684d38b8d3304cd287691a873dfe53927b01

wikidoc

MLH3

MLH3 DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene. # Function This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. Orthologs of human MLH3 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae. # Meiosis In addition to its role in DNA mismatch repair, MLH3 protein is also involved in meiotic crossing over. MLH3 forms a heterodimer with MLH1 that appears to be necessary for mouse oocytes to progress through metaphase II of meiosis. The MLH1-MLH3 heterodimers promote crossovers. Recombination during meiosis is often initiated by a DNA double-strand break (DSB) as illustrated in the accompanying diagram. During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination. The pathway leading to a CO involves a double Holliday junction (DHJ) intermediate. Holliday junctions need to be resolved for CO recombination to be completed. In the budding yeast Saccharomyces cerevisiae, as in the mouse, MLH3 forms a heterodimer with MLH1. Meiotic CO requires resolution of Holliday junctions through actions of the MLH1-MLH3 heterodimer. The MLH1-MLH3 heterodimer is an endonuclease that makes single-strand breaks in supercoiled double-stranded DNA. MLH1-MLH3 binds specifically to Holliday junctions and may act as part of a larger complex to process Holliday junctions during meiosis. MLH1-MLH3 heterodimer (MutL gamma) together with Exo1 and Sgs1 (ortholog of Bloom syndrome helicase) define a joint molecule resolution pathway that produces the majority of crossovers in budding yeast and, by inference, in mammals. # Interactions MLH3 has been shown to interact with MSH4.

MLH3 DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene.[1][2] # Function This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined.[2] Orthologs of human MLH3 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae. # Meiosis In addition to its role in DNA mismatch repair, MLH3 protein is also involved in meiotic crossing over.[3] MLH3 forms a heterodimer with MLH1 that appears to be necessary for mouse oocytes to progress through metaphase II of meiosis.[4] The MLH1-MLH3 heterodimers promote crossovers.[3] Recombination during meiosis is often initiated by a DNA double-strand break (DSB) as illustrated in the accompanying diagram. During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination. The pathway leading to a CO involves a double Holliday junction (DHJ) intermediate. Holliday junctions need to be resolved for CO recombination to be completed. In the budding yeast Saccharomyces cerevisiae, as in the mouse, MLH3 forms a heterodimer with MLH1. Meiotic CO requires resolution of Holliday junctions through actions of the MLH1-MLH3 heterodimer. The MLH1-MLH3 heterodimer is an endonuclease that makes single-strand breaks in supercoiled double-stranded DNA.[5][6] MLH1-MLH3 binds specifically to Holliday junctions and may act as part of a larger complex to process Holliday junctions during meiosis.[5] MLH1-MLH3 heterodimer (MutL gamma) together with Exo1 and Sgs1 (ortholog of Bloom syndrome helicase) define a joint molecule resolution pathway that produces the majority of crossovers in budding yeast and, by inference, in mammals.[7] # Interactions MLH3 has been shown to interact with MSH4.[8]

https://www.wikidoc.org/index.php/MLH3

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wikidoc

MMAB

MMAB Cob(I)yrinic acid a,c-diamide adenosyltransferase, mitochondrial is an enzyme that in humans is encoded by the MMAB gene. # Function This gene encodes an enzyme (cob(I)yrinic acid a,c-diamide adenosyltransferase) that catalyzes the final step in the conversion of vitamin B12 into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. # Clinical significance Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group.

MMAB Cob(I)yrinic acid a,c-diamide adenosyltransferase, mitochondrial is an enzyme that in humans is encoded by the MMAB gene.[1][2][3] # Function This gene encodes an enzyme (cob(I)yrinic acid a,c-diamide adenosyltransferase) that catalyzes the final step in the conversion of vitamin B12 into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase.[3] # Clinical significance Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group.[3]

https://www.wikidoc.org/index.php/MMAB

45cedc0e3c1430179dd3c56b1557fe697052b469

wikidoc

MMP1

MMP1 Matrix metalloproteinase-1 (MMP-1) also known as interstitial collagenase and fibroblast collagenase is an enzyme that in humans is encoded by the MMP1 gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. MMP-1 was the first vertebrate collagenase both purified to homogeneity as a protein, and cloned as a cDNA. # Structural Features MMP-1 has an archetypal structure consisting of a pre-domain, a pro-domain, a catalytic domain, a linker region and a hemopexin-like domain. The primary structure of MMP-1 was first published by Goldberg, G I, et al. Two main nomenclatures for the primary structure are currently in use, the original one from which the first amino-acid starts with the signalling peptide and a second one where the first amino-acid starts counting from the prodomain (proenzyme nomenclature). ## Catalytic Domain The Catalytic Domains of MMPs share very similar characteristics, having a general shape of oblate ellipsoid with a diameter of ~40 Å. Despite the similarity of the Catalytic domains of MMPs, this entry will focus only on the structural features of MMP-1 Catalytic Domain. ### Overall Structural Characteristics The Catalytic Domain of MMP-1 is composed of five highly twisted β-strands (sI-sV), three α-helix (hA-hC) and a total of eight loops, enclosing a total of five metal ions, three Ca2+ and two Zn2+, one of which with catalytic role. The Catalytic Domain (CAT) of MMP-1 starts with the F100 (non-truncated CAT) as the first amino-acid of the N-terminal loop of the CAT domain. The first published x-ray structure of the CAT domain was representative of the truncated form of this domain, where the first 7 amino-acids are not present. After the initial loop, the sequences follows to the first and longest β-sheet (sI). A second loop precedes large "amphipathic α-helix" (hA) that longitudinally spans protein site. The β-strands sII and sIII follows separated by the respective loops, loop 4 being commonly designated as "short loop" bridging sII to sIII. Following the sIII strand the sequence meets the 'S-shaped double loop' that is of primary importance for the peptide structure and catalytic activity (see further) as it extends to the cleft side "bulge", continuing to the only antiparallel β-strand sIV, which is prime importance for binding peptidic substrates or inhibitors by forming main chain hydrogen bond. Following sIV, loop Gln186-Gly192 and β-strand sV are responsible for contributing with many ligands to the several metal ions present in the protein (read further). A large open loop follows sV which has proven importance in substrate specificity within the MMPs family. A specific region (183)RWTNNFREY(191) as been identified as a critical segment of matrix metalloproteinase 1 for the expression of collagenolytic activity. On C-terminal part of the CAT Domain the hB α-helix, known as the "active-site helix" encompasses part of the "zinc-binding consensus sequence" HEXXHXXGXXH that is characteristic of the Metzincin superfamily. The α-helix hB finishes abruptly at Gly225 where the last loop of the domain starts. This last loop contains the "specificity loop" which is the shortest in the MMPs family. The Catalytic Domain ends at Gly261 with α-helix hC. # Function MMPs are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Specifically, MMP-1 breaks down the interstitial collagens, types I, II, and III. # Regulation Mechanical force may increase the expression of MMP1 in human periodontal ligament cells. # Interactions MMP1 has been shown to interact with CD49b.

MMP1 Matrix metalloproteinase-1 (MMP-1) also known as interstitial collagenase and fibroblast collagenase is an enzyme that in humans is encoded by the MMP1 gene.[1][2][3] The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3.[1] MMP-1 was the first vertebrate collagenase both purified to homogeneity as a protein, and cloned as a cDNA.[4][5] # Structural Features MMP-1 has an archetypal structure consisting of a pre-domain, a pro-domain, a catalytic domain, a linker region and a hemopexin-like domain.[6] The primary structure of MMP-1 was first published by Goldberg, G I, et al.[5] Two main nomenclatures for the primary structure are currently in use, the original one from which the first amino-acid starts with the signalling peptide and a second one where the first amino-acid starts counting from the prodomain (proenzyme nomenclature). ## Catalytic Domain The Catalytic Domains of MMPs share very similar characteristics, having a general shape of oblate ellipsoid with a diameter of ~40 Å.[7] Despite the similarity of the Catalytic domains of MMPs, this entry will focus only on the structural features of MMP-1 Catalytic Domain. ### Overall Structural Characteristics The Catalytic Domain of MMP-1 is composed of five highly twisted β-strands (sI-sV), three α-helix (hA-hC) and a total of eight loops, enclosing a total of five metal ions, three Ca2+ and two Zn2+, one of which with catalytic role.[8] The Catalytic Domain (CAT) of MMP-1 starts with the F100 (non-truncated CAT) as the first amino-acid of the N-terminal loop of the CAT domain. The first published x-ray structure of the CAT domain was representative of the truncated form of this domain, where the first 7 amino-acids are not present.[8] After the initial loop, the sequences follows to the first and longest β-sheet (sI). A second loop precedes large "amphipathic α-helix" (hA) that longitudinally spans protein site. The β-strands sII and sIII follows separated by the respective loops, loop 4 being commonly designated as "short loop" bridging sII to sIII. Following the sIII strand the sequence meets the 'S-shaped double loop' that is of primary importance for the peptide structure and catalytic activity (see further) as it extends to the cleft side "bulge", continuing to the only antiparallel β-strand sIV, which is prime importance for binding peptidic substrates or inhibitors by forming main chain hydrogen bond. Following sIV, loop Gln186-Gly192 and β-strand sV are responsible for contributing with many ligands to the several metal ions present in the protein (read further). A large open loop follows sV which has proven importance in substrate specificity within the MMPs family.[9] A specific region (183)RWTNNFREY(191) as been identified as a critical segment of matrix metalloproteinase 1 for the expression of collagenolytic activity.[10] On C-terminal part of the CAT Domain the hB α-helix, known as the "active-site helix" encompasses part of the "zinc-binding consensus sequence" HEXXHXXGXXH that is characteristic of the Metzincin superfamily.[11][12] The α-helix hB finishes abruptly at Gly225 where the last loop of the domain starts. This last loop contains the "specificity loop" which is the shortest in the MMPs family. The Catalytic Domain ends at Gly261 with α-helix hC. # Function MMPs are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Specifically, MMP-1 breaks down the interstitial collagens, types I, II, and III. # Regulation Mechanical force may increase the expression of MMP1 in human periodontal ligament cells.[13] # Interactions MMP1 has been shown to interact with CD49b.[14][15]

https://www.wikidoc.org/index.php/MMP1

6b42d41b41710efb94acbe97bc302d5677e00521

wikidoc

MMP2

MMP2 72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2. # Function Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix (ECM) in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. This gene encodes an enzyme which degrades type IV collagen, the major structural component of basement membranes. The enzyme plays a role in endometrial menstrual breakdown, regulation of vascularization and the inflammatory response. The role of MMP2 in lymphangiogenesis was considered in a modelling and theoretical study. # Activation Activation of MMP-2 requires proteolytic processing. A complex of membrane type 1 MMP (MT1-MMP/MMP14) and tissue inhibitor of metalloproteinase 2 recruits pro-MMP 2 from the extracellular milieu to the cell surface. Activation then requires an active molecule of MT1-MMP and auto catalytic cleavage. Clustering of integrin chains promotes activation of MMP-2. Another factor that will support the activation of MMP-2 is cell-cell clustering. A wild-type activated leukocyte cell adhesion molecule (ALCAM) is also required to activate MMP-2. # Clinical significance Mutations in the MMP2 gene are associated with Torg-Winchester syndrome, multicentric osteolysis, arthritis syndrome, and possibly keloids. ## Role of MMP-2 in chronic disease Activity of MMP-2 relative to the other gelatinase (MMP-9) has been associated with severity of chronic airway diseases including Idiopathic interstitial pneumonia and Bronchiectasis. In idiopathic interstitial pneumonia, MMP-2 activity was elevated in patients with the less severe disease phenotype which is more responsive and reversible with corticosteroid therapy. In non-cystic fibrosis bronchiectasis, MMP-2 concentration was elevated in patients with Haemophilus influenzae airway infection compared to Pseudomonas aeruginosa airway infection. Bronchiectasis patients with P. aeruginosa infection have a more rapid decline in lung function. Altered expression and activity levels of MMPs have been strongly implicated in the progression and metastasis of many forms of cancer. Increased MMP-2 activity has also been linked with a poor prognosis in multiple forms of cancer including colorectal, melanoma, breast, lung, ovarian, and prostate. Furthermore, changes in MMP-2 activity can come from alterations in levels of transcription, MMP secretion, MMP activation, or MMP inhibition. MMP production in many cancers may be upregulated in surrounding stromal tissue rather than simply in the tumor lesion. For instance, Mook, et al. showed that MMP-2 mRNA levels are strikingly similar between metastatic and non-metastatic lesions in colorectal cancer, but metastatic cases are correlated with higher levels of MMP-2 mRNA in surrounding healthy tissue. For this reason, it is difficult to fully understand the complex role of MMPs in cancer progression. ### Role in cancer cell invasion One of the major implications of MMPs in cancer progression is their role in ECM degradation, which allows cancer cells to migrate out of the primary tumor to form metastases. More specifically, MMP-2 (along with MMP-9) is capable of degrading type IV collagen, the most abundant component of the basement membrane. The basement membrane is important for maintaining tissue organization, providing structural support for cells, and influencing cell signaling and polarity. Degradation of the basement membrane is an essential step for the metastatic progression of most cancers. Cancer cell invasion, ECM degradation, and metastasis are highly linked with the presence of invadopodia, protrusive and adhesive structures on cancer cells. Invadopodia have been shown to concentrate MMPs (including MT1-MMP, MMP-2, and MMP-9) for localized release and activation. Furthermore, degradation products of MMP activity may further promote invadopodia formation and MMP activity. Finally, MMP-2 and several other MMPs have been shown to proteolytically activate TGF-β, which has been shown to promote epithelial mesenchymal transition (EMT), a key process involved in cancer metastasis. ### Role in cell signaling MMP degradation of the ECM affects cellular behavior through changes in integrin-cell binding, by releasing growth factors harbored by the ECM, by generating ECM degradation products, and by revealing cryptic binding sites in ECM molecules. For instance, MMP-2 degradation of collagen type I can reveal a previously inaccessible cryptic binding site that binds with the αvβ3 integrin expressed by human melanoma cells. Signaling through this integrin is necessary for melanoma cell viability and growth in a collagen matrix and can potentially rescue the cells from apoptosis. As another example, cleavage of laminin-5, a component of the basement membrane, by MMP-2 has been shown to reveal a cryptic site inducing migration of breast epithelial cells. More generally, by degrading the ECM, MMPs release growth factors that were previously bound to the ECM, allowing them to bind with cell receptors and influence cell signaling. Furthermore, many MMPs also activate other proMMPs along with growth factors. MMP-2 has also been shown to cleave other non-ECM substrates including growth factors such as TGF-β, FGF receptor-1, proTNF, IL-1β and various chemokines. For instance, MMP-2 has been implicated, along with MMP-9 in cleaving latent TGF-β, which has complex interactions with cancer cells. TGF-β generally plays a role in maintaining tissue homeostasis and preventing tumor progression. However, genetically unstable cancer cells can often evade regulation by TGF-β by altering TGF-β receptors in downstream signaling processes. Furthermore, expression of TGF-β is also correlated with immune tolerance and may help shield cancer cells from immune regulation. ### Role in neovascularization and lymphangiogenesis MMP-2 also plays an important role in the formation of new blood vessels within tumors, a process known as angiogenesis. This process is essential for tumor progression, because as tumors grow they need increasing supplies of oxygen and nutrients. Localized MMP-2 activity plays an important role in endothelial cell migration, a key feature of angiogenesis. Additionally, MMP-9 and other MMPs have been suggested to also play a complex, indirect role in angiogenesis by promoting VEGF mobilization and generating antiangiogenic factors. For instance, when studying carcinogenesis of pancreatic islets in transgenic mice, Bergers et al. showed that MMP-2 and MMP-9 were upregulated in angiogenic lesions and that the upregulation of these MMPs triggered the release of bioactive VEGF, a potent stimulator of angiogenesis. Additionally, the group determined that MMP-2 knockout mice showed decreased rates of tumor growth relative to tumor growth rates in wild type mice. Furthermore, increased expression and activity of MMP-2 has been tied to increased vascularization of lung carcinoma metastases in the central nervous system, which likely increases survival rate of these metastases. Finally, MMP-2 has been also shown to drive lymphangiogenesis, which is often excessive in tumor environments and can provide a route of metastasis for cancer cells. Detry, et al. showed that knocking down mmp2 in zebrafish prevented the formation of lymphatic vessels without altering angiogenesis, while MMP-2 inhibition slowed the migration of lymphatic endothelial cells and altered the morphology of new vessels. These results suggest that MMP-2 may alter tumor viability and invasion by regulating lymphangiogenesis in addition to angiogenesis. ### Inhibition of MMP-2 as cancer therapy Clinical trials for cancer therapies using MMP inhibitors have yielded generally unsuccessful results. These poor results are likely due to the fact that MMPs play complex roles in tissue formation and cancer progression, and indeed many MMPs have both pro and anti-tumorogenic properties. Furthermore, most clinical studies involve advanced stages of cancer, where MMP inhibitors are not particularly effective. Finally, there are no reliable biomarkers available for assessing the efficacy of MMP inhibitors and MMPs are not directly cytotoxic (so they do not cause tumor shrinkage), so it is difficult for researchers to determine whether the inhibitors have successfully reached their targets. However, initial clinical trials using broad spectrum MMP inhibitors did show some positive results. Phase I clinical trials showed that MMP inhibitors are generally safe with minimal adverse side effects. Additionally, trials with marimastat did show a slight increase in survival of patients with gastric or pancreatic cancer. Various research groups have already suggested many strategies for improving the effectiveness of MMP inhibitors in cancer treatment. First, highly specific MMP inhibitors could be used to target the functions of specific MMPs, which should allow doctors to increase the treatment dosage while minimizing adverse side effects. MMP inhibitors could also be administered along with cytotoxic agents or other proteinase inhibitors. Finally, MMP inhibitors could be used during earlier stages of cancer to prevent invasion and metastasis. Additionally, tumor overexpression of MMPs can be used to potentially target the release of chemotherapeutic agents specifically to tumor sites. For instance, cytotoxic agents or siRNA could be encapsulated in liposomes or viral vectors that only become activated upon proteolytic cleavage by a target MMP. Finally, the tumor-targeting properties of MMP inhibitors offer a potential strategy for identifying small tumors. Researchers could couple MMP inhibitors to imaging agents to help detect tumors before they spread. Though initial trials yielded disappointing results, MMP inhibitors offer significant potential for improving cancer treatment by slowing the process of cancer cell invasion and metastasis. # Interactions MMP2 has been shown to interact with: - CCL7, - THBS2, - TIMP2, - TIMP4, and - Thrombospondin 1.

MMP2 72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene.[1] The MMP2 gene is located on chromosome 16 at position 12.2.[2] # Function Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix (ECM) in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. This gene encodes an enzyme which degrades type IV collagen, the major structural component of basement membranes. The enzyme plays a role in endometrial menstrual breakdown, regulation of vascularization and the inflammatory response.[3] The role of MMP2 in lymphangiogenesis was considered in a modelling and theoretical study.[4] # Activation Activation of MMP-2 requires proteolytic processing. A complex of membrane type 1 MMP (MT1-MMP/MMP14) and tissue inhibitor of metalloproteinase 2 recruits pro-MMP 2 from the extracellular milieu to the cell surface. Activation then requires an active molecule of MT1-MMP and auto catalytic cleavage. Clustering of integrin chains promotes activation of MMP-2. Another factor that will support the activation of MMP-2 is cell-cell clustering. A wild-type activated leukocyte cell adhesion molecule (ALCAM) is also required to activate MMP-2. # Clinical significance Mutations in the MMP2 gene are associated with Torg-Winchester syndrome, multicentric osteolysis, arthritis syndrome,[5] and possibly keloids. ## Role of MMP-2 in chronic disease Activity of MMP-2 relative to the other gelatinase (MMP-9) has been associated with severity of chronic airway diseases including Idiopathic interstitial pneumonia and Bronchiectasis. In idiopathic interstitial pneumonia, MMP-2 activity was elevated in patients with the less severe disease phenotype which is more responsive and reversible with corticosteroid therapy.[6] In non-cystic fibrosis bronchiectasis, MMP-2 concentration was elevated in patients with Haemophilus influenzae airway infection compared to Pseudomonas aeruginosa airway infection.[7] Bronchiectasis patients with P. aeruginosa infection have a more rapid decline in lung function.[8] Altered expression and activity levels of MMPs have been strongly implicated in the progression and metastasis of many forms of cancer. Increased MMP-2 activity has also been linked with a poor prognosis in multiple forms of cancer including colorectal, melanoma, breast, lung, ovarian, and prostate.[9] Furthermore, changes in MMP-2 activity can come from alterations in levels of transcription, MMP secretion, MMP activation, or MMP inhibition. MMP production in many cancers may be upregulated in surrounding stromal tissue rather than simply in the tumor lesion. For instance, Mook, et al. showed that MMP-2 mRNA levels are strikingly similar between metastatic and non-metastatic lesions in colorectal cancer, but metastatic cases are correlated with higher levels of MMP-2 mRNA in surrounding healthy tissue.[10] For this reason, it is difficult to fully understand the complex role of MMPs in cancer progression. ### Role in cancer cell invasion One of the major implications of MMPs in cancer progression is their role in ECM degradation, which allows cancer cells to migrate out of the primary tumor to form metastases. More specifically, MMP-2 (along with MMP-9) is capable of degrading type IV collagen, the most abundant component of the basement membrane. The basement membrane is important for maintaining tissue organization, providing structural support for cells, and influencing cell signaling and polarity. Degradation of the basement membrane is an essential step for the metastatic progression of most cancers.[10] Cancer cell invasion, ECM degradation, and metastasis are highly linked with the presence of invadopodia, protrusive and adhesive structures on cancer cells. Invadopodia have been shown to concentrate MMPs (including MT1-MMP, MMP-2, and MMP-9) for localized release and activation.[11] Furthermore, degradation products of MMP activity may further promote invadopodia formation and MMP activity.[12] Finally, MMP-2 and several other MMPs have been shown to proteolytically activate TGF-β, which has been shown to promote epithelial mesenchymal transition (EMT), a key process involved in cancer metastasis.[13] ### Role in cell signaling MMP degradation of the ECM affects cellular behavior through changes in integrin-cell binding, by releasing growth factors harbored by the ECM, by generating ECM degradation products, and by revealing cryptic binding sites in ECM molecules.[14] For instance, MMP-2 degradation of collagen type I can reveal a previously inaccessible cryptic binding site that binds with the αvβ3 integrin expressed by human melanoma cells. Signaling through this integrin is necessary for melanoma cell viability and growth in a collagen matrix and can potentially rescue the cells from apoptosis.[15] As another example, cleavage of laminin-5, a component of the basement membrane, by MMP-2 has been shown to reveal a cryptic site inducing migration of breast epithelial cells.[16] More generally, by degrading the ECM, MMPs release growth factors that were previously bound to the ECM, allowing them to bind with cell receptors and influence cell signaling. Furthermore, many MMPs also activate other proMMPs along with growth factors.[14] MMP-2 has also been shown to cleave other non-ECM substrates including growth factors such as TGF-β, FGF receptor-1, proTNF, IL-1β and various chemokines.[17] For instance, MMP-2 has been implicated, along with MMP-9 in cleaving latent TGF-β, which has complex interactions with cancer cells. TGF-β generally plays a role in maintaining tissue homeostasis and preventing tumor progression. However, genetically unstable cancer cells can often evade regulation by TGF-β by altering TGF-β receptors in downstream signaling processes. Furthermore, expression of TGF-β is also correlated with immune tolerance and may help shield cancer cells from immune regulation.[18] ### Role in neovascularization and lymphangiogenesis MMP-2 also plays an important role in the formation of new blood vessels within tumors, a process known as angiogenesis. This process is essential for tumor progression, because as tumors grow they need increasing supplies of oxygen and nutrients. Localized MMP-2 activity plays an important role in endothelial cell migration, a key feature of angiogenesis. Additionally, MMP-9 and other MMPs have been suggested to also play a complex, indirect role in angiogenesis by promoting VEGF mobilization and generating antiangiogenic factors.[10] For instance, when studying carcinogenesis of pancreatic islets in transgenic mice, Bergers et al. showed that MMP-2 and MMP-9 were upregulated in angiogenic lesions and that the upregulation of these MMPs triggered the release of bioactive VEGF, a potent stimulator of angiogenesis. Additionally, the group determined that MMP-2 knockout mice showed decreased rates of tumor growth relative to tumor growth rates in wild type mice.[19] Furthermore, increased expression and activity of MMP-2 has been tied to increased vascularization of lung carcinoma metastases in the central nervous system, which likely increases survival rate of these metastases.[20] Finally, MMP-2 has been also shown to drive lymphangiogenesis, which is often excessive in tumor environments and can provide a route of metastasis for cancer cells. Detry, et al. showed that knocking down mmp2 in zebrafish prevented the formation of lymphatic vessels without altering angiogenesis, while MMP-2 inhibition slowed the migration of lymphatic endothelial cells and altered the morphology of new vessels.[10] These results suggest that MMP-2 may alter tumor viability and invasion by regulating lymphangiogenesis in addition to angiogenesis. ### Inhibition of MMP-2 as cancer therapy Clinical trials for cancer therapies using MMP inhibitors have yielded generally unsuccessful results. These poor results are likely due to the fact that MMPs play complex roles in tissue formation and cancer progression, and indeed many MMPs have both pro and anti-tumorogenic properties. Furthermore, most clinical studies involve advanced stages of cancer, where MMP inhibitors are not particularly effective. Finally, there are no reliable biomarkers available for assessing the efficacy of MMP inhibitors and MMPs are not directly cytotoxic (so they do not cause tumor shrinkage), so it is difficult for researchers to determine whether the inhibitors have successfully reached their targets.[9] However, initial clinical trials using broad spectrum MMP inhibitors did show some positive results. Phase I clinical trials showed that MMP inhibitors are generally safe with minimal adverse side effects. Additionally, trials with marimastat did show a slight increase in survival of patients with gastric or pancreatic cancer.[9] Various research groups have already suggested many strategies for improving the effectiveness of MMP inhibitors in cancer treatment. First, highly specific MMP inhibitors could be used to target the functions of specific MMPs, which should allow doctors to increase the treatment dosage while minimizing adverse side effects. MMP inhibitors could also be administered along with cytotoxic agents or other proteinase inhibitors. Finally, MMP inhibitors could be used during earlier stages of cancer to prevent invasion and metastasis.[9] Additionally, tumor overexpression of MMPs can be used to potentially target the release of chemotherapeutic agents specifically to tumor sites. For instance, cytotoxic agents or siRNA could be encapsulated in liposomes or viral vectors that only become activated upon proteolytic cleavage by a target MMP. Finally, the tumor-targeting properties of MMP inhibitors offer a potential strategy for identifying small tumors. Researchers could couple MMP inhibitors to imaging agents to help detect tumors before they spread. Though initial trials yielded disappointing results, MMP inhibitors offer significant potential for improving cancer treatment by slowing the process of cancer cell invasion and metastasis.[9] # Interactions MMP2 has been shown to interact with: - CCL7,[21] - THBS2,[22] - TIMP2,[23][24][25][26] - TIMP4,[25][26] and - Thrombospondin 1.[22]

https://www.wikidoc.org/index.php/MMP2

dbf1ee884c95ea8aadd7bcfb776583ef76f96947

wikidoc

MMP3

MMP3 Stromelysin-1 also known as matrix metalloproteinase-3 (MMP-3) is an enzyme that in humans is encoded by the MMP3 gene. The MMP3 gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. MMP-3 has an estimated molecular weight of 54 kDa. # Function Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix proteins and during tissue remodeling in normal physiological processes, such as embryonic development and reproduction, as well as in disease processes, such as arthritis, and tumour metastasis. Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The MMP-3 enzyme degrades collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, laminin, and elastin. In addition, MMP-3 can also activate other MMPs such as MMP-1, MMP-7, and MMP-9, rendering MMP-3 crucial in connective tissue remodeling. The enzyme is also thought to be involved in wound repair, progression of atherosclerosis, and tumor initiation. In addition to classical roles for MMP3 in extracellular space, MMP3 can enter in cellular nuclei and control transcription. # Gene regulation MMP3 itself can enter in nuclei of cells and regulate target gene such as CTGF/CCN2 gene. Expression of MMP3 is primarily regulated at the level of transcription, where the promoter of the gene responds to various stimuli, including growth factors, cytokines, tumor promoters, and oncogene products. A polymorphism in the promoter of the MMP3 gene was first reported in 1995. The polymorphism is caused by a variation in the number of adenosines located at position -1171 relative to the transcription start site, resulting in one allele having five adenosines (5A) and the other allele having six adenosines (6A). In vitro promoter functional analyses showed that the 5A allele had greater promoter activities as compared with the 6A allele. It has been shown in different studies that individuals carrying the 5A allele have increased susceptibility to diseases attributed to increased MMP expression, such as acute myocardial infarction and abdominal aortic aneurysm. On the other hand, the 6A allele has been found to be associated with diseases characterized by insufficient MMP-3 expression due to a lower promoter activity of the 6A allele, such as progressive coronary atherosclerosis. The -1171 5A/6A variant has also been associated with congenital anomalies such as cleft lip and palate, where individuals with cleft lip/palate presented significantly more 6A/6A genotypes than controls. Recently, the MMP3 gene was shown to be down-regulated in individuals with cleft lip and palate when compared to controls, reinforcing the nature of cleft lip/palate as a condition resulting from insufficient or defective embryonic tissue remodeling. # Structure Most members of the MMP family are organized into three basic, distinctive, and well-conserved domains based on structural considerations: an amino-terminal propeptide; a catalytic domain; and a hemopexin-like domain at the carboxy-terminal. The propeptide consists of approximately 80–90 amino acids containing a cysteine residue, which interacts with the catalytic zinc atom via its side chain thiol group. A highly conserved sequence (. . .PRCGXPD. . .) is present in the propeptide. Removal of the propeptide by proteolysis results in zymogen activation, as all members of the MMP family are produced in a latent form. The catalytic domain contains two zinc ions and at least one calcium ion coordinated to various residues. One of the two zinc ions is present in the active site and is involved in the catalytic processes of the MMPs. The second zinc ion (also known as structural zinc) and the calcium ion are present in the catalytic domain approximately 12 Å away from the catalytic zinc. The catalytic zinc ion is essential for the proteolytic activity of MMPs; the three histidine residues that coordinate with the catalytic zinc are conserved among all the MMPs. Little is known about the roles of the second zinc ion and the calcium ion within the catalytic domain, but the MMPs are shown to possess high affinities for structural zinc and calcium ions. The catalytic domain of MMP-3 can be inhibited by tissue inhibitors of metalloproteinases (TIMPs). The n-terminal fragment of the TIMP binds in the active site cleft much like the peptide substrate would bind. The Cys1 residue of the TIMP chelates to the catalytic zinc and forms hydrogen bonds with one of the carboxylate oxygens of the catalytic glutamate residue (Glu202, see mechanism below). These interactions force the zinc-bound water molecule that is essential to the enzyme's function to leave the enzyme. The loss of the water molecule and the blocking of the active site by TIMP disable the enzyme. The hemopexin-like domain of MMPs is highly conserved and shows sequence similarity to the plasma protein, hemopexin. The hemopexin-like domain has been shown to play a functional role in substrate binding and/or in interactions with the tissue inhibitors of metalloproteinases (TIMPs), a family of specific MMP protein inhibitors. # Mechanism The mechanism for MMP-3 is a variation on a larger theme seen in all matrix metalloproteinases. In the active site, a water molecule is coordinated to a glutamate residue (Glu202) and one of the zinc ions present in the catalytic domain. First, the coordinated water molecule performs a nucleophilic attack on the peptide substrate's scissile carbon while the glutamate simultaneously abstracts a proton from the water molecule. The abstracted proton is then removed from the glutamate by the nitrogen of the scissile amide. This forms a tetrahedral gem-diolate intermediate that is coordinated to the zinc atom. In order for the amide product to be released from the active site, the scissile amide must abstract a second proton from the coordinated water molecule. Alternatively, it has been shown for thermolysin (another metalloproteinase) that the amide product can be released in its neutral (R-NH2) form. The carboxylate product is released after a water molecule attacks the zinc ion and displaces the carboxylate product. The release of the carboxylate product is thought to be the rate-limiting step in the reaction. In addition to the water molecule directly involved in the mechanism, a second water molecule is suggested to be a part of the MMP-3 active site. This auxiliary water molecule is thought to stabilize the gem-diolate intermediate as well as the transition states by lowering the activation energy for their formation. This is demonstrated in the mechanism and reaction coordinate diagram below. # Disease relevance MMP-3 has been implicated in exacerbating the effects of traumatic brain injury (TBI) through its disruption of the blood-brain barrier (BBB). Different studies have shown that after the brain undergoes trauma and inflammation has begun, MMP production in the brain is increased. In a study conducted using MMP-3 wild type (WT) and knockout (KO) mice, MMP-3 was shown to increase BBB permeability after traumatic injury. The WT mice were shown to have lower claudin-5 and occludin levels than the KO mice after TBI. Claudin and occludin are proteins that are essential for the formation of the tight junctions between the cells of the blood-brain barrier. Tissue from uninjured WT and KO mice brains was also treated with active MMP-3. Both the WT and KO tissues showed a drop in claudin-5, occludin, and laminin-α1 (a basal lamina protein), suggesting that MMP-3 directly destroys tight junction and basal lamina proteins. MMP-3 also does damage to the blood-spinal cord barrier (BSCB), the functional equivalent of the blood-brain barrier, after spinal cord injury (SCI). In a similar study conducted using MMP-3 WT and KO mice, MMP-3 was shown to increase BSCB permeability, with the WT mice showing greater BSCB permeability than the KO mice after spinal cord injury. The same study also found decreased BSCB permeability when spinal cord tissues were treated with a MMP-3 inhibitor. These results suggest that the presence of MMP-3 serves to increase BSCB permeability after SCI. The study showed that MMP-3 accomplishes this damage by degrading claudin-5, occludin, and ZO-1 (another tight junction protein), similar to how MMP-3 damages the BBB. The increase in blood-brain barrier and blood-spinal cord barrier permeability allows for more neutrophils to infiltrate the brain and spinal cord at the site of inflammation. Neutrophils carry MMP-9., which has also been shown to degrade occludin. This leads to further disruption of the BBB and BSCB

MMP3 Stromelysin-1 also known as matrix metalloproteinase-3 (MMP-3) is an enzyme that in humans is encoded by the MMP3 gene. The MMP3 gene is part of a cluster of MMP genes which localize to chromosome 11q22.3.[1] MMP-3 has an estimated molecular weight of 54 kDa.[2] # Function Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix proteins and during tissue remodeling in normal physiological processes, such as embryonic development and reproduction, as well as in disease processes, such as arthritis, and tumour metastasis. Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The MMP-3 enzyme degrades collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, laminin, and elastin. In addition, MMP-3 can also activate other MMPs such as MMP-1, MMP-7, and MMP-9, rendering MMP-3 crucial in connective tissue remodeling.[3] The enzyme is also thought to be involved in wound repair, progression of atherosclerosis, and tumor initiation. In addition to classical roles for MMP3 in extracellular space, MMP3 can enter in cellular nuclei and control transcription.[4] # Gene regulation MMP3 itself can enter in nuclei of cells and regulate target gene such as CTGF/CCN2 gene.[4] Expression of MMP3 is primarily regulated at the level of transcription, where the promoter of the gene responds to various stimuli, including growth factors, cytokines, tumor promoters, and oncogene products.[5] A polymorphism in the promoter of the MMP3 gene was first reported in 1995.[6] The polymorphism is caused by a variation in the number of adenosines located at position -1171 relative to the transcription start site, resulting in one allele having five adenosines (5A) and the other allele having six adenosines (6A). In vitro promoter functional analyses showed that the 5A allele had greater promoter activities as compared with the 6A allele.[3] It has been shown in different studies that individuals carrying the 5A allele have increased susceptibility to diseases attributed to increased MMP expression, such as acute myocardial infarction and abdominal aortic aneurysm.[7][8] On the other hand, the 6A allele has been found to be associated with diseases characterized by insufficient MMP-3 expression due to a lower promoter activity of the 6A allele, such as progressive coronary atherosclerosis.[3][9][10] The -1171 5A/6A variant has also been associated with congenital anomalies such as cleft lip and palate, where individuals with cleft lip/palate presented significantly more 6A/6A genotypes than controls.[11] Recently, the MMP3 gene was shown to be down-regulated in individuals with cleft lip and palate when compared to controls,[12] reinforcing the nature of cleft lip/palate as a condition resulting from insufficient or defective embryonic tissue remodeling. # Structure Most members of the MMP family are organized into three basic, distinctive, and well-conserved domains based on structural considerations: an amino-terminal propeptide; a catalytic domain; and a hemopexin-like domain at the carboxy-terminal. The propeptide consists of approximately 80–90 amino acids containing a cysteine residue, which interacts with the catalytic zinc atom via its side chain thiol group. A highly conserved sequence (. . .PRCGXPD. . .) is present in the propeptide. Removal of the propeptide by proteolysis results in zymogen activation, as all members of the MMP family are produced in a latent form. The catalytic domain contains two zinc ions and at least one calcium ion coordinated to various residues. One of the two zinc ions is present in the active site and is involved in the catalytic processes of the MMPs. The second zinc ion (also known as structural zinc) and the calcium ion are present in the catalytic domain approximately 12 Å away from the catalytic zinc. The catalytic zinc ion is essential for the proteolytic activity of MMPs; the three histidine residues that coordinate with the catalytic zinc are conserved among all the MMPs. Little is known about the roles of the second zinc ion and the calcium ion within the catalytic domain, but the MMPs are shown to possess high affinities for structural zinc and calcium ions. The catalytic domain of MMP-3 can be inhibited by tissue inhibitors of metalloproteinases (TIMPs). The n-terminal fragment of the TIMP binds in the active site cleft much like the peptide substrate would bind. The Cys1 residue of the TIMP chelates to the catalytic zinc and forms hydrogen bonds with one of the carboxylate oxygens of the catalytic glutamate residue (Glu202, see mechanism below). These interactions force the zinc-bound water molecule that is essential to the enzyme's function to leave the enzyme. The loss of the water molecule and the blocking of the active site by TIMP disable the enzyme.[13] The hemopexin-like domain of MMPs is highly conserved and shows sequence similarity to the plasma protein, hemopexin. The hemopexin-like domain has been shown to play a functional role in substrate binding and/or in interactions with the tissue inhibitors of metalloproteinases (TIMPs), a family of specific MMP protein inhibitors.[14] # Mechanism The mechanism for MMP-3 is a variation on a larger theme seen in all matrix metalloproteinases. In the active site, a water molecule is coordinated to a glutamate residue (Glu202) and one of the zinc ions present in the catalytic domain. First, the coordinated water molecule performs a nucleophilic attack on the peptide substrate's scissile carbon while the glutamate simultaneously abstracts a proton from the water molecule. The abstracted proton is then removed from the glutamate by the nitrogen of the scissile amide. This forms a tetrahedral gem-diolate intermediate that is coordinated to the zinc atom.[15] In order for the amide product to be released from the active site, the scissile amide must abstract a second proton from the coordinated water molecule.[16] Alternatively, it has been shown for thermolysin (another metalloproteinase) that the amide product can be released in its neutral (R-NH2) form.[17][18] The carboxylate product is released after a water molecule attacks the zinc ion and displaces the carboxylate product.[19] The release of the carboxylate product is thought to be the rate-limiting step in the reaction.[18] In addition to the water molecule directly involved in the mechanism, a second water molecule is suggested to be a part of the MMP-3 active site. This auxiliary water molecule is thought to stabilize the gem-diolate intermediate as well as the transition states by lowering the activation energy for their formation.[15][20] This is demonstrated in the mechanism and reaction coordinate diagram below. # Disease relevance MMP-3 has been implicated in exacerbating the effects of traumatic brain injury (TBI) through its disruption of the blood-brain barrier (BBB). Different studies have shown that after the brain undergoes trauma and inflammation has begun, MMP production in the brain is increased.[21][22] In a study conducted using MMP-3 wild type (WT) and knockout (KO) mice, MMP-3 was shown to increase BBB permeability after traumatic injury.[23] The WT mice were shown to have lower claudin-5 and occludin levels than the KO mice after TBI. Claudin and occludin are proteins that are essential for the formation of the tight junctions between the cells of the blood-brain barrier.[24][25] Tissue from uninjured WT and KO mice brains was also treated with active MMP-3. Both the WT and KO tissues showed a drop in claudin-5, occludin, and laminin-α1 (a basal lamina protein), suggesting that MMP-3 directly destroys tight junction and basal lamina proteins. MMP-3 also does damage to the blood-spinal cord barrier (BSCB), the functional equivalent of the blood-brain barrier,[26] after spinal cord injury (SCI). In a similar study conducted using MMP-3 WT and KO mice, MMP-3 was shown to increase BSCB permeability, with the WT mice showing greater BSCB permeability than the KO mice after spinal cord injury. The same study also found decreased BSCB permeability when spinal cord tissues were treated with a MMP-3 inhibitor. These results suggest that the presence of MMP-3 serves to increase BSCB permeability after SCI.[27] The study showed that MMP-3 accomplishes this damage by degrading claudin-5, occludin, and ZO-1 (another tight junction protein), similar to how MMP-3 damages the BBB. The increase in blood-brain barrier and blood-spinal cord barrier permeability allows for more neutrophils to infiltrate the brain and spinal cord at the site of inflammation.[23] Neutrophils carry MMP-9.,[28] which has also been shown to degrade occludin.[29] This leads to further disruption of the BBB and BSCB[30]

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20a64e7aa8db933eaba0f91d9f19d3f56aa997ee

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MMP7

MMP7 Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the MMP7 gene. Matrilysin was discovered by Sellers and Woessner in the uterus of the rat in 1988. The complementary DNA (cDNA) of human MMP7 was isolated in 1988 by Muller et al. MMP7 is a member of the matrix metalloproteinase (MMP) family consisting of structural-related zinc-dependent endopeptidases. The primary role of cleaved/activated MMP7 is to break down extracellular matrix by degrading macromolecules including casein, type I, II, IV, and V gelatins, fibronectin, and proteoglycan. # Gene, regulation, and expression The human MMP7 is located on chromosome 11 q22.3. MMP genes are clustered in q region of human Chromosome 11 including matrilysin, collagenase-1, stromelysin1, stromelysin-2, and metalloelastase genes. It consists of 267 amino acids. The cDNA of MMP7 is 49% homologous to stromelysin-1. Comparing to other members of MMP family, MMP7 does not have a C-terminal protein domain. The promoter of the human MMP7 contains a TATA box, an activator protein 1 (AP-1) site, and two inverted polymavirus enhancer A-binding proteins 2 (PEA-3). The AP-1/PEA-3 binding motif is required and essential for MMP7 to be responsive to growth factors, oncogenes and phorbol ester. Also, the PEA and AP-1 are required for Matrilysin/CAT reporter constructs induced by tumor promoter 12-O-tetradecanoulphorbol-13-acetate (TPA) and epidermal growth factor (EGF). In addition, the high level expression of AP-1 and its binding proteins were found to be associated with mutant Ki-Ras suggesting the high expression of matrilysin in Ras activated cells is AP-1 dependent. The expression of MMP7 is regulated by the Wnt/ β catenin signaling pathway, and mediated by transformation growth factor β (TGF-β).TGF-β stimulates ECM and suppresses the steady-state level of MMP7, stromelysin mRNAs, and secretion of zymogens. The isoforms of TGF-β inhibit MMP7 mRNA and protein in the human endometrium via progesterone mediated pathway. However, the opposite effects of TGF-β on MMP7 were observed among transformed cells. In human glioma cell lines and human squamous cell carcinoma cell line II-4, TGF-β stimulates the expression of MMP7 mRNA and proteins, and facilities the invasive behavior of cells. The promoter region of the human MMP7 gene contains two or more sites that are homologous to the NR-IL6 binding sequences indicating MMP7 can bind to IL-1 and IL-6. In addition, the level of MMP7 mRNA is elevated followed the treatment of tumor necrosis factor α (TNF- α) and IL-1 β in human mesangial cells. MMP7 are commonly expressed in epithelial cells including ductal epithelium of exocrine glands in skin, salivary glands, pancreas, glandular epithelium of intestine and reproductive organ, liver, and breast. In addition, MMP7 is highly expressed in the luminal surface of dysplastic glands in human colorectal cancers. # Structure A MMP7 protein is bounded by four metal ions including a catalytic zinc ion, a structural zinc ion, and two calcium ions. The catalytic zinc ion binds to three His residues in the HEXGHXXGXXH region in tetracoordination. The calcium ion binding play important role in stabilizing the secondary structure. MMP7 has a shallow hydrophobic substrate-binding pocket. In contrast to MMP9 which has the longest hinge, MMP7 lacks hemopexin and does not have a hinge. Instead, MMP7 contains a variable C-terminal hemopexin-like domain facilitates substrate specificity. The protein of MMP7 is secreted as zymogen. The prodoamin of MMP7 contains an approximately 9 kD highly conserved “cysteine switch” PRCGXPD sequence near the C-terminal containing cysteine residues. Cysteine residues bind to the catalytic zinc keeping the protein latent. The dissociation of cysteine –Zinc coordination starts from the cleavage of the first 30 amino acids of the prodomain, which leads to a conformation change, and further results in autoproteolysis and the cleavage of the whole prodomain at Glu-Tyr site. According to Woessner et al., the Mr of MMP7 is 28,000 for the latent form and 19,000 Mr for the active form after the cleavage of its prodomain. # Interactions Promatrilysin (Pro-MMP7) is converted from the latent form to the active form by endoproteinases, and plasmin. Plasmin cleaves at the site recognizable to trypsin, is considered as the most possible physiological activator. In vitro, plasmin can activate pro-MMP7 to 50% of its full activity. Also, researchers used activated recombinant pro-MMP7 and purified substrates to investigate the proteolytic activity of MMp7 in vitro, and found that MMP7 cleaves many protein substrates mainly including ECM components, proMMPs, and nonmatrix proteins. MMP7 cleaves the glycoprotein entactin that links laminin and collagen IV at about 100-600 times faster than collagenase-1. In addition, MMP7 can activate other MMPs. Activated MMP7 and APMA can increase the activity of collagenase-1, and MMP7 can also convert the latent progelatinase A to its active form. # Function Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades proteoglycans, fibronectin, elastin and casein and differs from most MMP family members in that it lacks a conserved C-terminal protein domain. The enzyme is involved in wound healing, and studies in mice suggest that it regulates the activity of defensins in intestinal mucosa. MMP7 was initially characterized by Woessner et al. It digests components of the extracellular matrix, cleaves the α 2 (I) chain of gelatin more rapidly, and digests the B chain of insulin at Ala-Leu, and Thyr-Leu. The optimal pH of MMP7 is at 7 and the pI is at 5.9. MMP4 is inhibited by α 2-macroglubulin and TIMP. The inhibition of MMP7 activity commonly relies on metal-chelating agents including EDTA and 1,10-phenantroline, especially zinc chelation. Therefore, the selectivity of MMP7 inhibition is challenging since almost all members of MMPs family contain catalytic domains with zinc binding sites. TIMP-1 and 2 noncovalently bound to active MMP7 at the catalytic site inhibiting MMP7 activity. The activated MMP7 can also cleave the propeptides of proMMP2 and proMMP9 to facilitate tumor invasion. ## Normal tissue development Quondamatteo et al. immunohistochemically stained MMP7, and localized MMP7 in early human liver development. They reported that MMP7 was presented in some hepatocytes and endothelial cells in the 6th gestational week, and only hematopoietic cells remained after that time. ## Tissue remodeling In order for MMPs to escape TIMP inhibition, active MMP7s are recruited to the plasma membrane of epithelium inducing membrane-associated growth factors processing for epithelial repair and proliferation. In human endometrium, the expression of MMP7 mRNA increases at menstruation and remains high during the proliferative phase. Also, MMP-7 binds to the plasma membrane of epithelium containing cholesterol-rich domain. The bounded MMP7 is active and resistant to TIMP inhibition. It promotes the activity of the epithelial plasma membrane and associated substrates including E-cadherin, β4-integrin, TNF-alpha, RAS, heparin-binding EGF, IGF binding proteins and plasminogen. Further, this process promotes epithelial cell migration, proliferation and apoptosis. For menstruation, it promotes the endometrium regeneration after menstrual breakdown. Huang et al. reported that the proteolytic activity of MMP7 plays major role in tissue remodeling in biliary atresia-associated liver fibrosis. # Clinical significance MMP7 cleaves collagen III/IV/V/IX/X/XI and proteoglycan indicating that MMP inhibitors can potentially be used in therapies that involved in inhibition tissue degradation, remodeling, anti-angiogenesis and inhibition of tumor invasion. ## Role in Cancer MMP7 is found to potentially involved in tumor metastasis and inflammatory processes. The upregulation of MMP7 is associated with many malignant tumors including esophagus, stomach, colon, liver, pancreas, and renal cell carcinomas. High MMP7 expression facilitates cancer invasion and angiogenesis by degrading extracellular matrix macromolecules and connective tissues. These degradations are associated with many mechanisms including embryogenesis, postpartum uterine involution, tissue repair, angiogenesis, bone remodeling, arthritis, decubitus ulcer, and tumor metastasis/invasion. Activated MMP7 activates MMP2 and MMP9 zymogens, and mediates the proteolytic process of the precursors of tumor necrosis factors and urokinase plasminogen activators. ## Colon cancer and MMP7 expression MMP7 cleaves cell surface proteins, promotes adhesion of cancer cells, and increases the potential of tumor metastasis. Higashi et al. reported that the binding of MMP7 to cholesterol sulfate on the cell surface plays a critical role in the cell membrane-related proteolytic action. Also, the internal Ile 29, Arg33, Arg51, and Trp 55 and 171-173 residues at MMP7 C-terminal located on the opposite side of the catalytic site of MMP7 are required for cholesterol sulfate binding. Wildtype MMP7 can digest fibronectin, but mutant MMP7 fails to induce the aggregation of colon cancer cells. In addition, Qasim et al. reported that MMP7 is highly expressed in advanced colorectal adenomatous polys with severe dysplasia. Further, MMP7 is involved in converting colorectal adenomas into malignant state and facilitating the growth.

MMP7 Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the MMP7 gene.[1] Matrilysin was discovered by Sellers and Woessner in the uterus of the rat in 1988.[2] The complementary DNA (cDNA) of human MMP7 was isolated in 1988 by Muller et al.[3] MMP7 is a member of the matrix metalloproteinase (MMP) family consisting of structural-related zinc-dependent endopeptidases. The primary role of cleaved/activated MMP7 is to break down extracellular matrix by degrading macromolecules including casein, type I, II, IV, and V gelatins, fibronectin, and proteoglycan.[3][4] # Gene, regulation, and expression The human MMP7 is located on chromosome 11 q22.3. MMP genes are clustered in q region of human Chromosome 11 including matrilysin, collagenase-1, stromelysin1, stromelysin-2, and metalloelastase genes. It consists of 267 amino acids. The cDNA of MMP7 is 49% homologous to stromelysin-1.[3] Comparing to other members of MMP family, MMP7 does not have a C-terminal protein domain.[5] The promoter of the human MMP7 contains a TATA box, an activator protein 1 (AP-1) site, and two inverted polymavirus enhancer A-binding proteins 2 (PEA-3). The AP-1/PEA-3 binding motif is required and essential for MMP7 to be responsive to growth factors, oncogenes and phorbol ester. Also, the PEA and AP-1 are required for Matrilysin/CAT reporter constructs induced by tumor promoter 12-O-tetradecanoulphorbol-13-acetate (TPA) and epidermal growth factor (EGF). In addition, the high level expression of AP-1 and its binding proteins were found to be associated with mutant Ki-Ras suggesting the high expression of matrilysin in Ras activated cells is AP-1 dependent.[3] The expression of MMP7 is regulated by the Wnt/ β catenin signaling pathway, and mediated by transformation growth factor β (TGF-β).TGF-β stimulates ECM and suppresses the steady-state level of MMP7, stromelysin mRNAs, and secretion of zymogens. The isoforms of TGF-β inhibit MMP7 mRNA and protein in the human endometrium via progesterone mediated pathway. However, the opposite effects of TGF-β on MMP7 were observed among transformed cells. In human glioma cell lines and human squamous cell carcinoma cell line II-4, TGF-β stimulates the expression of MMP7 mRNA and proteins, and facilities the invasive behavior of cells.[6] The promoter region of the human MMP7 gene contains two or more sites that are homologous to the NR-IL6 binding sequences indicating MMP7 can bind to IL-1 and IL-6. In addition, the level of MMP7 mRNA is elevated followed the treatment of tumor necrosis factor α (TNF- α) and IL-1 β in human mesangial cells.[3] MMP7 are commonly expressed in epithelial cells including ductal epithelium of exocrine glands in skin, salivary glands, pancreas, glandular epithelium of intestine and reproductive organ, liver, and breast. In addition, MMP7 is highly expressed in the luminal surface of dysplastic glands in human colorectal cancers.[4] # Structure A MMP7 protein is bounded by four metal ions including a catalytic zinc ion, a structural zinc ion, and two calcium ions. The catalytic zinc ion binds to three His residues in the HEXGHXXGXXH region in tetracoordination. The calcium ion binding play important role in stabilizing the secondary structure. MMP7 has a shallow hydrophobic substrate-binding pocket. In contrast to MMP9 which has the longest hinge, MMP7 lacks hemopexin and does not have a hinge. Instead, MMP7 contains a variable C-terminal hemopexin-like domain facilitates substrate specificity.[6] The protein of MMP7 is secreted as zymogen. The prodoamin of MMP7 contains an approximately 9 kD highly conserved “cysteine switch” PRCGXPD sequence near the C-terminal containing cysteine residues. Cysteine residues bind to the catalytic zinc keeping the protein latent. The dissociation of cysteine –Zinc coordination starts from the cleavage of the first 30 amino acids of the prodomain, which leads to a conformation change, and further results in autoproteolysis and the cleavage of the whole prodomain at Glu-Tyr site. According to Woessner et al., the Mr of MMP7 is 28,000 for the latent form and 19,000 Mr for the active form after the cleavage of its prodomain.[3] # Interactions Promatrilysin (Pro-MMP7) is converted from the latent form to the active form by endoproteinases, and plasmin. Plasmin cleaves at the site recognizable to trypsin, is considered as the most possible physiological activator. In vitro, plasmin can activate pro-MMP7 to 50% of its full activity. Also, researchers used activated recombinant pro-MMP7 and purified substrates to investigate the proteolytic activity of MMp7 in vitro, and found that MMP7 cleaves many protein substrates mainly including ECM components, proMMPs, and nonmatrix proteins. MMP7 cleaves the glycoprotein entactin that links laminin and collagen IV at about 100-600 times faster than collagenase-1. In addition, MMP7 can activate other MMPs. Activated MMP7 and APMA can increase the activity of collagenase-1, and MMP7 can also convert the latent progelatinase A to its active form.[3] # Function Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades proteoglycans, fibronectin, elastin and casein and differs from most MMP family members in that it lacks a conserved C-terminal protein domain. The enzyme is involved in wound healing, and studies in mice suggest that it regulates the activity of defensins in intestinal mucosa.[7] MMP7 was initially characterized by Woessner et al. It digests components of the extracellular matrix, cleaves the α 2 (I) chain of gelatin more rapidly, and digests the B chain of insulin at Ala-Leu, and Thyr-Leu. The optimal pH of MMP7 is at 7 and the pI is at 5.9. MMP4 is inhibited by α 2-macroglubulin and TIMP.[2] The inhibition of MMP7 activity commonly relies on metal-chelating agents including EDTA and 1,10-phenantroline, especially zinc chelation. Therefore, the selectivity of MMP7 inhibition is challenging since almost all members of MMPs family contain catalytic domains with zinc binding sites. TIMP-1 and 2 noncovalently bound to active MMP7 at the catalytic site inhibiting MMP7 activity. The activated MMP7 can also cleave the propeptides of proMMP2 and proMMP9 to facilitate tumor invasion.[8] ## Normal tissue development Quondamatteo et al. immunohistochemically stained MMP7, and localized MMP7 in early human liver development. They reported that MMP7 was presented in some hepatocytes and endothelial cells in the 6th gestational week, and only hematopoietic cells remained after that time.[9] ## Tissue remodeling In order for MMPs to escape TIMP inhibition, active MMP7s are recruited to the plasma membrane of epithelium inducing membrane-associated growth factors processing for epithelial repair and proliferation. In human endometrium, the expression of MMP7 mRNA increases at menstruation and remains high during the proliferative phase. Also, MMP-7 binds to the plasma membrane of epithelium containing cholesterol-rich domain. The bounded MMP7 is active and resistant to TIMP inhibition. It promotes the activity of the epithelial plasma membrane and associated substrates including E-cadherin, β4-integrin, TNF-alpha, RAS, heparin-binding EGF, IGF binding proteins and plasminogen. Further, this process promotes epithelial cell migration, proliferation and apoptosis. For menstruation, it promotes the endometrium regeneration after menstrual breakdown.[6] Huang et al. reported that the proteolytic activity of MMP7 plays major role in tissue remodeling in biliary atresia-associated liver fibrosis.[10] # Clinical significance MMP7 cleaves collagen III/IV/V/IX/X/XI and proteoglycan indicating that MMP inhibitors can potentially be used in therapies that involved in inhibition tissue degradation, remodeling, anti-angiogenesis and inhibition of tumor invasion.[4][8] ## Role in Cancer MMP7 is found to potentially involved in tumor metastasis and inflammatory processes.[8] The upregulation of MMP7 is associated with many malignant tumors including esophagus, stomach, colon, liver, pancreas, and renal cell carcinomas. High MMP7 expression facilitates cancer invasion and angiogenesis by degrading extracellular matrix macromolecules and connective tissues. These degradations are associated with many mechanisms including embryogenesis, postpartum uterine involution, tissue repair, angiogenesis, bone remodeling, arthritis, decubitus ulcer, and tumor metastasis/invasion. Activated MMP7 activates MMP2 and MMP9 zymogens, and mediates the proteolytic process of the precursors of tumor necrosis factors and urokinase plasminogen activators.[4] ## Colon cancer and MMP7 expression MMP7 cleaves cell surface proteins, promotes adhesion of cancer cells, and increases the potential of tumor metastasis. Higashi et al. reported that the binding of MMP7 to cholesterol sulfate on the cell surface plays a critical role in the cell membrane-related proteolytic action. Also, the internal Ile 29, Arg33, Arg51, and Trp 55 and 171-173 residues at MMP7 C-terminal located on the opposite side of the catalytic site of MMP7 are required for cholesterol sulfate binding. Wildtype MMP7 can digest fibronectin, but mutant MMP7 fails to induce the aggregation of colon cancer cells.[11] In addition, Qasim et al. reported that MMP7 is highly expressed in advanced colorectal adenomatous polys with severe dysplasia. Further, MMP7 is involved in converting colorectal adenomas into malignant state and facilitating the growth.[12]

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MMP9

MMP9 Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracellular matrix. In humans the MMP9 gene encodes for a signal peptide, a propeptide, a catalytic domain with inserted three repeats of fibronectin type II domain followed by a C-terminal hemopexin-like domain. # Function Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, angiogenesis, bone development, wound healing, cell migration, learning and memory, as well as in pathological processes, such as arthritis, intracerebral hemorrhage, and metastasis. Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades type IV and V collagens and other extracellular matrix proteins. Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced mobilization of hematopoietic progenitor cells from bone marrow, and murine studies suggest a role in tumor-associated tissue remodeling. Thrombospondins, intervertebral disc proteins, regulate interaction with matrix metalloproteinases (MMPs) 2 and 9, which are key effectors of ECM remodeling. ## Neutrophil action MMP9, along with elastase, appears to be a regulatory factor in neutrophil migration across the basement membrane. MMP9 plays several important functions within neutrophil action, such as degrading extracellular matrix, activation of IL-1β, and cleavage of several chemokines. In a mouse model, MMP9 deficiency resulted in resistance to endotoxin shock, suggesting that MMP9 is important in sepsis. ## Angiogenesis MMP9 may play an important role in angiogenesis and neovascularization. For example, MMP9 appears to be involved in the remodeling associated with malignant glioma neovascularization. It is also a key regulator of growth plate formation- both growth plate angiogenesis and the generation of hypertrophic chondrocytes. Knock-out models of MMP9 result in delayed apoptosis, vascularization, and ossification of hypertrophic chondrocytes. Lastly, there is significant evidence that Gelatinase B is required for the recruitment of endothelial stem cells, a critical component of angiogenesis ## Wound repair MMP9 is greatly upregulated during human respiratory epithelial healing. Using a MMP9 deficient mouse model, it was seen that MMP9 coordinated epithelial wound repair and deficient mice were unable to remove the fibrinogen matrix during wound healing. When interacting with TGF-ß1, Gelatinase B also stimulates collagen contraction, aiding in wound closure. # Structure MMP9 is synthesized as preproenzyme of 707 amino-acid residues, including a 19 amino acid signal peptide and secreted as an inactive pro-MMP. The human MMP9 proenzyme consists of five domains. The amino-terminal propeptide, the zinc-binding catalytic domain and the carboxyl-terminal hemopexin-like domain are conserved. Its primary structure comprises several domain motifs. The propeptide domain is characterized by a conserved PRCGVPD sequence. The Cys within this sequence is known as the “cysteine switch”. It ligates the catalytic zinc to maintain the enzyme in an inactive state. Activation is achieved through an interacting protease cascade involving plasmin and stromelysin 1 (MMP-3). Plasmin generates active MMP-3 from its zymogen. Active MMP-3 cleaves the propeptide from the 92-kDa pro-MMP-9, yielding an 82-kDa enzymatically active enzyme. In the active enzyme a substrate, or a fluorogenic activity probe., replaces the propetide in the enzyme active site where it is cleaved. The catalytic domain contains two zinc and three calcium atoms. The catalytic zinc is coordinated by three histidines from the conserved HEXXHXXGXXH binding motif. The other zinc atom and the three calcium atoms are structural. A conserved methionine, which forms a unique “Met-turn” structure categorizes MMP9 as a metzincin. Three type II fibronectin repeats are inserted in the catalytic domain, although these domains are omitted in most crystallographic structures of MMP9 in complex with inhibitors.The active form of MMP9 also contains a C-terminal hemopexin-like domain. This domain is ellipsoidal in shape, formed by four β-propeller blades and an α-helix. Each blade consists of four antiparallel β-strands arranged around a funnel-like tunnel that contains two calcium and two chloride ions. The hemopexin domain is important to facilitate the cleavage of triple helical interstitial collagens. # Clinical significance MMP9 has been found to be associated with numerous pathological processes, including cancer, placental malaria, immunologic and cardiovascular diseases. ## Arthritis Elevated MMP9 levels can be found in the cases of rheumatoid arthritis and focal brain ischemia. ## Cancer One of MMP9's most widely associated pathologies is the relationship to cancer, due to its role in extracellular matrix remodeling and angiogenesis. For example, its increased expression was seen in a metastatic mammary cancer cell line. Gelatinase B plays a central role in tumor progression, from angiogenesis, to stromal remodeling, and ultimately metastasis. However, because of its physiologic function, it may be difficult to leverage Gelatinase B inhibition into cancer therapy modalities. However, Gelatinase B has been investigated in tumor metastasis diagnosis- Complexes of Gelatinase B/Tissue Inhibitors of Metalloproteinases are seen to be increased in gastrointestinal cancer and gynecologic malignancies MMPs such as MMP9 can be involved in the development of several human malignancies, as degradation of collagen IV in basement membrane and extracellular matrix facilitates tumor progression, including invasion, metastasis, growth and angiogenesis. ## Cardiovascular MMP9 levels increase with the progression of idiopathic atrial fibrillation. MMP9 has been found to be associated with the development of aortic aneurysms, and its disruption prevents the development of aortic aneurysms. Doxycycline suppresses the growth of aortic aneurysms through its inhibition of MMP9. ## Pregnancy-associated malaria (Placental malaria) A study on Ghanaian population showed that MMP-9 single nucleotide polymorphism 1562 C > T (rs3918242) was protective against placental malaria which suggests a possible role of MMP-9 in susceptibility to malaria. # Antagonist of MMP-9 Activity of plant cannabis extract and active fraction by THCA was verified on colon tissues taken from Inflammatory bowel disease (IBD) patients, was shown to suppress cyclooxygenase-2 (COX2) and MMP9 gene expression in both cell culture and colon tissue.

MMP9 Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracellular matrix. In humans the MMP9 gene [1] encodes for a signal peptide, a propeptide, a catalytic domain with inserted three repeats of fibronectin type II domain followed by a C-terminal hemopexin-like domain.[2] # Function Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, angiogenesis, bone development, wound healing, cell migration, learning and memory, as well as in pathological processes, such as arthritis, intracerebral hemorrhage,[3] and metastasis.[4] Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades type IV and V collagens and other extracellular matrix proteins.[5] Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced mobilization of hematopoietic progenitor cells from bone marrow, and murine studies suggest a role in tumor-associated tissue remodeling.[1] Thrombospondins, intervertebral disc proteins, regulate interaction with matrix metalloproteinases (MMPs) 2 and 9, which are key effectors of ECM remodeling.[6] ## Neutrophil action MMP9, along with elastase, appears to be a regulatory factor in neutrophil migration across the basement membrane.[7] MMP9 plays several important functions within neutrophil action, such as degrading extracellular matrix, activation of IL-1β, and cleavage of several chemokines.[8] In a mouse model, MMP9 deficiency resulted in resistance to endotoxin shock, suggesting that MMP9 is important in sepsis.[9] ## Angiogenesis MMP9 may play an important role in angiogenesis and neovascularization. For example, MMP9 appears to be involved in the remodeling associated with malignant glioma neovascularization.[10] It is also a key regulator of growth plate formation- both growth plate angiogenesis and the generation of hypertrophic chondrocytes. Knock-out models of MMP9 result in delayed apoptosis, vascularization, and ossification of hypertrophic chondrocytes.[11] Lastly, there is significant evidence that Gelatinase B is required for the recruitment of endothelial stem cells, a critical component of angiogenesis [12] ## Wound repair MMP9 is greatly upregulated during human respiratory epithelial healing.[13] Using a MMP9 deficient mouse model, it was seen that MMP9 coordinated epithelial wound repair and deficient mice were unable to remove the fibrinogen matrix during wound healing.[14] When interacting with TGF-ß1, Gelatinase B also stimulates collagen contraction, aiding in wound closure.[15] # Structure MMP9 is synthesized as preproenzyme of 707 amino-acid residues, including a 19 amino acid signal peptide and secreted as an inactive pro-MMP. The human MMP9 proenzyme consists of five domains. The amino-terminal propeptide, the zinc-binding catalytic domain and the carboxyl-terminal hemopexin-like domain are conserved. Its primary structure comprises several domain motifs. The propeptide domain is characterized by a conserved PRCGVPD sequence. The Cys within this sequence is known as the “cysteine switch”. It ligates the catalytic zinc to maintain the enzyme in an inactive state.[2] Activation is achieved through an interacting protease cascade involving plasmin and stromelysin 1 (MMP-3). Plasmin generates active MMP-3 from its zymogen. Active MMP-3 cleaves the propeptide from the 92-kDa pro-MMP-9, yielding an 82-kDa enzymatically active enzyme.[17] In the active enzyme a substrate, or a fluorogenic activity probe.,[16] replaces the propetide in the enzyme active site where it is cleaved. The catalytic domain contains two zinc and three calcium atoms. The catalytic zinc is coordinated by three histidines from the conserved HEXXHXXGXXH binding motif. The other zinc atom and the three calcium atoms are structural. A conserved methionine, which forms a unique “Met-turn” structure categorizes MMP9 as a metzincin.[18] Three type II fibronectin repeats are inserted in the catalytic domain, although these domains are omitted in most crystallographic structures of MMP9 in complex with inhibitors.The active form of MMP9 also contains a C-terminal hemopexin-like domain. This domain is ellipsoidal in shape, formed by four β-propeller blades and an α-helix. Each blade consists of four antiparallel β-strands arranged around a funnel-like tunnel that contains two calcium and two chloride ions.[19] The hemopexin domain is important to facilitate the cleavage of triple helical interstitial collagens. . # Clinical significance MMP9 has been found to be associated with numerous pathological processes, including cancer, placental malaria, immunologic and cardiovascular diseases. ## Arthritis Elevated MMP9 levels can be found in the cases of rheumatoid arthritis[20] and focal brain ischemia.[21] ## Cancer One of MMP9's most widely associated pathologies is the relationship to cancer, due to its role in extracellular matrix remodeling and angiogenesis. For example, its increased expression was seen in a metastatic mammary cancer cell line.[22] Gelatinase B plays a central role in tumor progression, from angiogenesis, to stromal remodeling, and ultimately metastasis.[23] However, because of its physiologic function, it may be difficult to leverage Gelatinase B inhibition into cancer therapy modalities. However, Gelatinase B has been investigated in tumor metastasis diagnosis- Complexes of Gelatinase B/Tissue Inhibitors of Metalloproteinases are seen to be increased in gastrointestinal cancer and gynecologic malignancies [24] MMPs such as MMP9 can be involved in the development of several human malignancies, as degradation of collagen IV in basement membrane and extracellular matrix facilitates tumor progression, including invasion, metastasis, growth and angiogenesis.[25] ## Cardiovascular MMP9 levels increase with the progression of idiopathic atrial fibrillation.[26] MMP9 has been found to be associated with the development of aortic aneurysms,[27] and its disruption prevents the development of aortic aneurysms.[28] Doxycycline suppresses the growth of aortic aneurysms through its inhibition of MMP9.[29] ## Pregnancy-associated malaria (Placental malaria) A study on Ghanaian population showed that MMP-9 single nucleotide polymorphism 1562 C > T (rs3918242) was protective against placental malaria which suggests a possible role of MMP-9 in susceptibility to malaria.[30] # Antagonist of MMP-9 Activity of plant cannabis extract and active fraction by THCA was verified on colon tissues taken from Inflammatory bowel disease (IBD) patients, was shown to suppress cyclooxygenase-2 (COX2) and MMP9 gene expression in both cell culture and colon tissue.[31]

https://www.wikidoc.org/index.php/MMP9

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wikidoc

MoCA

MoCA # Overview The Montreal Cognitive Assessment (MoCA) was created in 1996 by Dr. Ziad Nasreddine in Montreal, Canada. It was validated in the setting of mild cognitive impairment, and has subsequently been adopted in numerous other settings clinically. The MoCA test is a one-page 30-point test administered in approximately 10 minutes. The test and administration instructions are freely accessible for clinicians at www.mocatest.org. The test is available in 36 languages and dialects. There are 3 alternate forms in the english, designed for use in longitudinal settings. # Discription The MoCA assesses several cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. - The short-term memory recall task (5 points) involves two learning trials of five nouns and delayed recall after approximately 5 minutes. *Visuospatial abilities are assessed using a clock-drawing task (3 points) and a three-dimensional cube copy (1 point). - Multiple aspects of executive functions are assessed using an alternation task adapted from the trail-making B task (1 point), a phonemic fluency task (1 point), and a two-item verbal abstraction task (2 points). - Attention, concentration and working memory are evaluated using a sustained attention task (target detection using tapping; 1 point), a serial subtraction task (3 points), and digits forward and backward (1 point each). - Language is assessed using a three-item confrontation naming task with low-familiarity animals (lion, camel, rhinoceros; 3 points), repetition of two syntactically complex sentences (2 points), and the aforementioned fluency task. - Orientation to time and place is evaluated (6 points). The time taken for test can vary, it's usually can be administered in 10 minutes. Maximum score that can be achieved on MoCA is 30, and scores above 26 are considered normal. # Uses MoCA is used to detect mild cognitive impairment in: # Other Applications Since the MoCA assesses multiple cognitive domains, it may be a useful cognitive screening tool for several neurological diseases that affect younger populations, such as traumatic brain injury, depression, and schizophrenia. # International Versions Because MoCA is english specific, linguistic and cultural translations are made in order to adapt the test in other countries. For instance, in the Filipino version that is still being developed, Filipino translation of the English words is supplemented with changes in some of the images that locals can identify such as with the replacement of rhinoceros with an owl. The MoCA test has now been translated to 36 languages and dialects. # Recommendation The MoCA has been recommended by: The National Institutes of Health and the Canadian Stroke Consortium for detection of vascular cognitive Impairment (Hachinski et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke. 2006, Sep;37(9):2220-41). The Canadian Consensus Guidelines for Diagnosis and Treatment of Dementia for detection of Mild Cognitive Impairment and Alzheimer’s disease (Third Canadian Consensus Conference on Diagnosis and Treatment of Dementia, Alzheimer's & Dementia: The Journal of the Alzheimer's Association October 2007 (Vol. 3, Issue 4). # Validation Study The MoCA test validation study (Nasreddine et al., 2005) has shown the MoCA to be a promising tool for detecting Mild Cognitive Impairment (MCI) and Early Alzheimer's disease compared with the well-known Mini-Mental State Examination (MMSE). However, it had been established that the MMSE is not well suited for mild cognitive impairment, which raises the question whether it is an adequate "standard" to compare performance with the MoCA. According to the validation study (Nasreddine et al., 2005), the sensitivity and specificity of the MoCA for detecting MCI (n=94 subjects) were 90% and 87% respectively, compared with 18% and 100% respectively for the MMSE. Subsequent work in other settings are less promising, though generally superior to the MMSE. In the same study, the sensitivity and specificity of the MoCA for detecting Early AD (n=93 subjects) were 100% and 87% respectively, compared with 78% and 100% respectively for the MMSE. Normal Controls (n=90 subjects) had an average age of 72.84 and average education of 13.33 years. Multiple cultural and linguistic variables may affect the norms of the MoCA across different countries and languages. Several cut-off scores have been suggested across different languages to compensate for education level of the population, and several modifications were also necessary to accommodate certain linguistic and cultural differences across different languages/countries. However, most of these versions have not been validated. # Upcoming Developments - MoCA-MIS (Montreal Cognitive Assessment Memory Index Score): To predict mild cognitive impairment conversion to alzheimer's disease. Abstract presented at AAIC Conference, Vancouver 2012 - MoCA-ACE: Collect data for Age (18-99 years), Culture (10 languages), and Education (3-15 and more years) - MoCA-Drive: MoCA's ability to predict outcome on a road test - MoCA-Alternate versions: To develop parallel versions of the test to decrease possible learning effects when the test is frequently administered - MoCA-Basic: An effort to adapt MoCA for illiterate and less educated - Mini-MoCA: Shorter version of the MoCA - MoCA-ADL: An correlation of cognition domains of the MoCA with everyday function - MoCA-App: To increase reach via tablet/smart phones - MoCA-Certification: Online program aimed to improve standardized administration and interpretation # Studies on MoCA Alzheimer / MCI - Roalf et al. Comparative accuracies of two common screening instruments for classification of Alzheimer's disease, mild cognitive impairment, and healthy aging. Alzheimer's & Dementia Volume 9, Issue 5 , Pages 529-537, September 2013. - Gagnon et al. Correcting the MoCA for Education: Effect on Sensitivity. Can J neurol Sci. 2013; 40: 678-683. - Alagiakrishnan K et al. Montreal cognitive assessment is superior to standardized mini-mental status exam in detecting mild cognitive impairment in the middle-aged and elderly patients with type 2 diabetes mellitus. Biomed Res Int. 2013;2013:186106. - Wang et al. Montreal Cognitive Assessment and Mini-Mental State Examination performance in patients with mild-to-moderate dementia with Lewy bodies, Alzheimer's disease, and normal participants in Taiwan. Int Psychogeriatr. 2013 Aug 7:1-10. - Fujiwara et al. Physical and Sociopsychological Characteristics of Older Community Residents With Mild Cognitive Impairment as Assessed by the Japanese Version of the Montreal Cognitive Assessment. J Geriatr Psychiatry Neurol. 2013 Aug 6. . - Jiang et al. The association between mild cognitive impairment and doing housework. Aging Ment Health. 2013 Aug 6. - Ladas et al. Eye Blink Rate as a biological marker of Mild Cognitive Impairment. Int J Psychophysiol. 2013 Aug 1. - Dong et al. Comparison of the Montreal Cognitive Assessment and the Mini-Mental State Examination in detecting multi-domain mild cognitive impairment in a Chinese sub-sample drawn from a population-based study. Int Psychogeriatr. 2013 Jul 22:1-8. - Niu et al. Non-high-density lipoprotein cholesterol and other risk factors of mild cognitive impairment among Chinese type 2 diabetic patients. J Diabetes Complications. 2013 Sep-Oct;27(5):443-6. Epub 2013 Jul 9. - Ismail et al. Canadian academy of geriatric psychiatry survey of brief cognitive screening instruments. Can Geriatr J. 2013 Jun 3;16(2):54-60. - Gluhm, S et al. Cognitive Performance on the Mini-Mental State Examination and the Montreal Cognitive Assessment Across the Healthy Adult Lifespan. Cognitive & Behavioral Neurology: March 2013 - Volume 26 - Issue 1 - p 1–5 - Freitas S. et al. Montreal Cognitive Assessment: validation study for mild cognitive impairment and Alzheimer disease. Alzheimer Dis Assoc Disord. 2013 Jan;27(1) 37-43. - Larner et al. Comparing diagnostic accuracy of cognitive screening instruments: a weighted comparison approach. Dement Geriatr Cogn Dis Extra. 2013 Jan;3(1):60-5. - Boiko et al. . Zh Nevrol Psikhiatr Im S S Korsakova. 2013;113(2):28-32. - Salma S. Soleman Hernandez et al. Apathy, cognitive function and motor function in Alzheimer's disease. Dement Neuropsychol 2012 December;6(4):236-243. - Parunyou Julayanont, Melanie Brousseau, Michael Borrie, Howard Chertkow, Natalie Phillips, Ziad Nasreddine. Montreal Cognitive Assessment Memory Index Score, MoCA-MIS, As a Predictor of Mild Cognitive Impairment Conversion to Alzheimer's Disease. Abstract presented at AAIC Conference, Vancouver 2012. - Freitas S. et al. (2012). Montreal Cognitive Assessment (MoCA): Validation study for Mild Cognitive Impairment and Alzheimer's disease. Alzheimer Disease and Associated Disorders, doi: 10.1097/WAD.0b013e3182420bfe. - David R. Roalf et al. Comparative accuracies of two common screening instruments for classification of Alzheimer's disease, mild cognitive impairment, and healthy aging. Alzheimer's & Dementia Journal (2012) 1-9 Article in press. Published online 26 - Michal Lifshitz et al. Validation of the Hebrew Version of the MoCA Test as a Screening Instrument for the Early Detection of Mild Cognitive Impairment in Elderly Individuals. J Geriatr Psychiatry Neurol 2012 25:155. - Magierska J. et al. Clinical application of the Polish adaptation of the Montreal Cognitive Assessment (MoCA) test in screening for cognitive impairment. Neurologia i neurochirurgia polska 2012, 46(2):130-139 - Kriscinda A. Whitney, Brad Mossbarger, Steven M. Herman, Summer L. Ibarra. Is the Montreal Cognitive Assessment Superior to the Mini-Mental State Examination in Detecting Subtle Cognitive Impairment Among Middle-Aged Outpatient U.S. Military Veterans? Archives of Clinical Neuropsychology Advance Access published July 4, 2012. doi:10.1093/arclin/acs060. - Markwick A, Zamboni G, de Jager CA. Profiles of cognitive subtest impairment in the Montreal Cognitive Assessment (MoCA) in a research cohort with normal Mini-Mental State Examination (MMSE) scores. J Clin Exp Neuropsychol. 2012 Aug;34(7):750-7. Epub 2012 Apr 3. - Larner A.J.. Screening utility of the Montreal Cognitive Assessment (MoCA): in place of -or as well as - the MMSE? International psychogeriatrics; 2012 Mar;24(3):391-6. - Zhao S. et al. A clinical memory battery for screening for amnestic mild cognitive impairment in an elderly chinese population. Journal of clinical neuroscience, 18(6), 774-9, 2011. Elsevier Ltd. - Olson R, et al. Prospective comparison of two cognitive screening tests: diagnostic accuracy and correlation with community integration and quality of life. Journal of neuro-oncology, 105, 337-344, 2011. - Catherine C. Price et al. Clock Drawing in the Montreal Cognitive Assessment: Recommendations for Dementia Assessment. Dementia and Geriatric Cognitive Disorders 2011;31:179-187. - H. Chertkow, N. Phillips, Z. Nasreddine, V. Whitehead. Severity of mild cognitive impairment does not predict progression. Presented at the ADI Toronto, March 29, 2011. - Anne M. Damian et al. The Montreal Cognitive Assessment and the Mini-Mental State Examination as Screening Instruments for Cognitive Impairment: Item Analyses and Threshold Scores. Dementia and Geriatric Cognitive Disorders, 2011;31:126-131. - Mitchell A. J., Malladi S. Screening and case finding tools for the detection of dementia. Part 1: evidence-based meta-analysis of multidomain tests. The American Journal of Geriatric psychiatry, 18(9), 759-82, 2010. - Thissen AJ et al. Applicability and validity of the Dutch version of the Montreal Cognitive Assessment (MoCA-d) in diagnosing MCI.Gerontol Geriatr 2010 Dec;41(6):231-40. - Defranceso M. et al. Conversion from MCI (Mild Cognitive Impairment) to Alzheimer's disease: diagnostic options and predictors). Neuropsychiatr;2010;24(2):88-98. - Cuttini C. et al. Initiation in Dementia: Are we detecting it? Department of Medicine, division of Geriatrics, Queen's University,Kingston, Ontario, Canada. Abstract presented at the Canadian Conference on Dementia, Toronto, Oct. 1-3, 2010. - Michael Lerch et al. Could the Montreal Cognitive Assessment (MoCA) be the new "gold standard" in cognitive evaluation in geriatric patients: a clinical comparison. The Journal of the Alzheimer's Association, Vol. 6, Issue 4, Supplement page S494, July 2010. - Kaynak Selekler et al. Power of discrimination of Montreal Cognitive Assessment (MoCA) Scale in Turkish Patients with Mild Cognitive Impairment and Alzheimer's Disease. Turkish Journal of Geriatrics 2010;13(3) 166-171. - Fujiwara Y. et al. Brief screening tool for mild cognitive impairment in older Japanese: Validation of the Japanese version of the Montreal Cognitive Assessment. Geriatr Gerontol. Int. 2010;10:225-232. - Guo Qi-Hao et al. Application study of quick cognitive screening test in identifying mild cognitive impairment. Neuroscience Bulletin, February 2010, 26(1):47:54. - Walter Wittich, Natalie Phillips, Ziad Nasreddine, Howard Chertkow. Sensitivity and specificity of the Montreal Cognitive Assessment modified for individuals who are visually impaired. Journal of Visual Impairment & Blindness, June 2010, 104(6), 360-368. - Luis CA et al. Cross validation of the Montreal Cognitive Assessment in community dwelling older adults residing in the Southeastern US. International Journal of Geriatric Psychiatry, Online issue, October 21st, 2008, published 2009;24: 197-201. - Ging-Yuek R. Hsiung et al. A Pilot Study on Computerized Cognitive Training in Mild Cognitive Impairment. 5th Canadian Conference on Dementia in Toronto, Oct. 1-3, 2009. The Canadian Journal of Geriatrics, Volume 12, Issue 3, Sept. 2009, page 124. - Defrancesco M. et al. Association of Mild Cognitive Impairment (MCI) and depression. Neuropsychiatr;2009;23(3):144-50. - Dekkers M. et al. Awareness in patients with mild cognitive impairment (MCI. Tijdschr Gerontol Geriatr;2009 Feb;40(1):17-23. - A. Garcia et al. Apathy in Dementia: Are we detecting it? 5th Canadian Conference on Dementia in Toronto, Oct. 1-3, 2009. The Canadian Journal of Geriatrics, Volume 12, Issue 3, Sept. 2009, page 121. - Lisa Sweet, phd et al. The Montreal Cognitive Assessment (MoCA) in Geriatric Rehabilitation: Psychometric Properties and Association with Rehabilitation Outcomes. 5th Canadian Conference on Dementia in Toronto, Oct. 1-3, 2009. The Canadian Journal of Geriatrics, Volume 12, Issue 3, Sept. 2009, page 113. - Benjamin Lam et al. Validation of the Montreal Cognitive Assessment against Detailed Neuropsychological Measures. 5th Canadian Conference on Dementia in Toronto, Oct. 1-3, 2009. The Canadian Journal of Geriatrics, Volume 12, Issue 3, Sept. 2009, page 138. - Hemrungrojn S et al. The cognitive domains from Thai-Montreal cognitive assessment test to discriminate between amnestic MCI and mild AD from normal aging. Presented at the International Psychogeriatric Association Conference, Sept. 2009, Montreal, Quebec, Canada. - Koski L. et al. Measuring Cognition in a Geriatric Outpatient Clinic: Rasch Analysis of the Montreal Cognitive Assessment. Journal of Geriatric Psychiatry and Neurology, Volume 22, Number 3, Sept. 2009, page 151-160. - Rahman, Tomader Taha Abdel; El Gaafary, Maha Mohamed. Montreal Cognitive Assessment Arabic version: Reliability and validity prevalence of mild cognitive impairment among elderly attending geriatric clubs in Cairo. Geriatrics and Gerontology International, Volume 9, Number 1, March 2009, pp. 54-61 (8). - JL Richard et al. Use of the MoCA in Patients Presenting to a Memory Disorders Clinic. Am J Geriatr Psychiatry 2009; 17:A112. - Liu-Ambrose T.Y. et al. Increased Risk of Falling in Older Mild Cognitive Impairment. Physical Therapy, 88(12), 1482-91, 2008. - Jun-Young Lee et al. Brief Screening for Mild Cognitive Impairment in Elderly Outpatient Clinic: Validation of the Korean Version of the Montreal Cognitive Assessment. J Geriatr Psychiatry Neurol, June 2008, 21;2:104-110. - Nestor SM et al. The Montreal Cognitive Assessment: a retrospective pilot study measuring longitudinal cognitive change in people with mild cognitive impairment. Presented at the Annual Meeting of the Canadian Geriatrics Society, Montreal, Canada. Canadian J of Geriatrics, Volume 11, Issue 1, March 2008, p63. - Smith M et al. Case finding of people with cognitive impairment using screening clinics during Alzheimer awareness month. Presented at the Annual Meeting of the Canadian Geriatrics Society, Montreal, Canada. Canadian J of Geriatrics, Volume 11, Issue 1, March 2008, p37. - Tobinick et al. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. Journal of Neuroinflammation, January 2008, 5:2 (e-publication). - Rolf Sebaldt et al. Detection of Cognitive Impairment and Dementia Using the Animal Fluency Test: The Decide Study, The Canadian Journal of Neurological Sciences, Volume 36, Issue 5, Sept. 2009, page 599. - Song S et al. Executive impairment and MoCA performance in mild cognitive impairment and Alzheimer's disease. Presented at the International Neuropsychological Society Annual Meeting. Buenos Aires, Argentina. July 2-5, 2008, p. 258. - Wen HB et al. The application of Montreal cognitive assessment in urban Chinese residents of Beijing. Zhonghua Nei Ke Za Zhi. 2008 Jan;47(1):36-9. Chinese. - Shiroky et al. Can you have dementia with an MMSE score of 30. Am J of Alzheimers Dis Other Demen Oct-Nov 2007;22:5;406-415. - Smith T et al. The Montreal Cognitive Assessment: validity and utility in a memory clinic setting. Can J Psychiatry, 2007 May; 52(5):329-32. - J. Reban. Montrealsky kognitivni test/MoCA/: prinos k diagnostice predemenci, Ceska Geriatricka, Revue 2006 (4):224-229. - Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment (MoCA): A Brief Screening Tool For Mild Cognitive Impairment. Journal of the American Geriatrics Society 53:695-699, 2005. - Nasreddine ZS et al. The Montreal Cognitive Assessment (MoCA): a Brief Cognitive Screening Tool for Detection of Mild Cognitive Impairment. Neurology, Volume 62, Number 7 S(5) April 2004, A132. Presented at the American Academy of Neurology Meeting, San Francisco, May 2004. - Nasreddine ZS et al. The Montreal Cognitive Assessment (MoCA): a Brief Cognitive Screening Tool for Detection of Mild Cognitive Iimpairment. Presented at the 8th International Montreal/Springfield Symposium on Advances in Alzheimer Therapy. , p.90, April 14-17, 2004. - Nasreddine ZS et al. Sensitivity and Specificity of The Montreal Cognitive Assessment (MoCA) for Detection of Mild Cognitive Deficits. Can J Neurol Sci., Volume 30, Number 2, Supplement 2/May 2003, p.30. Presented at Canadian Congress of Neurological Sciences Meeting, Quebec City, Quebec, June 2003. Frontotemporal - Freitas S. et al. Montreal Cognitive Assessment (MoCA): Validation study for Frontotemporal Dementia. J Geriatr Psychiatry Neurol. 2012 Sep;25(3):146-54. HIV - Overton et al. The Alzheimer's disease-8 and Montreal Cognitive Assessment as screening tools for neurocognitive impairment in HIV-infected persons. J Neurovirol. 2013 Feb;19(1):109-16. - Vance et al. Assessing and Treating Forgetfulness and Cognitive Problems in Adults with HIV. Journal of the Association of nurses in aids care Vol. 24, No. 1S, January/February 2013. - Chartier, M. et al. The Montreal Cognitive Assessment (MoCA): A pilot study of a brief screening tool for mild and moderate cognitive impairment in HIV-positive Veterans. Poster presentation at the American Conference for the Treatment of HIV. (2011, April). - Meera Oza. Brain injury and lower cognitive function are common in people with HIV (CROI 2011). The AIDS Beacon. - Koski L. et al. Computerized testing augments pencil-and-paper tasks in measuring HIV-associated mild cognitive impairment. HIV Med. 2011 Mar 13. doi: 10.1111/j.1468-1293.2010.00910.x. (Epub ahead of print). Huntington - Ondrej Bezdicek et al. Validity of the Montreal Cognitive Assessment in the Detection of Cognitive Dysfunction in Huntington's Disease. Neuropsychology: Adult, 20:1, 33-40, 2013. - Videnovic A. et al. The Montreal Cognitive Assessment as a screening tool for cognitive dysfunction in Huntington's disease. Movement Disorders, 2010: 25(3):401-4. - Mickes Laura et al. A Comparison of Two Brief Screening Measures of Cognitive Impairment in Huntington's Disease. Movement Disorders, Volume 25, Issue 13, pages 2229-2233, Oct. 2010. - Lessig S. et al. Usefulness of Two Brief Cognitive Screening Measures in Huntington's Disease. Poster. Neurotherapeutics, Volume 7, Number 1, 2010, page 139. Lewy Body - Wang et al. Montreal Cognitive Assessment and Mini-Mental State Examination performance in patients with mild-to-moderate dementia with Lewy bodies, Alzheimer's disease, and normal participants in Taiwan. Int Psychogeriatr. 2013 Aug 7:1-10. Multiple Sclerosis - Dagenais E. et al. Value of the MoCA Test as a Screening Instrument in Multiple Sclerosis. Can J Neurol Sci. May 2013; 40:(3):410-5. - Lauren Krupp et al. The Montreal Cognitive Assessment (MoCA) as a Screening Tool for Cognitive Functioning in Multiple Sclérosis (MS). Neurology, Volume 76, Number 9, March 1, 2011. Abstract P06.082. - K. Waspe et al. Evaluation of Modified Montreal Cognitive assessment in multiple sclerosis: a pilot study. Multiple Sclerosis, 2008;14(supp 1) p. S29. Presented at ECTRIMS meeting, Montreal, Sept. 2008. Neuropsychology - Freitas S. et al. (2012). Construct validity of the Montreal Cognitive Assessment (MoCA). Journal of International Neuropsychology Society, 18,242-250. doi:10.1017/S1355617711001573. Parkinson - Arun Aggarwal et al. Cognitive Screening Tool in Parkinson's Disease: Mini Mental State Examination (MMSE) Versus Montreal Cognitive Assessment (MoCA). Doi:10.4172/scientificreports.279. - Roser Ribosa et al. Comparative Accuracy of the PD-CRS, Mattis DRS, MoCA and SCOPA-COG for Screening Mild Cognitive Impairment in Parkinson's Disease. Neurology, Volume 76, Number 9, March 1, 2011. Abstract P06.088. - Melissa J. et al. Validating the Montreal Cognitive Assessment for the Diagnosis of Mild Cognitive Impairment in Parkinson's Disease. Neurology, Volume 76, Number 9, March 1, 2011. Abstract P07.084. - J.C. Dalrymple-Alford et al. The MoCA: Well-suited screen for cognitive impairment in Parkinson disease. Neurology 2010;75;1717. - Chou K.L. et al. A recommended scale for cognitive screening in clinical trials of Parkinson's disease. Movement disorders, 25(15), 2501-7, 2010. - Hanna-Pladdy B. et al. Utility of the NeuroTrax computerized Battery for Cognitive Screening in Parkinson's Disease: Comparison with the MMSE and the MoCA. International Journal of Neuroscience, August 2010;120(8):538-43. - Meike Kasten et al. Validity of the MoCA and MMSE in the detection of MCI and Dementia in Parkinson's disease. Neurology 2010 75;479-479. - Sarah H. et al. Pilot study of a three-step diagnostic pathway for young and old patients with Parkinson's disease dementia: screen, test and then diagnose. International Journal of Geriatric Psychiatry 2010;25:258-265. - Luo Xia-Guang et al. Cognitive Deterioration Rates in Patients with Parkinson's Disease from Northeastern China. Dementia and Geriatric Cognitive Disorders 2010;30:64-70. - Melzer T R et al. Cognition and the limbic system in early Parkinson's disease: A DTI investigation. Abstract, NeuroImage 2009, 47 (Suppl. 1): S115. - Hoops S et al. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology 2009, November 24; 73(21):1738-1745. - Sarra et al. Montreal Cognitive Assessment Performance in Patients with Parkinson's Disease with "Normal" Global Cognition According to Mini-Mental State Examination Score. J Am Geriatr Soc, Volume 57, Number 2, February 2009, pp. 304-308(5). - Gill DJ et al. The Montreal Cognitive Assessment as a screening tool for cognitive impairment in Parkinson's disease. Mov Disorders, Volume 23, Number 7, 2008, pp. 1043-1046. - Lessig S et al. Examination of the Montreal Cognitive Assessment (MoCA) and MMSE in Parkinson's disease (PD). Abstract T-82. Presented at American Neurological Association Meeting, Salt Lake City, Utah, Sept. 24th, 2008. - Zadikoff C et al. A comparison of the Mini-Mental state exam to the Montreal Cognitive Assessment in identifying cognitive deficits in Parkinson's disease. Mov Disorders, 2008 January 30;23(2):297-9. Pulmonary disease - Villeneuve S. et al. Mild Cognitive Impairment in Moderate to Severe chronic obstructive pulmonary disease (COPD): A preliminary study. Chest 2012, 142(6):1516-1523. doi: 10.1378/chest.11-3035 REM - Gagnon JF. et al. The Montreal Cognitive Assessment: A Screening Tool for Mild Cognitive Impairment in REM Sleep Behavior Disorder. Movement Disorders 2010, May 15;25(7):936-40. Schizophrenia - Fisekovic et al. Correlation between moca and mmse for the assessment of cognition in schizophrenia. Acta Inform Med. 2012 Sep;20(3):186-9. Sleep Apnea - Wang WH et al. Relationship between brain-derived neurotrophic factor and cognitive function of obstructive sleep apnea/hypopnea syndrome patients. Asian Pac J Trop Med. 2012 Nov;5(11):906-10. doi: 10.1016/S1995-7645(12)60169-2. - Chen R. et al. Neurocognitive impairment in Chinese patients with obstructive sleep apnoea hypopnoea syndrome. REspirology, 16(5), 842-848, 2011. Sport Medicine - Debert CT et al. Montreal cognitive assessment (MoCA): baseline evaluation of cognition in the athletic population. Abstracts from the 4th International Conference on Concussion in Sport (Zurich, 2012) Br J Sports Med 2013;47:e1 doi:10.1136/bjsports-2012-092101.12. Stroke Rehabilitation - Aggarwal A, Kean E. Comparison of the Folstein Mini Mental State Examination (MMSE) to the Montreal Cognitive Assessment (MoCA) as a Cognitive Screening Tool in an Inpatient Rehabilitation Setting. Neuroscience & Medicine, 2010, 1, 39-42. Substance Disorders - Rojo-Mota et al. . Rev Neurol. 2013 Feb 1;56(3):129-36. - Copersino ML et al. Rapid cognitive screening of patients with substance abuse disorders. Experimental and Clinical Psychopharmacology 17(5):337-344, 2009. Trauma - De Guise et al. The Montreal Cognitive Assessment in Persons with Traumatic Brain Injury. Applied Neuropsychology. Adult. Published online: 22 Aug 2013 - Wong et al. 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Visual Impairment - Walter Wittich, Natalie Phillips, Ziad Nasreddine, Howard Chertkow. Sensitivity and specificity of the Montreal Cognitive Assessment modified for individuals who are visually impaired. Journal of Visual Impairment & Blindness, June 2010, 104(6), 360-368. Other - Phabphal K., Kanjanasatien J. Montreal Cognitive Assessment in cryptogenic epilepsy patients with normal Mini-Mental State Examination scores. Epileptic disorders, 13(4), 375-81., 2011. - Adhikari T. et al. Cognitive dysfunction in SLE: development of a screening tool. Lupus, 20, 1142-6, 2011. - Irak-Dersu I et al. Effect of dilating drops on cognitive function. Presented at 35th annual North American Neuro-ophthalmology meeting, February 24, 2009, Lake Tahoe, Nevada. - Irak-Dersu I et al. The Effect of Mydriatic Eye Drops on Cognitive Function in Claucoma Patients. Presented at 19th annual American Glaucoma Society meeting, March 6, 2009, San Diego, CA. Normative Data - Kenny et al. Normative values of cognitive and physical function in older adults: findings from the Irish Longitudinal Study on Ageing. J Am Geriatr Soc. 2013 May;61 Suppl 2:S279-90. - Ziad S. Nasreddine, Heidi Rossetti, Natalie Phillips, et al. Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample. Neurology 2012;78;765 - Rossetti H.C., et al. Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample. Neurology, 77(13), 1272-5, 2011. Low education - Johns, EK et al. The effect of education on performance on the Montreal Cognitive Assessment (MoCA): Normative data from the community. The Canadian Journal of Geriatrics, 11, 32-73. (Poster presented at the 28th annual meeting of the Canadian Geriatrics Society, Montreal, Quebec, April 2008. - Johns, EK et al. The Montreal Cognitive Assessment: Normative data in the community. Journal of the International Neuropsychological Society, 14 (Suppl.1), i-292. (Poster presented at the 36th annual meeting of the International Neuropsychological Society, Waikoloa, Hawaii, February 2008). Young adults - Ratchford TL et al. Normative Data for the Montreal Cognitive Assessment (MoCA) in Young Adults. P05.128. Presented at the American Academy of Neurology Meeting. April 2008. Neurology 70, March 11, 2008 (Suppl 1) A283. Reviews - Lilly, Pfizer/JNJ/Elan's mild-to-moderate Alzheimer's failures may spur use of more sensitive cognitive screening tools for early disease - experts. BioPharm Insight, published 2012-12-28. - Ziad S. Nasreddine, Gao Jing. The MoCA-Development and use in China for detection of cognition impairment. - Chin J. Neurol, Feb. 2012, Vol. 45, No. 2. - Ronald C. Petersen. Mild Cognitive Impairment. N Engl J Med 2011;364:2227-34. - Zahinoor Ismail et al. Brief cognitive screening instruments: an update. Int J Geriatr Psychiatry 2010;25: 111-120. - Bredje A. 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Canadian Journal of Neurological Sciences, 2010;37:264-268. ## Language Validation Studies Alternate forms - Ana S. Costa, Bruno Fimm, Paul Friesen, Herve Soundjock, Claudia Rottschy, Therese Gross, Frank Eitner, Arno Reich, Jorg B.Schulz, Ziad S. Nasreddine, Kathrin Reetz. Alternate-Form Reliability of the Montreal Cognitive Assessment Screening Test in a Clinical Setting. Dement Geriatr Cogn Disord 2012;33:379-384. - Howard Chertkow, Ziad Nasreddine, Natalie A. Phillips et al. The Montreal Cognitive Assessment (MoCA): Validation of Alternate Forms and New Recommendations for Education Corrections. Abstract presented at AAIC Conference Paris, July 2011. Arabic - Rahman et al. Montreal Cognitive Assessment Arabic version: Reliability and validity prevalence of mild cognitive impairment among elderly attending geriatric clubs in Cairo. Geriatrics and Gerontology International, Vol. 9, number 1, March 2009, pp. 54-61 (8). Chinese - Dong et al. Comparison of the Montreal Cognitive Assessment and the Mini-Mental State Examination in detecting multi-domain mild cognitive impairment in a Chinese sub-sample drawn from a population-based study. Int Psychogeriatr. 2013 Jul 22:1-8. - Niu et al. Non-high-density lipoprotein cholesterol and other risk factors of mild cognitive impairment among Chinese type 2 diabetic patients. J Diabetes Complications. 2013 Sep-Oct;27(5):443-6. Epub 2013 Jul 9. - Wang et al. The relationship between cognitive impairment and cerebral blood flow changes after transient ischaemic attack. Neurol Res. 2013 Jul;35(6):580-5. Zavoreo et al. Cognitive decline and cerebral vasoreactivity in asymptomatic patients with severe internal carotid artery stenosis. Acta Neurol Belg. 2013 Apr 6 - Cheng et al. Effects of carotid artery stenting on cognitive function in patients with mild cognitive impairment and carotid stenosis. Exp Ther Med. 2013 Apr;5(4):1019-1024. - Wong et al. Comparison of montreal cognitive assessment and mini-mental state examination in evaluating cognitive domain deficit following aneurysmal subarachnoid haemorrhage. PLoS One. 2013;8(4). Epub 2013 Apr 3. - Zhang et al. Relationship between cerebral microbleeds and cognitive function in lacunar infarct. J Int Med Res. 2013 Apr;41(2):347-55. - Wong et al. Validity of the Montreal Cognitive Assessment for traumatic brain injury patients with intracranial haemorrhage. Brain Inj. 2013;27(4):394-8. . Epub 2013 Mar 8. - Tu et al. Reliability, validity, and optimal cutoff score of the montreal cognitive assessment (changsha version) in ischemic cerebrovascular disease patients of hunan province, China. Dement Geriatr Cogn Dis Extra. 2013 Feb 16;3(1):25-36. - Tan et al. . Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013 Jan;33(1):27-30. Article in Chinese. - Zhao et al. Executive dysfunction in patients with cerebral hypoperfusion after cerebral angiostenosis/occlusion. Neurol Med Chir (Tokyo). 2013;53(3):141-7. - Hu JB et al. Cross-cultural difference and validation of the Chinese version of Montreal Cognitive Assessment in older adults residing in Eastern China: *Preliminary findings. Arch Gerontol Geriatr. 2013 Jan-Feb;56(1):38-43. doi: 10.1016/j.archger.2012.05.008 Epub 2012 Jun 13. Chia-Fen Tsai, Wei-Ju Lee, Shuu-Jiun Wang, Ben-Chang Shia, Ziad Nasreddine and Jong-Ling Fuh. Psychometrics of the Montreal Cognitive Assessment (MoCA) and its subscales: validation of the Taiwanese version of the MoCA and an item response theory analysis. International Psychogeriatrics (2012), 24:4, 651-658. - Adrian Wong et al. The Validity, Reliability and Clinical Utility of the Hong Kong Montreal Cognitive Assessment (HK-MoCA) in patients with cerebral small vessel disease, Dement Geriatr Cogn Disord, Aug. 2009;28-81-87. - Wong A et al. The Validity, Reliability and Utility of the Cantonese Montreal Cognitive Assessment (MoCA) in Chinese Patients with Confluent White Matter - Lesions. Hong Kong Med J, Volume 14, Number 6, Supplement 6, December 2008. - Wen HB et al. The application of Montreal cognitive assessment in urban Chinese residents of Beijing. Zhonghua Nei Ke Za Zhi. 2008. Jan;47(1):36-9. Chinese. Croatian - Martinic-Popovic I. et al. Early detection of mild cognitive impairment in patients with cerebrovascular disease. Acta Clin Croat 2006;45-77-85. Czech - J.Reban. Montrealsky kognitivni test/MoCA/: prinos k diagnostice predemenci, Ceska Geriatricka Revue 2006 (4): 224-229. Dutch - Thissen AJ et al. Applicability and validity of the Dutch version of the Montreal Cognitive Assessment (MoCA-d) in diagnosing MCI. Gerontol Geriatr. 2010 Dec;41(6):231-40. - Janneke Thissen et al. Validity of the Montreal Cognitive Assessment Dutch Version (MoCA-D), presented at the international Psychogeriatric Association Conference, Sept. 2009, Montreal, Quebec, Canada. English - Costa A, Fimm B, Friesen P, Soundjock H, Rottschy C, Gross T, Eitner F, Reich A, Schulz JB, Nasreddine ZS, Reetz K. Alternate-form Reliability of the Montreal Cognitive Assessment (MoCA) screening test in a clinical setting. Demen Geriatr Cogn Disord 2012;33(6):379-84. - Luis CA et al. Cross validation of the Montreal Cognitive Assessment in community dwelling older adults residing in the Southeastern US. International Journal of Geriatric Psychiatry, Online issue, October 21st, 2008, published 2009;24: 197-201. - Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment (MoCA): A brief screening tool for mild cognitive impairment. J Am Geriatr. Soc. 53:695-699, 2005. French - Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment (MoCA): A brief screening tool for mild cognitive impairment. J Am Geriatr. Soc. 53:695-699, 2005. Hebrew - Michal Lifshitz et al. Validation of the Hebrew Version of the MoCA Test as a Screening Instrument for the Early Detection of Mild Cognitive Impairment in Elderly Individuals. Journal of Geriatric Psychiatry and Neurology 2012 25(3) 155-161. Italian - Pasi et al. Factors predicting the Montreal cognitive assessment (MoCA) applicability and performances in a stroke unit. J Neurol. 2013 Jun;260(6):1518-26. Japanese - Fujiwara et al. Physical and Sociopsychological Characteristics of Older Community Residents With Mild Cognitive Impairment as Assessed by the Japanese Version of the Montreal Cognitive Assessment. J Geriatr Psychiatry Neurol. 2013 Aug 6. . - Kenji Narazakia, Yu Nofujib et al. Normative Data for the Montreal Cognitive Assessment in a Japanese Community-Dwelling Older Population. Neuroepidemiology 2013;40:23-29. - Ihara et al. Association of Physical Activity with the Visuospatial/Executive Functions of the Montreal Cognitive Assessment in Patients with Vascular Cognitive Impairment. J Stroke Cerebrovasc Dis. 2012 Nov 12. pii: S1052-3057(12)00339-4. - Fujiwara Y. et al. Brief screening tool for mild cognitive impairment in older Japanese: Validation of the Japanese version of the Montreal Cognitive Assessment. Geriatr Gerontol Int. 2010;10:225-232. Korean - Hwang et al. Effects of falls experience on cognitive functions and physical activities in community-dwelling individuals with chronic stroke. Int J Rehabil Res. 2013 Jun;36(2):134-9. - Jun-Young Lee et al. Brief Screening for Mild Cognitive Impairment in Elderly Outpatient Clinic: Validation of the Korean Version of Montreal Cognitive Assessment 2008; J Geriatr Psychiatry Neurol, June 2008, 21;2:104-110. Korean-K2 - Kang YW et al. Reliability Validity, and Normative Study of the Korean-Montreal Cognitive Assessment (K-MoCA) as an Instrument for screening of Vascular Cognitive Impairment (VCI). The Korean Journal of Clinical Psychology. 2009;28:549-562. Persian - Sikaroodi et al. Cognitive impairments in patients with cerebrovascular risk factors: A comparison of Mini Mental Status Exam and Montreal Cognitive Assessment. Clin Neurol Neurosurg. 2013 Aug;115(8):1276-80. Polish - Magierska J et al. Clinical application of the Polish adaptation of the Montreal Cognitive Assessment (MoCA) test in screening for cognitive impairment. Neurologia i neurochirurgia polska 2012, 46(2):130-139. - Joanna Magierska, Radoslaw Magierski, Tomasz Sobow, Iwona Kloszewska. The Polish adaptation of the Montreal Cognitive Assessment (MoCA) and preliminary results of its clinical utility in the screening for cognitive impairment. Presented at ICAD Conference Poster 2008, Chicago. Portuguese - Freitas S. et al. (2012). Construct validity of the Montreal Cognitive Assessment (MoCA). Journal of International Neuropsychology Society, 18,242-250. doi:10.1017/S1355617711001573. - Freitas S. et al. (2012). Montreal Cognitive Assessment (MoCA): Validation study for Mild Cognitive Impairment and Alzheimer's disease. Alzheimer Disease and Associated Disorders, doi: 10.1097/WAD.0b013e3182420bfe. - Freitas S. Simoes M.R, Alves L. & Santana (2012). Montreal Cognitive Assessment (MoCA): Influence of sociodemographic and health variables. Archives of Clinical Neuropsychology, 27, 165-175. doi:10.1093/arclin/acr116. - Freitas S. et al. (2011). Montreal Cognitive Assessment (MoCA): Normative study for the Portuguese population. Journal of Clinical and Experimental Neuropsychology, 33(9), 989-996. doi:10.1080/13803395.2011.589374 - Duro D et al. Validation studies of the Portuguese experimental version of the Montreal Cognitive Assessment (MoCA): confirmatory factor analysis. J Neurol. 2010 May;257(5):728-34. - Freitas S, Santana I, Simoes, M.R. (2010). The sensitivity of the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) to cognitive decline: A longitudinal study. Alzheimer's & Dementia, 6(4), S353-S354 Abstract. - Freitas S, et al. (2010). Estudos de adaptacao do Montreal Cognitive Assessment (MoCA) para a populacao portuguesa. Avaliacao Psicologica, 9(3), 345-357. Portuguese (Brazil) - Bertolucci PH et al. Brazilian Portuguese version for the Montreal Cognitive Assessment (MoCA) and the preliminary results. Presented at Alzheimer's Association International Conference on Alzheimer's Disease. Alzheimer's and Dementia, Volume 4, Issue 4, Supplement 1, July 2008, Page T686. - Bertolucci PH et al. Brazilian Portuguese version for the Montreal Cognitive Assessment (MoCA) and the preliminary results. Presented at Alzheimer's Association International Conference on Alzheimer's Disease. Alzheimer's and Dementia, Vol. 4, Issue 4 Supplement 1, July 2008, page T686. - Claudia M. Memoria et al. Brief screening for mild cognitive impairment: validation of the Brazilian version of the Montreal Cognitive Assessment. Int J Geriatr Psychiatry, 2013 Jan;28(1) 34-40. Russian - Boiko et al. . Zh Nevrol Psikhiatr Im S S Korsakova. 2013;113(2):28-32. Sinhalese - Karunaratne S. et al. Validation of the Sinhala version of the Montreal Cognitive Assessment in screening for dementia. Ceylon Medical Journal, 56(4), 147-153, 2011. Spanish - Gomez F et al. Applicability of the MoCA-S test in populations with little education in Colombia. Int J Geriatr Psychiatry 2012, Sep 20. doi: 10.1002/gps.3885. Thai - Tangwongchai S et al. The Validity of Thai version of the Montreal Cognitive Assessment (MoCA-T), Presented at the International Psychogeriatric Association Conference, Sept. 2009, Montreal, Quebec, Canada. Turkish - Selekler K. & Cangoz B. (October 2009). Predictive Validity Study of MoCA on Turkish Patients with MCI and Alzheimer Dementia. (Poster). 19th World Congress of Neurology (WCN 2009), Bangkok, Thailand. - Kaynak Selekler et al. Power of discrimination of Montreal Cognitive Assessment (MoCA) Scale in Turkish Patients with Mild Cognitive Impairment and Alzheimer's Disease. Turkish Journal of Geriatrics 2010;13(3) 166-171.

MoCA Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2] # Overview The Montreal Cognitive Assessment (MoCA) was created in 1996 by Dr. Ziad Nasreddine in Montreal, Canada. It was validated in the setting of mild cognitive impairment, and has subsequently been adopted in numerous other settings clinically. The MoCA test is a one-page 30-point test administered in approximately 10 minutes. The test and administration instructions are freely accessible for clinicians at www.mocatest.org. The test is available in 36 languages and dialects. There are 3 alternate forms in the english, designed for use in longitudinal settings. # Discription The MoCA assesses several cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. - The short-term memory recall task (5 points) involves two learning trials of five nouns and delayed recall after approximately 5 minutes. *Visuospatial abilities are assessed using a clock-drawing task (3 points) and a three-dimensional cube copy (1 point). - Multiple aspects of executive functions are assessed using an alternation task adapted from the trail-making B task (1 point), a phonemic fluency task (1 point), and a two-item verbal abstraction task (2 points). - Attention, concentration and working memory are evaluated using a sustained attention task (target detection using tapping; 1 point), a serial subtraction task (3 points), and digits forward and backward (1 point each). - Language is assessed using a three-item confrontation naming task with low-familiarity animals (lion, camel, rhinoceros; 3 points), repetition of two syntactically complex sentences (2 points), and the aforementioned fluency task. - Orientation to time and place is evaluated (6 points). The time taken for test can vary, it's usually can be administered in 10 minutes. Maximum score that can be achieved on MoCA is 30, and scores above 26 are considered normal. [1] # Uses MoCA is used to detect mild cognitive impairment in: # Other Applications Since the MoCA assesses multiple cognitive domains, it may be a useful cognitive screening tool for several neurological diseases that affect younger populations, such as traumatic brain injury, depression, and schizophrenia. # International Versions Because MoCA is english specific, linguistic and cultural translations are made in order to adapt the test in other countries. For instance, in the Filipino version that is still being developed, Filipino translation of the English words is supplemented with changes in some of the images that locals can identify such as with the replacement of rhinoceros with an owl.[3] The MoCA test has now been translated to 36 languages and dialects.[4] # Recommendation The MoCA has been recommended by: The National Institutes of Health and the Canadian Stroke Consortium for detection of vascular cognitive Impairment (Hachinski et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke. 2006, Sep;37(9):2220-41). The Canadian Consensus Guidelines for Diagnosis and Treatment of Dementia for detection of Mild Cognitive Impairment and Alzheimer’s disease (Third Canadian Consensus Conference on Diagnosis and Treatment of Dementia, Alzheimer's & Dementia: The Journal of the Alzheimer's Association October 2007 (Vol. 3, Issue 4). # Validation Study The MoCA test validation study (Nasreddine et al., 2005) has shown the MoCA to be a promising tool for detecting Mild Cognitive Impairment (MCI) and Early Alzheimer's disease compared with the well-known Mini-Mental State Examination (MMSE). However, it had been established that the MMSE is not well suited for mild cognitive impairment, which raises the question whether it is an adequate "standard" to compare performance with the MoCA. According to the validation study (Nasreddine et al., 2005), the sensitivity and specificity of the MoCA for detecting MCI (n=94 subjects) were 90% and 87% respectively, compared with 18% and 100% respectively for the MMSE. Subsequent work in other settings are less promising, though generally superior to the MMSE. In the same study, the sensitivity and specificity of the MoCA for detecting Early AD (n=93 subjects) were 100% and 87% respectively, compared with 78% and 100% respectively for the MMSE. Normal Controls (n=90 subjects) had an average age of 72.84 and average education of 13.33 years. Multiple cultural and linguistic variables may affect the norms of the MoCA across different countries and languages. Several cut-off scores have been suggested across different languages to compensate for education level of the population, and several modifications were also necessary to accommodate certain linguistic and cultural differences across different languages/countries. However, most of these versions have not been validated. # Upcoming Developments - MoCA-MIS (Montreal Cognitive Assessment Memory Index Score): To predict mild cognitive impairment conversion to alzheimer's disease. Abstract presented at AAIC Conference, Vancouver 2012 - MoCA-ACE: Collect data for Age (18-99 years), Culture (10 languages), and Education (3-15 and more years) - MoCA-Drive: MoCA's ability to predict outcome on a road test - MoCA-Alternate versions: To develop parallel versions of the test to decrease possible learning effects when the test is frequently administered - MoCA-Basic: An effort to adapt MoCA for illiterate and less educated - Mini-MoCA: Shorter version of the MoCA - MoCA-ADL: An correlation of cognition domains of the MoCA with everyday function - MoCA-App: To increase reach via tablet/smart phones - MoCA-Certification: Online program aimed to improve standardized administration and interpretation[5] # Studies on MoCA Alzheimer / MCI - Roalf et al. Comparative accuracies of two common screening instruments for classification of Alzheimer's disease, mild cognitive impairment, and healthy aging. Alzheimer's & Dementia Volume 9, Issue 5 , Pages 529-537, September 2013. - Gagnon et al. Correcting the MoCA for Education: Effect on Sensitivity. Can J neurol Sci. 2013; 40: 678-683. - Alagiakrishnan K et al. Montreal cognitive assessment is superior to standardized mini-mental status exam in detecting mild cognitive impairment in the middle-aged and elderly patients with type 2 diabetes mellitus. Biomed Res Int. 2013;2013:186106. - Wang et al. Montreal Cognitive Assessment and Mini-Mental State Examination performance in patients with mild-to-moderate dementia with Lewy bodies, Alzheimer's disease, and normal participants in Taiwan. Int Psychogeriatr. 2013 Aug 7:1-10. [Epub ahead of print] - Fujiwara et al. Physical and Sociopsychological Characteristics of Older Community Residents With Mild Cognitive Impairment as Assessed by the Japanese Version of the Montreal Cognitive Assessment. J Geriatr Psychiatry Neurol. 2013 Aug 6. [Epub ahead of print]. - Jiang et al. The association between mild cognitive impairment and doing housework. Aging Ment Health. 2013 Aug 6. - Ladas et al. Eye Blink Rate as a biological marker of Mild Cognitive Impairment. Int J Psychophysiol. 2013 Aug 1. - Dong et al. Comparison of the Montreal Cognitive Assessment and the Mini-Mental State Examination in detecting multi-domain mild cognitive impairment in a Chinese sub-sample drawn from a population-based study. Int Psychogeriatr. 2013 Jul 22:1-8. [Epub ahead of print] - Niu et al. Non-high-density lipoprotein cholesterol and other risk factors of mild cognitive impairment among Chinese type 2 diabetic patients. J Diabetes Complications. 2013 Sep-Oct;27(5):443-6. Epub 2013 Jul 9. - Ismail et al. Canadian academy of geriatric psychiatry survey of brief cognitive screening instruments. Can Geriatr J. 2013 Jun 3;16(2):54-60. - Gluhm, S et al. Cognitive Performance on the Mini-Mental State Examination and the Montreal Cognitive Assessment Across the Healthy Adult Lifespan. Cognitive & Behavioral Neurology: March 2013 - Volume 26 - Issue 1 - p 1–5 - Freitas S. et al. Montreal Cognitive Assessment: validation study for mild cognitive impairment and Alzheimer disease. Alzheimer Dis Assoc Disord. 2013 Jan;27(1) 37-43. - Larner et al. Comparing diagnostic accuracy of cognitive screening instruments: a weighted comparison approach. Dement Geriatr Cogn Dis Extra. 2013 Jan;3(1):60-5. - Boiko et al. [Possibilities of medical correction of moderate cognitive impairment]. [Article in Russian] Zh Nevrol Psikhiatr Im S S Korsakova. 2013;113(2):28-32. - Salma S. Soleman Hernandez et al. Apathy, cognitive function and motor function in Alzheimer's disease. Dement Neuropsychol 2012 December;6(4):236-243. - Parunyou Julayanont, Melanie Brousseau, Michael Borrie, Howard Chertkow, Natalie Phillips, Ziad Nasreddine. Montreal Cognitive Assessment Memory Index Score, MoCA-MIS, As a Predictor of Mild Cognitive Impairment Conversion to Alzheimer's Disease. Abstract presented at AAIC Conference, Vancouver 2012. - Freitas S. et al. (2012). Montreal Cognitive Assessment (MoCA): Validation study for Mild Cognitive Impairment and Alzheimer's disease. Alzheimer Disease and Associated Disorders, doi: 10.1097/WAD.0b013e3182420bfe. - David R. Roalf et al. Comparative accuracies of two common screening instruments for classification of Alzheimer's disease, mild cognitive impairment, and healthy aging. Alzheimer's & Dementia Journal (2012) 1-9 Article in press. Published online 26 - Michal Lifshitz et al. Validation of the Hebrew Version of the MoCA Test as a Screening Instrument for the Early Detection of Mild Cognitive Impairment in Elderly Individuals. J Geriatr Psychiatry Neurol 2012 25:155. - Magierska J. et al. Clinical application of the Polish adaptation of the Montreal Cognitive Assessment (MoCA) test in screening for cognitive impairment. Neurologia i neurochirurgia polska 2012, 46(2):130-139 - Kriscinda A. Whitney, Brad Mossbarger, Steven M. Herman, Summer L. Ibarra. Is the Montreal Cognitive Assessment Superior to the Mini-Mental State Examination in Detecting Subtle Cognitive Impairment Among Middle-Aged Outpatient U.S. Military Veterans? Archives of Clinical Neuropsychology Advance Access published July 4, 2012. doi:10.1093/arclin/acs060. - Markwick A, Zamboni G, de Jager CA. Profiles of cognitive subtest impairment in the Montreal Cognitive Assessment (MoCA) in a research cohort with normal Mini-Mental State Examination (MMSE) scores. J Clin Exp Neuropsychol. 2012 Aug;34(7):750-7. Epub 2012 Apr 3. - Larner A.J.. Screening utility of the Montreal Cognitive Assessment (MoCA): in place of -or as well as - the MMSE? International psychogeriatrics; 2012 Mar;24(3):391-6. - Zhao S. et al. A clinical memory battery for screening for amnestic mild cognitive impairment in an elderly chinese population. Journal of clinical neuroscience, 18(6), 774-9, 2011. Elsevier Ltd. - Olson R, et al. Prospective comparison of two cognitive screening tests: diagnostic accuracy and correlation with community integration and quality of life. Journal of neuro-oncology, 105, 337-344, 2011. - Catherine C. Price et al. Clock Drawing in the Montreal Cognitive Assessment: Recommendations for Dementia Assessment. Dementia and Geriatric Cognitive Disorders 2011;31:179-187. - H. Chertkow, N. Phillips, Z. Nasreddine, V. Whitehead. Severity of mild cognitive impairment does not predict progression. Presented at the ADI Toronto, March 29, 2011. - Anne M. Damian et al. The Montreal Cognitive Assessment and the Mini-Mental State Examination as Screening Instruments for Cognitive Impairment: Item Analyses and Threshold Scores. Dementia and Geriatric Cognitive Disorders, 2011;31:126-131. - Mitchell A. J., Malladi S. Screening and case finding tools for the detection of dementia. Part 1: evidence-based meta-analysis of multidomain tests. The American Journal of Geriatric psychiatry, 18(9), 759-82, 2010. - Thissen AJ et al. Applicability and validity of the Dutch version of the Montreal Cognitive Assessment (MoCA-d) in diagnosing MCI.Gerontol Geriatr 2010 Dec;41(6):231-40. - Defranceso M. et al. Conversion from MCI (Mild Cognitive Impairment) to Alzheimer's disease: diagnostic options and predictors). Neuropsychiatr;2010;24(2):88-98. - Cuttini C. et al. Initiation in Dementia: Are we detecting it? Department of Medicine, division of Geriatrics, Queen's University,Kingston, Ontario, Canada. Abstract presented at the Canadian Conference on Dementia, Toronto, Oct. 1-3, 2010. - Michael Lerch et al. Could the Montreal Cognitive Assessment (MoCA) be the new "gold standard" in cognitive evaluation in geriatric patients: a clinical comparison. The Journal of the Alzheimer's Association, Vol. 6, Issue 4, Supplement page S494, July 2010. - Kaynak Selekler et al. Power of discrimination of Montreal Cognitive Assessment (MoCA) Scale in Turkish Patients with Mild Cognitive Impairment and Alzheimer's Disease. Turkish Journal of Geriatrics 2010;13(3) 166-171. - Fujiwara Y. et al. Brief screening tool for mild cognitive impairment in older Japanese: Validation of the Japanese version of the Montreal Cognitive Assessment. Geriatr Gerontol. Int. 2010;10:225-232. - Guo Qi-Hao et al. Application study of quick cognitive screening test in identifying mild cognitive impairment. Neuroscience Bulletin, February 2010, 26(1):47:54. - Walter Wittich, Natalie Phillips, Ziad Nasreddine, Howard Chertkow. Sensitivity and specificity of the Montreal Cognitive Assessment modified for individuals who are visually impaired. Journal of Visual Impairment & Blindness, June 2010, 104(6), 360-368. - Luis CA et al. Cross validation of the Montreal Cognitive Assessment in community dwelling older adults residing in the Southeastern US. International Journal of Geriatric Psychiatry, Online issue, October 21st, 2008, published 2009;24: 197-201. - Ging-Yuek R. Hsiung et al. A Pilot Study on Computerized Cognitive Training in Mild Cognitive Impairment. 5th Canadian Conference on Dementia in Toronto, Oct. 1-3, 2009. The Canadian Journal of Geriatrics, Volume 12, Issue 3, Sept. 2009, page 124. - Defrancesco M. et al. Association of Mild Cognitive Impairment (MCI) and depression. Neuropsychiatr;2009;23(3):144-50. - Dekkers M. et al. Awareness in patients with mild cognitive impairment (MCI. Tijdschr Gerontol Geriatr;2009 Feb;40(1):17-23. - A. Garcia et al. Apathy in Dementia: Are we detecting it? 5th Canadian Conference on Dementia in Toronto, Oct. 1-3, 2009. The Canadian Journal of Geriatrics, Volume 12, Issue 3, Sept. 2009, page 121. - Lisa Sweet, phd et al. The Montreal Cognitive Assessment (MoCA) in Geriatric Rehabilitation: Psychometric Properties and Association with Rehabilitation Outcomes. 5th Canadian Conference on Dementia in Toronto, Oct. 1-3, 2009. The Canadian Journal of Geriatrics, Volume 12, Issue 3, Sept. 2009, page 113. - Benjamin Lam et al. Validation of the Montreal Cognitive Assessment against Detailed Neuropsychological Measures. 5th Canadian Conference on Dementia in Toronto, Oct. 1-3, 2009. The Canadian Journal of Geriatrics, Volume 12, Issue 3, Sept. 2009, page 138. - Hemrungrojn S et al. The cognitive domains from Thai-Montreal cognitive assessment test to discriminate between amnestic MCI and mild AD from normal aging. Presented at the International Psychogeriatric Association Conference, Sept. 2009, Montreal, Quebec, Canada. - Koski L. et al. Measuring Cognition in a Geriatric Outpatient Clinic: Rasch Analysis of the Montreal Cognitive Assessment. Journal of Geriatric Psychiatry and Neurology, Volume 22, Number 3, Sept. 2009, page 151-160. - Rahman, Tomader Taha Abdel; El Gaafary, Maha Mohamed. Montreal Cognitive Assessment Arabic version: Reliability and validity prevalence of mild cognitive impairment among elderly attending geriatric clubs in Cairo. Geriatrics and Gerontology International, Volume 9, Number 1, March 2009, pp. 54-61 (8). - JL Richard et al. Use of the MoCA in Patients Presenting to a Memory Disorders Clinic. Am J Geriatr Psychiatry 2009; 17:A112. - Liu-Ambrose T.Y. et al. Increased Risk of Falling in Older Mild Cognitive Impairment. Physical Therapy, 88(12), 1482-91, 2008. - Jun-Young Lee et al. Brief Screening for Mild Cognitive Impairment in Elderly Outpatient Clinic: Validation of the Korean Version of the Montreal Cognitive Assessment. J Geriatr Psychiatry Neurol, June 2008, 21;2:104-110. - Nestor SM et al. The Montreal Cognitive Assessment: a retrospective pilot study measuring longitudinal cognitive change in people with mild cognitive impairment. Presented at the Annual Meeting of the Canadian Geriatrics Society, Montreal, Canada. Canadian J of Geriatrics, Volume 11, Issue 1, March 2008, p63. - Smith M et al. Case finding of people with cognitive impairment using screening clinics during Alzheimer awareness month. Presented at the Annual Meeting of the Canadian Geriatrics Society, Montreal, Canada. Canadian J of Geriatrics, Volume 11, Issue 1, March 2008, p37. - Tobinick et al. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. Journal of Neuroinflammation, January 2008, 5:2 (e-publication). - Rolf Sebaldt et al. Detection of Cognitive Impairment and Dementia Using the Animal Fluency Test: The Decide Study, The Canadian Journal of Neurological Sciences, Volume 36, Issue 5, Sept. 2009, page 599. - Song S et al. Executive impairment and MoCA performance in mild cognitive impairment and Alzheimer's disease. Presented at the International Neuropsychological Society Annual Meeting. Buenos Aires, Argentina. July 2-5, 2008, p. 258. - Wen HB et al. The application of Montreal cognitive assessment in urban Chinese residents of Beijing. Zhonghua Nei Ke Za Zhi. 2008 Jan;47(1):36-9. Chinese. - Shiroky et al. Can you have dementia with an MMSE score of 30. Am J of Alzheimers Dis Other Demen Oct-Nov 2007;22:5;406-415. - Smith T et al. The Montreal Cognitive Assessment: validity and utility in a memory clinic setting. Can J Psychiatry, 2007 May; 52(5):329-32. - J. Reban. Montrealsky kognitivni test/MoCA/: prinos k diagnostice predemenci, Ceska Geriatricka, Revue 2006 (4):224-229. - Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment (MoCA): A Brief Screening Tool For Mild Cognitive Impairment. 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Montreal Cognitive Assessment (MoCA): Validation study for Frontotemporal Dementia. J Geriatr Psychiatry Neurol. 2012 Sep;25(3):146-54. HIV - Overton et al. The Alzheimer's disease-8 and Montreal Cognitive Assessment as screening tools for neurocognitive impairment in HIV-infected persons. J Neurovirol. 2013 Feb;19(1):109-16. - Vance et al. Assessing and Treating Forgetfulness and Cognitive Problems in Adults with HIV. Journal of the Association of nurses in aids care Vol. 24, No. 1S, January/February 2013. - Chartier, M. et al. The Montreal Cognitive Assessment (MoCA): A pilot study of a brief screening tool for mild and moderate cognitive impairment in HIV-positive Veterans. Poster presentation at the American Conference for the Treatment of HIV. (2011, April). - Meera Oza. Brain injury and lower cognitive function are common in people with HIV (CROI 2011). The AIDS Beacon. - Koski L. et al. Computerized testing augments pencil-and-paper tasks in measuring HIV-associated mild cognitive impairment. HIV Med. 2011 Mar 13. doi: 10.1111/j.1468-1293.2010.00910.x. (Epub ahead of print). Huntington - Ondrej Bezdicek et al. Validity of the Montreal Cognitive Assessment in the Detection of Cognitive Dysfunction in Huntington's Disease. Neuropsychology: Adult, 20:1, 33-40, 2013. - Videnovic A. et al. The Montreal Cognitive Assessment as a screening tool for cognitive dysfunction in Huntington's disease. Movement Disorders, 2010: 25(3):401-4. - Mickes Laura et al. A Comparison of Two Brief Screening Measures of Cognitive Impairment in Huntington's Disease. Movement Disorders, Volume 25, Issue 13, pages 2229-2233, Oct. 2010. - Lessig S. et al. Usefulness of Two Brief Cognitive Screening Measures in Huntington's Disease. Poster. Neurotherapeutics, Volume 7, Number 1, 2010, page 139. Lewy Body - Wang et al. Montreal Cognitive Assessment and Mini-Mental State Examination performance in patients with mild-to-moderate dementia with Lewy bodies, Alzheimer's disease, and normal participants in Taiwan. Int Psychogeriatr. 2013 Aug 7:1-10. [Epub ahead of print] Multiple Sclerosis - Dagenais E. et al. Value of the MoCA Test as a Screening Instrument in Multiple Sclerosis. Can J Neurol Sci. May 2013; 40:(3):410-5. - Lauren Krupp et al. The Montreal Cognitive Assessment (MoCA) as a Screening Tool for Cognitive Functioning in Multiple Sclérosis (MS). Neurology, Volume 76, Number 9, March 1, 2011. Abstract P06.082. - K. Waspe et al. Evaluation of Modified Montreal Cognitive assessment in multiple sclerosis: a pilot study. Multiple Sclerosis, 2008;14(supp 1) p. S29. Presented at ECTRIMS meeting, Montreal, Sept. 2008. Neuropsychology - Freitas S. et al. (2012). Construct validity of the Montreal Cognitive Assessment (MoCA). Journal of International Neuropsychology Society, 18,242-250. doi:10.1017/S1355617711001573. Parkinson - Arun Aggarwal et al. Cognitive Screening Tool in Parkinson's Disease: Mini Mental State Examination (MMSE) Versus Montreal Cognitive Assessment (MoCA). Doi:10.4172/scientificreports.279. - Roser Ribosa et al. Comparative Accuracy of the PD-CRS, Mattis DRS, MoCA and SCOPA-COG for Screening Mild Cognitive Impairment in Parkinson's Disease. Neurology, Volume 76, Number 9, March 1, 2011. Abstract P06.088. - Melissa J. et al. Validating the Montreal Cognitive Assessment for the Diagnosis of Mild Cognitive Impairment in Parkinson's Disease. Neurology, Volume 76, Number 9, March 1, 2011. Abstract P07.084. - J.C. Dalrymple-Alford et al. The MoCA: Well-suited screen for cognitive impairment in Parkinson disease. Neurology 2010;75;1717. - Chou K.L. et al. A recommended scale for cognitive screening in clinical trials of Parkinson's disease. Movement disorders, 25(15), 2501-7, 2010. - Hanna-Pladdy B. et al. Utility of the NeuroTrax computerized Battery for Cognitive Screening in Parkinson's Disease: Comparison with the MMSE and the MoCA. International Journal of Neuroscience, August 2010;120(8):538-43. - Meike Kasten et al. Validity of the MoCA and MMSE in the detection of MCI and Dementia in Parkinson's disease. Neurology 2010 75;479-479. - Sarah H. et al. Pilot study of a three-step diagnostic pathway for young and old patients with Parkinson's disease dementia: screen, test and then diagnose. International Journal of Geriatric Psychiatry 2010;25:258-265. - Luo Xia-Guang et al. Cognitive Deterioration Rates in Patients with Parkinson's Disease from Northeastern China. Dementia and Geriatric Cognitive Disorders 2010;30:64-70. - Melzer T R et al. Cognition and the limbic system in early Parkinson's disease: A DTI investigation. Abstract, NeuroImage 2009, 47 (Suppl. 1): S115. - Hoops S et al. 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Validity and Applications of the Montreal Cognitive Assessment for the Assessment of Vascular Cognitive Impairment. Cerebrovasc Dis. 2013 Jul 30;36(1):6-18. [Epub ahead of print] - Wu et al. The effects of educational background on Montreal Cognitive Assessment screening for vascular cognitive impairment, no dementia, caused by ischemic stroke. J Clin Neurosci. 2013 Jul 24. [Epub ahead of print] - Harkness et al. Cognitive function and self-care management in older patients with heart failure. Eur J Cardiovasc Nurs. 2013 Jun 3. [Epub ahead of print] - Pasi et al. Factors predicting the Montreal cognitive assessment (MoCA) applicability and performances in a stroke unit. J Neurol. 2013 Jun;260(6):1518-26. - Hwang et al. Effects of falls experience on cognitive functions and physical activities in community-dwelling individuals with chronic stroke. Int J Rehabil Res. 2013 Jun;36(2):134-9. - Marzolini et al. The effects of an aerobic and resistance exercise training program on cognition following stroke. Neurorehabil Neural Repair. 2013 Jun;27(5):392-402. - Shopin et al. Cognitive Assessment in Proximity to Acute Ischemic Stroke/Transient Ischemic Attack: Comparison of the Montreal Cognitive Assessment Test and MindStreams Computerized Cognitive Assessment Battery. Dement Geriatr Cogn Disord. 2013;36(1-2):36-42. 13 May 23. - Cheng et al. Effects of carotid artery stenting on cognitive function in patients with mild cognitive impairment and carotid stenosis. Exp Ther Med. 2013 Apr;5(4):1019-1024. - Zhang et al. Relationship between cerebral microbleeds and cognitive function in lacunar infarct. J Int Med Res. 2013 Apr;41(2):347-55. - Wong et al. Comparison of montreal cognitive assessment and mini-mental state examination in evaluating cognitive domain deficit following aneurysmal subarachnoid haemorrhage. PLoS One. 2013;8(4). Epub 2013 Apr 3. - Zhao et al. Executive dysfunction in patients with cerebral hypoperfusion after cerebral angiostenosis/occlusion. Neurol Med Chir (Tokyo). 2013;53(3):141-7. - Ball et al. Mild cognitive impairment in high-risk patients with chronic atrial fibrillation: a forgotten component of clinical management? Heart. 2013 Apr;99(8):542-7. - Mai et al. Screening for cognitive impairment in a stroke prevention clinic using the MoCA. Can J Neurol Sci. 2013 Mar;40(2):192-7. - Tu et al. Reliability, validity, and optimal cutoff score of the montreal cognitive assessment (changsha version) in ischemic cerebrovascular disease patients of hunan province, China. Dement Geriatr Cogn Dis Extra. 2013 Feb 16;3(1):25-36. - Tan et al. [Clinical research of early intervention of modified shuyu pill in vascular cognitive impairment no dementia]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013 Jan;33(1):27-30. Article in Chinese. - Ihara et al. Association of Physical Activity with the Visuospatial/Executive Functions of the Montreal Cognitive Assessment in Patients with Vascular Cognitive Impairment. J Stroke Cerebrovasc Dis. 2012 Nov 12. pii: S1052-3057(12)00339-4. - Masafumi Ihara et al. Association of Physical Activity with the Visuospatial / Executive Functions of the Montreal Cognitive Assessment in Patients with Vascular Cognitive Impairment. doi:10.1016/ j. strokecerebrovasdis.2012.10.007. - Freitas S, Simoes MR, Alves L, Vicente M, Santana I. Montreal Cognitive Assessment (MoCA): Validation Study for Vascular Dementia. J Int Neuropsychol Soc. 2012 Nov;18(6):1031-40. - Sarah T. Pendlebury et al. Telephone Assessment of Cognition After Transient Ischemic Attack and Stroke: Modified Telephone Interview of Cognitive Status and Telephone Montreal Cognitive Assessment Versus Face-to-Face Montreal Cognitive Assessment and Neuropsychological Battery. Stroke, published online November 8, 2012. doi:10.1161/STROKEAHA.112.673384. - Fu GX, Miao Y, Yan H, Zhong Y. Common carotid flow velocity is associated with cognition in older adults. Can J Neurol Sci. 2012 Jul;39(4):502-7. - Jan Cameron et al. Screening for mild cognitive impairment in patients with heart failure: Montreal Cognitive Assessment versus Mini Mental State Exam. Eur J Cardiovasc Nurs published online 18 April 2012. - Mirena Valkova, Boyko Stamenov, Dora Peychinska. Screening for poststroke cognitive impairment via Mini-Mental State Examination and Montreal Cognitive Assessment Scale. Journal of IMAB-Annual Proceeding 2012, vol. 18, book 3. - Guo-Xiang et al. Common Carotid Flow Velocity is Associated with Cognition in Older Adults. - Can J Neurol Sci. 2012;39:502-507. - Baracchini C. et al. Carotid endarterectomy protects elderly patients from cognitive decline: A prospective study. Surgery, September, 1-8, 2011. Elsevier Inc. - MacKenzie G. et al. Detecting cognitive impairment in clients with mild stroke or transient ischemic attack attending a stroke prevention clinic. Can J Neurosci Nurs. 2011;33(1):47-50. - Cumming T.B., Bernhardt J. and Linden T. The Montreal Cognitive Assessment: short cognitive evaluation in a large stroke trial. Stroke, 42(9), 2642-4, 2011. - Toglia J, Fitzgerald K et al. The Mini-Mental State Examination and Montreal Cognitive Assessment in persons with mild subacute stroke: relationship to functional outcome. Archives of physical medicine and rehabilitation, 92(5), 792-8, 2011. Elsevier Inc. - Martinic-Popovic et al. Cognitive performance in asymptomatic patients with advanced carotid disease. Cognitive and behavioral neurology, 24(3) , 145-51, 2011. - Athilingam P. et al. Montreal Cognitive Assessment and Mini-Mental Satus Examination compared as cognitive screening tools in heart failure. Heart & lung, 40(6), 521-9, 2011. Elsevier Inc. - Olivier Godefroy et al. Is the Montreal Cognitive Assessment Superior to the Mini-Mental State Examination to detect Poststroke Cognitive Impairment?: A Study with neuropsychological evaluation. Stroke 2011;42:00-00. Published online Apr 7, 2011. - Martinic Popovic, A. Lovrencic-Huzjan, A. M. Simundic, V. Demarin. Mild cognitive impairment in patients with carotid disease. Presented at the ADI Toronto, March 29, 2011. - You J-song, Chen R-Zhao et al. The Chinese (Cantonese) Montreal Cognitive Assessment in Patients with Subcortical Ischemic Vascular Dementia. Dementia and Geriatric Cognitive Disorders Extra, 1(1), 276-282, 2011. - Weiner Myron Frederick, Hynan L.S., Rossetti H. et al. The relationship of Montreal Cognitive Assessment scores to framingham coronary and stroke risk scores. Open Journal of Psychiatry, 01(02), 49-55, 2011. - Harkness K et al. Screening for Cognitive Deficits Using the Montreal Cognitive Assessment Tool in Outpatients ≥65 Years of Age With Heart Failure. Am J. Cardiol. 2011, Feb 9. Abstract. - S. N. McLennan et al. Validity of the Montreal Cognitive Assessment (MoCA) as a Screening Test for Mild Cognitive Impairment (MCI) in a Cardiovascular Population. Journal of Geriatric Psychiatry and Neurology 2011 Mar;24(1):33-8. - Ira H. Bernstein et al. Psychometric Evaluation of the Montreal Cognitive Assessment (MoCA) in Three Diverse Samples. The Clinical Neuropsychologist 2010, 1-8, iFirst. - Cameron J. et al. Does cognitive impairment predict poor self-care in patients with heart failure? European Journal of Health failure 2010, 12, 508-515. - Pendlebury S.T. et al. Underestimation of Cognitive Impairment by Mini-Mental State Examination Versus the Montreal Cognitive Assessment in Patients with Transient Ischemic Attack and Stroke. A Population-Based Study. Stroke Journal of the American Heart Association, 41(6):1290-1293, June 2010. - Dong Y et al. The Montreal Cognitive Assessment (MoCA) is superior to the Mini-Mental State Examination (MMSE) for the detection of vascular cognitive impairment after acute stroke. J Neurol Sci;2010 Dec 15;299(1-2):15-8. - Pendlebury S et al. Impairment on Montreal Cognitive Assessment in transient ischaemic attack and stroke patients with normal Mini-Mental State Examination score is clinically relevant. Journal Neurol Neurosurg. Psychiatry 2010 81:e68 Abstract. - McLennan SN et al. Cognitive Impairment Predicts Functional Capacity in Dementia-Free Patients With Cardiovascular Disease. J Cardiovasc Nurs. 2010 September/October;25(5):390-397 Abstract. - Martinic-Popovic et al. Assessment of subtle cognitive impairment in stroke-free patients with carotid disease. Acta clinica Croatica, 48, 231-240, 2009. - Wong A. et al. The Validity, Reliability and Clinical Utility of the Hong Kong Montreal Cognitive Assessment (HK-MoCA) in Patients with Cerebral Small Vessel Disease, Dement Geriatr Cognitive Disorders, August 2009;28:81-87. - Rolf Sebaldt et al. Detection of Cognitive Impairment and Dementia Using the Animal Fluency Test: The Decide Study, The Canadian Journal of Neurological Sciences, Volume 36, Issue 5, Sept. 2009, page 599. - Wong A et al. The Validity, Reliability and Utility of the Cantonese Montreal Cognitive Assessment (MoCA) in Chinese Patients with Confluent White Matter Lesions. Hong Kong Med J, Volume 14, Number 6, Supplement 6, December 2008. - Boulanger JM et al. A prospective cognitive evaluation in post stroke/TIA patients using the Montreal Cognitive Assessment test (MoCA). Presented at Nice, France. European Stroke Conference, May 2008. - Ponrathi Athilingam. The Montreal Cognitive Assessment (MoCA): An appropriate tool to assess subtle cognitive changes in people with heart failure? Section: "Innovations in Nursing Practice with Older Adults". Presented at the ENRS 20th scientific conference. Philadelphia, March 27th, 2008. - Martinic Popovic I. et al. Mild cognitive impairment in symptomatic and asymptomatic cerebrovascular disease. Journal of the Neurological Sciences, Volume 257, Issues 1-2, 15 June 2007, pages 185-193. - J Malcolm O Arnold et al. Canadian Cardiovascular Society Consensus Conference recommendations on heart failure update 2007: Prevention, management during intercurrent illness or actue decompensation, and use of biomarkers. Can J Cardiol, Volume 23, Number 1, January 2007. - Martinic-Popovic I. et al. Early detection of mild cognitive impairment in patients with cerebrovascular disease. Acta Clin Croat 2006; 45:77-85. - Hachinski et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke. 2006, Sept.:37(9):2220-41. Teaching - Guy Lacombe, Pierre-Michel Roy, Ziad Nasreddine, Tamas Fülop. Teaching medical students to evaluate cognition using MoCA. Abstract presented at AAIC Conference, Paris, July 2011. Visual Impairment - Walter Wittich, Natalie Phillips, Ziad Nasreddine, Howard Chertkow. Sensitivity and specificity of the Montreal Cognitive Assessment modified for individuals who are visually impaired. Journal of Visual Impairment & Blindness, June 2010, 104(6), 360-368. Other - Phabphal K., Kanjanasatien J. Montreal Cognitive Assessment in cryptogenic epilepsy patients with normal Mini-Mental State Examination scores. Epileptic disorders, 13(4), 375-81., 2011. - Adhikari T. et al. Cognitive dysfunction in SLE: development of a screening tool. Lupus, 20, 1142-6, 2011. - Irak-Dersu I et al. Effect of dilating drops on cognitive function. Presented at 35th annual North American Neuro-ophthalmology meeting, February 24, 2009, Lake Tahoe, Nevada. - Irak-Dersu I et al. The Effect of Mydriatic Eye Drops on Cognitive Function in Claucoma Patients. Presented at 19th annual American Glaucoma Society meeting, March 6, 2009, San Diego, CA. Normative Data - Kenny et al. Normative values of cognitive and physical function in older adults: findings from the Irish Longitudinal Study on Ageing. J Am Geriatr Soc. 2013 May;61 Suppl 2:S279-90. - Ziad S. Nasreddine, Heidi Rossetti, Natalie Phillips, et al. Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample. Neurology 2012;78;765 - Rossetti H.C., et al. Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample. Neurology, 77(13), 1272-5, 2011. Low education - Johns, EK et al. The effect of education on performance on the Montreal Cognitive Assessment (MoCA): Normative data from the community. The Canadian Journal of Geriatrics, 11, 32-73. (Poster presented at the 28th annual meeting of the Canadian Geriatrics Society, Montreal, Quebec, April 2008. - Johns, EK et al. The Montreal Cognitive Assessment: Normative data in the community. Journal of the International Neuropsychological Society, 14 (Suppl.1), i-292. (Poster presented at the 36th annual meeting of the International Neuropsychological Society, Waikoloa, Hawaii, February 2008). Young adults - Ratchford TL et al. Normative Data for the Montreal Cognitive Assessment (MoCA) in Young Adults. P05.128. Presented at the American Academy of Neurology Meeting. April 2008. Neurology 70, March 11, 2008 (Suppl 1) A283. Reviews - Lilly, Pfizer/JNJ/Elan's mild-to-moderate Alzheimer's failures may spur use of more sensitive cognitive screening tools for early disease - experts. BioPharm Insight, published 2012-12-28. - Ziad S. Nasreddine, Gao Jing. The MoCA-Development and use in China for detection of cognition impairment. - Chin J. Neurol, Feb. 2012, Vol. 45, No. 2. - Ronald C. Petersen. Mild Cognitive Impairment. N Engl J Med 2011;364:2227-34. - Zahinoor Ismail et al. Brief cognitive screening instruments: an update. Int J Geriatr Psychiatry 2010;25: 111-120. - Bredje A. Appels, MSc and Erick Scherder, Phd. the Diagnostic Accuracy of Dementia-Screening Instruments With an Administration Time of 10 to 45 Minutes for *Use in Secondary Care: A Systematic Review. American Journal of Alzheimer's Disease & Other Dementias 2010, 25(4) 301-316. - Manuel Montero-Odasso, Susan W. Muir. Simplifying detection of mild cognitive impairment subtypes. Journal of the American Geriatrics Society, May 2010-Vol.58, no. 5. - Guo Qi-Hao et al. Application study of quick cognitive screening test in identifying mild cognitive impairment. Neuroscience Bulletin, February 2010, 26(1):47:54. - Lonie Jane A. et al. Screening for mild cognitive impairment: a systematic review. International Journal of Geriatric Psychiatry 2009; 24: 902-915. - Shiroky et al. Can you have dementia with an MMSE score of 30. Am J of Alzheimers Dis & Other Demen, Oct.-Nov. 2007;22:5; 406-415. - Chertkow H, Nasreddine Z, et al. Mild cognitive impairment and cognitive impairment, no dementia: Part A, concept and diagnosis Alzheimer's & Dementia: The Journal of the Alzheimer's Association October 2007 (Vol. 3, Issue 4, pages 266-282). - Howe E. Initial screening of patients for Alzheimer's disease and minimal cognitive impairment. Psychiatry, Volume 4 (7), July 2007, 24-27. - Gauthier et al. Mild cognitive impairment. Lancet. 2006 April 15;367(9518):1262-70, Review. - Hachinski et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 2006, Sept.;37(9):2220-41. - Allan L et al. Mild Cognitive Impairment: An Opportunity to Identify Patients at High Risk for Progression to Alzheimer's Disease. Clin Ther 2006;28:991-1001. - Olson R., Parkinson M., McKenzie M. Selection Bias Introduced by Neuropsychological Assessments. Canadian Journal of Neurological Sciences, 2010;37:264-268. ## Language Validation Studies Alternate forms - Ana S. Costa, Bruno Fimm, Paul Friesen, Herve Soundjock, Claudia Rottschy, Therese Gross, Frank Eitner, Arno Reich, Jorg B.Schulz, Ziad S. Nasreddine, Kathrin Reetz. Alternate-Form Reliability of the Montreal Cognitive Assessment Screening Test in a Clinical Setting. Dement Geriatr Cogn Disord 2012;33:379-384. - Howard Chertkow, Ziad Nasreddine, Natalie A. Phillips et al. The Montreal Cognitive Assessment (MoCA): Validation of Alternate Forms and New Recommendations for Education Corrections. Abstract presented at AAIC Conference Paris, July 2011. Arabic - Rahman et al. Montreal Cognitive Assessment Arabic version: Reliability and validity prevalence of mild cognitive impairment among elderly attending geriatric clubs in Cairo. Geriatrics and Gerontology International, Vol. 9, number 1, March 2009, pp. 54-61 (8). Chinese - Dong et al. Comparison of the Montreal Cognitive Assessment and the Mini-Mental State Examination in detecting multi-domain mild cognitive impairment in a Chinese sub-sample drawn from a population-based study. Int Psychogeriatr. 2013 Jul 22:1-8. [Epub ahead of print] - Niu et al. Non-high-density lipoprotein cholesterol and other risk factors of mild cognitive impairment among Chinese type 2 diabetic patients. J Diabetes Complications. 2013 Sep-Oct;27(5):443-6. Epub 2013 Jul 9. - Wang et al. The relationship between cognitive impairment and cerebral blood flow changes after transient ischaemic attack. Neurol Res. 2013 Jul;35(6):580-5. Zavoreo et al. Cognitive decline and cerebral vasoreactivity in asymptomatic patients with severe internal carotid artery stenosis. Acta Neurol Belg. 2013 Apr 6 - Cheng et al. Effects of carotid artery stenting on cognitive function in patients with mild cognitive impairment and carotid stenosis. Exp Ther Med. 2013 Apr;5(4):1019-1024. - Wong et al. Comparison of montreal cognitive assessment and mini-mental state examination in evaluating cognitive domain deficit following aneurysmal subarachnoid haemorrhage. PLoS One. 2013;8(4). Epub 2013 Apr 3. - Zhang et al. Relationship between cerebral microbleeds and cognitive function in lacunar infarct. J Int Med Res. 2013 Apr;41(2):347-55. - Wong et al. Validity of the Montreal Cognitive Assessment for traumatic brain injury patients with intracranial haemorrhage. Brain Inj. 2013;27(4):394-8. . Epub 2013 Mar 8. - Tu et al. Reliability, validity, and optimal cutoff score of the montreal cognitive assessment (changsha version) in ischemic cerebrovascular disease patients of hunan province, China. Dement Geriatr Cogn Dis Extra. 2013 Feb 16;3(1):25-36. - Tan et al. [Clinical research of early intervention of modified shuyu pill in vascular cognitive impairment no dementia]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013 Jan;33(1):27-30. Article in Chinese. - Zhao et al. Executive dysfunction in patients with cerebral hypoperfusion after cerebral angiostenosis/occlusion. Neurol Med Chir (Tokyo). 2013;53(3):141-7. - Hu JB et al. Cross-cultural difference and validation of the Chinese version of Montreal Cognitive Assessment in older adults residing in Eastern China: *Preliminary findings. Arch Gerontol Geriatr. 2013 Jan-Feb;56(1):38-43. doi: 10.1016/j.archger.2012.05.008 Epub 2012 Jun 13. Chia-Fen Tsai, Wei-Ju Lee, Shuu-Jiun Wang, Ben-Chang Shia, Ziad Nasreddine and Jong-Ling Fuh. Psychometrics of the Montreal Cognitive Assessment (MoCA) and its subscales: validation of the Taiwanese version of the MoCA and an item response theory analysis. International Psychogeriatrics (2012), 24:4, 651-658. - Adrian Wong et al. The Validity, Reliability and Clinical Utility of the Hong Kong Montreal Cognitive Assessment (HK-MoCA) in patients with cerebral small vessel disease, Dement Geriatr Cogn Disord, Aug. 2009;28-81-87. - Wong A et al. The Validity, Reliability and Utility of the Cantonese Montreal Cognitive Assessment (MoCA) in Chinese Patients with Confluent White Matter - Lesions. Hong Kong Med J, Volume 14, Number 6, Supplement 6, December 2008. - Wen HB et al. The application of Montreal cognitive assessment in urban Chinese residents of Beijing. Zhonghua Nei Ke Za Zhi. 2008. Jan;47(1):36-9. Chinese. Croatian - Martinic-Popovic I. et al. Early detection of mild cognitive impairment in patients with cerebrovascular disease. Acta Clin Croat 2006;45-77-85. Czech - J.Reban. Montrealsky kognitivni test/MoCA/: prinos k diagnostice predemenci, Ceska Geriatricka Revue 2006 (4): 224-229. Dutch - Thissen AJ et al. Applicability and validity of the Dutch version of the Montreal Cognitive Assessment (MoCA-d) in diagnosing MCI. Gerontol Geriatr. 2010 Dec;41(6):231-40. - Janneke Thissen et al. Validity of the Montreal Cognitive Assessment Dutch Version (MoCA-D), presented at the international Psychogeriatric Association Conference, Sept. 2009, Montreal, Quebec, Canada. English - Costa A, Fimm B, Friesen P, Soundjock H, Rottschy C, Gross T, Eitner F, Reich A, Schulz JB, Nasreddine ZS, Reetz K. Alternate-form Reliability of the Montreal Cognitive Assessment (MoCA) screening test in a clinical setting. Demen Geriatr Cogn Disord 2012;33(6):379-84. - Luis CA et al. Cross validation of the Montreal Cognitive Assessment in community dwelling older adults residing in the Southeastern US. International Journal of Geriatric Psychiatry, Online issue, October 21st, 2008, published 2009;24: 197-201. - Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment (MoCA): A brief screening tool for mild cognitive impairment. J Am Geriatr. Soc. 53:695-699, 2005. French - Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment (MoCA): A brief screening tool for mild cognitive impairment. J Am Geriatr. Soc. 53:695-699, 2005. Hebrew - Michal Lifshitz et al. Validation of the Hebrew Version of the MoCA Test as a Screening Instrument for the Early Detection of Mild Cognitive Impairment in Elderly Individuals. Journal of Geriatric Psychiatry and Neurology 2012 25(3) 155-161. Italian - Pasi et al. Factors predicting the Montreal cognitive assessment (MoCA) applicability and performances in a stroke unit. J Neurol. 2013 Jun;260(6):1518-26. Japanese - Fujiwara et al. Physical and Sociopsychological Characteristics of Older Community Residents With Mild Cognitive Impairment as Assessed by the Japanese Version of the Montreal Cognitive Assessment. J Geriatr Psychiatry Neurol. 2013 Aug 6. [Epub ahead of print]. - Kenji Narazakia, Yu Nofujib et al. Normative Data for the Montreal Cognitive Assessment in a Japanese Community-Dwelling Older Population. Neuroepidemiology 2013;40:23-29. - Ihara et al. Association of Physical Activity with the Visuospatial/Executive Functions of the Montreal Cognitive Assessment in Patients with Vascular Cognitive Impairment. J Stroke Cerebrovasc Dis. 2012 Nov 12. pii: S1052-3057(12)00339-4. - Fujiwara Y. et al. Brief screening tool for mild cognitive impairment in older Japanese: Validation of the Japanese version of the Montreal Cognitive Assessment. Geriatr Gerontol Int. 2010;10:225-232. Korean - Hwang et al. Effects of falls experience on cognitive functions and physical activities in community-dwelling individuals with chronic stroke. Int J Rehabil Res. 2013 Jun;36(2):134-9. - Jun-Young Lee et al. Brief Screening for Mild Cognitive Impairment in Elderly Outpatient Clinic: Validation of the Korean Version of Montreal Cognitive Assessment 2008; J Geriatr Psychiatry Neurol, June 2008, 21;2:104-110. Korean-K2 - Kang YW et al. Reliability Validity, and Normative Study of the Korean-Montreal Cognitive Assessment (K-MoCA) as an Instrument for screening of Vascular Cognitive Impairment (VCI). The Korean Journal of Clinical Psychology. 2009;28:549-562. Persian - Sikaroodi et al. Cognitive impairments in patients with cerebrovascular risk factors: A comparison of Mini Mental Status Exam and Montreal Cognitive Assessment. Clin Neurol Neurosurg. 2013 Aug;115(8):1276-80. Polish - Magierska J et al. Clinical application of the Polish adaptation of the Montreal Cognitive Assessment (MoCA) test in screening for cognitive impairment. Neurologia i neurochirurgia polska 2012, 46(2):130-139. - Joanna Magierska, Radoslaw Magierski, Tomasz Sobow, Iwona Kloszewska. The Polish adaptation of the Montreal Cognitive Assessment (MoCA) and preliminary results of its clinical utility in the screening for cognitive impairment. Presented at ICAD Conference Poster 2008, Chicago. Portuguese - Freitas S. et al. (2012). Construct validity of the Montreal Cognitive Assessment (MoCA). Journal of International Neuropsychology Society, 18,242-250. doi:10.1017/S1355617711001573. - Freitas S. et al. (2012). Montreal Cognitive Assessment (MoCA): Validation study for Mild Cognitive Impairment and Alzheimer's disease. Alzheimer Disease and Associated Disorders, doi: 10.1097/WAD.0b013e3182420bfe. - Freitas S. Simoes M.R, Alves L. & Santana (2012). Montreal Cognitive Assessment (MoCA): Influence of sociodemographic and health variables. Archives of Clinical Neuropsychology, 27, 165-175. doi:10.1093/arclin/acr116. - Freitas S. et al. (2011). Montreal Cognitive Assessment (MoCA): Normative study for the Portuguese population. Journal of Clinical and Experimental Neuropsychology, 33(9), 989-996. doi:10.1080/13803395.2011.589374 - Duro D et al. Validation studies of the Portuguese experimental version of the Montreal Cognitive Assessment (MoCA): confirmatory factor analysis. J Neurol. 2010 May;257(5):728-34. - Freitas S, Santana I, Simoes, M.R. (2010). The sensitivity of the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) to cognitive decline: A longitudinal study. Alzheimer's & Dementia, 6(4), S353-S354 Abstract. - Freitas S, et al. (2010). Estudos de adaptacao do Montreal Cognitive Assessment (MoCA) para a populacao portuguesa. Avaliacao Psicologica, 9(3), 345-357. Portuguese (Brazil) - Bertolucci PH et al. Brazilian Portuguese version for the Montreal Cognitive Assessment (MoCA) and the preliminary results. Presented at Alzheimer's Association International Conference on Alzheimer's Disease. Alzheimer's and Dementia, Volume 4, Issue 4, Supplement 1, July 2008, Page T686. - Bertolucci PH et al. Brazilian Portuguese version for the Montreal Cognitive Assessment (MoCA) and the preliminary results. Presented at Alzheimer's Association International Conference on Alzheimer's Disease. Alzheimer's and Dementia, Vol. 4, Issue 4 Supplement 1, July 2008, page T686. - Claudia M. Memoria et al. Brief screening for mild cognitive impairment: validation of the Brazilian version of the Montreal Cognitive Assessment. Int J Geriatr Psychiatry, 2013 Jan;28(1) 34-40. Russian - Boiko et al. [Possibilities of medical correction of moderate cognitive impairment]. [Article in Russian] Zh Nevrol Psikhiatr Im S S Korsakova. 2013;113(2):28-32. Sinhalese - Karunaratne S. et al. Validation of the Sinhala version of the Montreal Cognitive Assessment in screening for dementia. Ceylon Medical Journal, 56(4), 147-153, 2011. Spanish - Gomez F et al. Applicability of the MoCA-S test in populations with little education in Colombia. Int J Geriatr Psychiatry 2012, Sep 20. doi: 10.1002/gps.3885. Thai - Tangwongchai S et al. The Validity of Thai version of the Montreal Cognitive Assessment (MoCA-T), Presented at the International Psychogeriatric Association Conference, Sept. 2009, Montreal, Quebec, Canada. Turkish - Selekler K. & Cangoz B. (October 2009). Predictive Validity Study of MoCA on Turkish Patients with MCI and Alzheimer Dementia. (Poster). 19th World Congress of Neurology (WCN 2009), Bangkok, Thailand. - Kaynak Selekler et al. Power of discrimination of Montreal Cognitive Assessment (MoCA) Scale in Turkish Patients with Mild Cognitive Impairment and Alzheimer's Disease. Turkish Journal of Geriatrics 2010;13(3) 166-171.[6]

https://www.wikidoc.org/index.php/MOCA

f9b833cbdf347dbd36712e5546c06ed4a0477897

wikidoc

MPPP

MPPP MPPP (1-methyl-4-phenyl-4-propionoxypiperidine, Desmethylprodine) is an opioid analgesic drug. It is not used in clinical practice, but has been illegally manufactured for recreational drug use. It is an analog of meperidine (Demerol), but since it is not used in medicine, the DEA has labeled it a Schedule I drug in the United States. In fact, it is the reversed ester of meperidine and is listed as having 70% of the potency of morphine. The drug was first illicitly synthesised by a graduate student called Barry Kidston. Kidston had apparently studied a 1947 paper by Albert Zeiring. By reversing the ester of the meperidine skeleton, a drug approaching the potency of morphine was produced. However, the intermediate tertiary alcohol is liable to dehydration in acidic conditions if the reaction temperature rises above -30°C, and since Kidston did not realise this and esterified the intermediate with propanoic anhydride at room temperature, MPTP was formed as a major impurity. 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPP+), a metabolite of MPTP, causes rapid onset of irreversible symptoms similar to Parkinson's Disease. MPTP is metabolized to the neurotoxin MPP+ by the enzyme MAO-B, which is expressed in neurons. This selectively kills brain tissue in the area of the brain called the substantia nigra and causes Parkinsonian symptoms.

MPPP MPPP (1-methyl-4-phenyl-4-propionoxypiperidine, Desmethylprodine) is an opioid analgesic drug. It is not used in clinical practice, but has been illegally manufactured for recreational drug use. It is an analog of meperidine (Demerol), but since it is not used in medicine, the DEA has labeled it a Schedule I drug in the United States. In fact, it is the reversed ester of meperidine and is listed as having 70% of the potency of morphine. The drug was first illicitly synthesised by a graduate student called Barry Kidston. Kidston had apparently studied a 1947 paper by Albert Zeiring. By reversing the ester of the meperidine skeleton, a drug approaching the potency of morphine was produced. However, the intermediate tertiary alcohol is liable to dehydration in acidic conditions if the reaction temperature rises above -30°C, and since Kidston did not realise this and esterified the intermediate with propanoic anhydride at room temperature, MPTP was formed as a major impurity.[1] 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPP+), a metabolite of MPTP, causes rapid onset of irreversible symptoms similar to Parkinson's Disease.[2][1] MPTP is metabolized to the neurotoxin MPP+ by the enzyme MAO-B, which is expressed in neurons. This selectively kills brain tissue in the area of the brain called the substantia nigra and causes Parkinsonian symptoms.[3] Template:Pharm-stub

https://www.wikidoc.org/index.php/MPPP

ee517ad48d47b42ab0f8aca2c39fe601538ea3e3

wikidoc

MPTP

MPTP MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) is a neurotoxin that causes permanent symptoms of Parkinson's disease by killing certain neurons in the substantia nigra of the brain. It is used to study the disease in monkeys. While MPTP itself does not have opioid effects, it is related to MPPP, a synthetic opioid drug with effects similar to those of heroin and morphine. MPTP can be accidentally produced during the illicit manufacture of MPPP, and that is how its Parkinson-inducing effects were first discovered. # Toxicity Injection of MPTP causes rapid onset of Parkinsonism, hence users of MPPP contaminated with MPTP will develop these symptoms. MPTP itself is not toxic, and as a lipophilic compound can cross the blood-brain barrier. Once inside the brain, MPTP is metabolized into the toxic cation 1-methyl-4-phenylpyridinium (MPP+) by the enzyme MAO-B of glial cells. MPP+ primarily kills dopamine-producing neurons in a part of the brain called the substantia nigra. MPP+ interferes with complex I of the electron transport chain, a component of mitochondrial metabolism, which leads to cell death and causes the buildup of free radicals, toxic molecules that contribute further to cell destruction. MPTP has quite selective abilities to cause neuronal death in dopaminergic cells, apparently through a high-affinity uptake process in nerve terminals normally used to reuptake dopamine after it has been released into the synaptic cleft. The dopamine transporter moves MPP+ inside the cell. The resulting gross depletion of dopaminergic neurons has severe implications on cortical control of complex movements. The direction of complex movement is based from the substantia nigra to the putamen and caudate nucleus which then relay signals to the rest of the brain. This pathway is controlled via dopamine-using neurons, which MPTP selectively destroys, resulting over time in parkinsonism. MPTP causes parkinsonism in primates including humans. Rodents are much less susceptible. Rats are almost immune to the adverse effects of MPTP. Mice suffer from cell death in the substantia nigra (to differing degree according to the strain of mice used) but do not show parkinsonian symptoms. It is believed that the lower levels of MAO B in the rodent brain's capillaries may be responsible for this. # Discovery in users of illicit drugs The neurotoxicity of MPTP was hinted at in 1976 after Barry Kidston, a 23-year-old chemistry graduate student in Maryland, synthesized MPPP incorrectly and injected the result. It was contaminated with MPTP, and within three days he began exhibiting symptoms of Parkinson's disease. The National Institute of Mental Health found traces of MPTP and other meperidine analogues in his lab. They tested the substances on rats, but due to rodents' tolerance for this type of neurotoxin nothing was observed. Kidston's parkinsonism was successfully treated with Levo-dopa but he died 18 months later from a cocaine overdose. Upon autopsy, destruction of dopamine-neurons in the substantia nigra was discovered. In 1982, seven people in Santa Clara County, California were diagnosed with Parkinsonism after using MPPP contaminated with MPTP. The neurologist J. William Langston in collaboration with NIH tracked down MPTP as the cause, researched its effects on primates, and was eventually able to successfully treat motor symptoms of three of the seven patients with neural grafts of fetal stem cells from aborted human fetuses in collaboration with neuroscientists from Lund University Hospital in Sweden. This experience was documented in a book he authored, The Case of the Frozen Addicts (ISBN 0-679-42465-2), about his quest for a cure, which was later featured in two NOVA productions by PBS. # Contribution of MPTP to research into Parkinson's disease Langston et al.(1984) found that injections of MPTP in squirrel monkeys resulted in parkinsonism, symptoms of which were subsequently reduced by Levo-dopa, a precursor for the neurotransmitter dopamine, currently the drug-of-choice in treatment of Parkinson's. The symptoms and brain structures of MPTP-induced Parkinson's are fairly indistinguishable to the point that MPTP may be used to simulate the disease in order to study Parkinson's physiology and possible treatments within the laboratory. Mouse studies have shown that susceptibility to MPTP increases with age. Knowledge of MPTP and its use in reliably recreating Parkinson's disease in experimental models has inspired scientists to investigate the possibilities of surgically replacing neuron loss through fetal tissue implants, subthalamic electrical stimulation and stem cell research, all of which have demonstrated initial, provisional successes. It has been postulated that Parkinson's disease may be caused by minute amounts of MPP+ like compounds from ingestion or exogenously through repeated exposure and that these substances are too minute to be detected significantly by epidemiological studies. In 2000 another animal model for Parkinson's Disease was found. It was shown that the pesticide and insecticide rotenone causes parkinsonism in rats by killing dopaminergic neurons in the substantia nigra. Like MPP+, rotenone also interferes with complex I of the electron transport chain. # Synthesis and uses MPTP was first synthesized as an analgesic in 1947 by Ziering et al.. It can be formed by mixing formaldehyde, methylamine and alpha-methylstyrene. It was tested as a treatment for various conditions, but the tests were halted when Parkinson-like symptoms were noticed in monkeys. In one test of the substance, two of six human subjects died. MPTP is used in industry as a chemical intermediate; the chloride of the toxic metabolite MPP+ was turned into the herbicide Cyperquat.

MPTP Template:Chembox new MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) is a neurotoxin that causes permanent symptoms of Parkinson's disease by killing certain neurons in the substantia nigra of the brain. It is used to study the disease in monkeys. While MPTP itself does not have opioid effects, it is related to MPPP, a synthetic opioid drug with effects similar to those of heroin and morphine. MPTP can be accidentally produced during the illicit manufacture of MPPP, and that is how its Parkinson-inducing effects were first discovered. # Toxicity Injection of MPTP causes rapid onset of Parkinsonism, hence users of MPPP contaminated with MPTP will develop these symptoms. MPTP itself is not toxic, and as a lipophilic compound can cross the blood-brain barrier. Once inside the brain, MPTP is metabolized into the toxic cation 1-methyl-4-phenylpyridinium (MPP+) by the enzyme MAO-B of glial cells. MPP+ primarily kills dopamine-producing neurons in a part of the brain called the substantia nigra. MPP+ interferes with complex I of the electron transport chain, a component of mitochondrial metabolism, which leads to cell death and causes the buildup of free radicals, toxic molecules that contribute further to cell destruction. MPTP has quite selective abilities to cause neuronal death in dopaminergic cells, apparently through a high-affinity uptake process in nerve terminals normally used to reuptake dopamine after it has been released into the synaptic cleft. The dopamine transporter moves MPP+ inside the cell. The resulting gross depletion of dopaminergic neurons has severe implications on cortical control of complex movements. The direction of complex movement is based from the substantia nigra to the putamen and caudate nucleus which then relay signals to the rest of the brain. This pathway is controlled via dopamine-using neurons, which MPTP selectively destroys, resulting over time in parkinsonism. MPTP causes parkinsonism in primates including humans. Rodents are much less susceptible. Rats are almost immune to the adverse effects of MPTP. Mice suffer from cell death in the substantia nigra (to differing degree according to the strain of mice used) but do not show parkinsonian symptoms. It is believed that the lower levels of MAO B in the rodent brain's capillaries may be responsible for this.[1] # Discovery in users of illicit drugs The neurotoxicity of MPTP was hinted at in 1976 after Barry Kidston, a 23-year-old chemistry graduate student in Maryland, synthesized MPPP incorrectly and injected the result. It was contaminated with MPTP, and within three days he began exhibiting symptoms of Parkinson's disease. The National Institute of Mental Health found traces of MPTP and other meperidine analogues in his lab. They tested the substances on rats, but due to rodents' tolerance for this type of neurotoxin nothing was observed. Kidston's parkinsonism was successfully treated with Levo-dopa but he died 18 months later from a cocaine overdose. Upon autopsy, destruction of dopamine-neurons in the substantia nigra was discovered.[2] In 1982, seven people in Santa Clara County, California were diagnosed with Parkinsonism after using MPPP contaminated with MPTP. The neurologist J. William Langston in collaboration with NIH tracked down MPTP as the cause, researched its effects on primates, and was eventually able to successfully treat motor symptoms of three of the seven patients with neural grafts of fetal stem cells from aborted human fetuses in collaboration with neuroscientists from Lund University Hospital in Sweden. This experience was documented in a book he authored, The Case of the Frozen Addicts (ISBN 0-679-42465-2), about his quest for a cure, which was later featured in two NOVA productions by PBS. # Contribution of MPTP to research into Parkinson's disease Langston et al.(1984) found that injections of MPTP in squirrel monkeys resulted in parkinsonism, symptoms of which were subsequently reduced by Levo-dopa, a precursor for the neurotransmitter dopamine, currently the drug-of-choice in treatment of Parkinson's. The symptoms and brain structures of MPTP-induced Parkinson's are fairly indistinguishable to the point that MPTP may be used to simulate the disease in order to study Parkinson's physiology and possible treatments within the laboratory. Mouse studies have shown that susceptibility to MPTP increases with age. Knowledge of MPTP and its use in reliably recreating Parkinson's disease in experimental models has inspired scientists to investigate the possibilities of surgically replacing neuron loss through fetal tissue implants, subthalamic electrical stimulation and stem cell research[1], all of which have demonstrated initial, provisional successes. It has been postulated that Parkinson's disease may be caused by minute amounts of MPP+ like compounds from ingestion or exogenously through repeated exposure and that these substances are too minute to be detected significantly by epidemiological studies.[3] In 2000 another animal model for Parkinson's Disease was found. It was shown that the pesticide and insecticide rotenone causes parkinsonism in rats by killing dopaminergic neurons in the substantia nigra. Like MPP+, rotenone also interferes with complex I of the electron transport chain.[4] # Synthesis and uses MPTP was first synthesized as an analgesic in 1947 by Ziering et al.. It can be formed by mixing formaldehyde, methylamine and alpha-methylstyrene. It was tested as a treatment for various conditions, but the tests were halted when Parkinson-like symptoms were noticed in monkeys. In one test of the substance, two of six human subjects died.[5] MPTP is used in industry as a chemical intermediate; the chloride of the toxic metabolite MPP+ was turned into the herbicide Cyperquat.[5]

https://www.wikidoc.org/index.php/MPTP

bd10f48a92abe7592ea59443b1765eb7215cd326

wikidoc

MRAS

MRAS Ras-related protein M-Ras, also known as muscle RAS oncogene homolog and R-Ras3, is a protein that in humans is encoded by the MRAS gene on chromosome 3. It is ubiquitously expressed in many tissues and cell types. This protein functions as a signal transducer for a wide variety of signaling pathways, including those promoting neural and bone formation as well as tumor growth. The MRAS gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. # Structure ## Gene The MRAS gene resides on chromosome 3 at the band 3q22.3 and includes 10 exons. This gene produces 2 isoforms through alternative splicing. ## Protein M-Ras is a member of the small GTPase superfamily under the Ras family, which also includes Rap1, Rap2, R-Ras, and R-Ras2 (TC21). This protein spans a length of 209 residues. Its N-terminal amino acid sequence shares 60-75% identity with that in the Ras protein while its effector region is identical with that in Ras. M-Ras shares a similar structure with H-Ras and Rap2A with the exception of its switch 1 conformation when bound to guanosine 5'-(beta,gamma-imido)triphosphate (Gpp(NH)p). Of the two states M-Ras can switch between, M-Ras is predominantly found in its state 1 conformation, which does not bind Ras effectors. # Function The MRAS gene is expressed specifically in brain, heart, myoblasts, myotubes, fibroblasts, skeletal muscles, and uterus, suggesting a specific role of M-Ras in these tissue and cells. M-Ras is involved in many biological processes by activating a wide variety of proteins. For instance, it is activated by Ras guanine nucleotide exchange factors and can bind/activate some Ras protein effectors. M-Ras also weakly stimulates the mitogen-activated protein kinase (MAPK) activity and ERK2 activity, but modestly stimulates trans-activation from different nuclear response elements which bind transcription factors, such as SRF, ETS/TCF, Jun/Fos, and NF- kB/Rel. M-Ras has been found to induce Akt kinase activity in the PI3-K pathway, and it may play a role in cell survival of neural-derived cells. Moreover, M-Ras plays a crucial role in the downregulation of OCT4 and NANOG protein levels upon differentiation and has been demonstrated to modulate cell fate at early steps of development during neurogenesis. M-Ras, induced and activated by BMP-2 signaling, also participates in the osteoblastic determination, differentiation, and transdifferentiation under p38 MAPK and JNK regulation. M-Ras is involved in TNF-alpha-stimulated and Rap1-mediated LFA-1 activation in splenocytes. More generally, cells transfected with M-Ras exhibit dendritic appearances with microspikes, suggesting that M-Ras may participate in reorganization of the actin cytoskeleton. In addition, it is reported that M-Ras forms a complex with SCRIB and SHOC2, a polarity protein with tumor suppressor properties, and may play a key role in tumorigenic growth. # Clinical significance In humans, other members of the Ras subfamilies carry mutations in human cancers. Furthermore, the Ras proteins are not only involved in tumorigenesis but also in many developmental disorders. For instance, the Ras-related proteins appear to be overexpressed in human carcinomas of the oral cavity, esophagus, stomach, skin, and breast, as well as in lymphomas. More currently, Ras family members such as R-RAS, R-RAS2 and also R-RAS3 have also been implicated as main factors in triggering neural transformation, with R-RAS2 as the most significant element. ## Clinical marker A multi-locus genetic risk score study based on a combination of 27 loci, including the MRAS gene, identified individuals at increased risk for both incidence and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). # Interactions MRAS has been shown to interact with RASSF5 and RALGDS.

MRAS Ras-related protein M-Ras, also known as muscle RAS oncogene homolog and R-Ras3, is a protein that in humans is encoded by the MRAS gene on chromosome 3.[1][2][3] It is ubiquitously expressed in many tissues and cell types.[4] This protein functions as a signal transducer for a wide variety of signaling pathways, including those promoting neural and bone formation as well as tumor growth.[5][6][7][8] The MRAS gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[9] # Structure ## Gene The MRAS gene resides on chromosome 3 at the band 3q22.3 and includes 10 exons.[3] This gene produces 2 isoforms through alternative splicing.[10] ## Protein M-Ras is a member of the small GTPase superfamily under the Ras family, which also includes Rap1, Rap2, R-Ras, and R-Ras2 (TC21).[10] This protein spans a length of 209 residues. Its N-terminal amino acid sequence shares 60-75% identity with that in the Ras protein while its effector region is identical with that in Ras. M-Ras shares a similar structure with H-Ras and Rap2A with the exception of its switch 1 conformation when bound to guanosine 5'-(beta,gamma-imido)triphosphate (Gpp(NH)p). Of the two states M-Ras can switch between, M-Ras is predominantly found in its state 1 conformation, which does not bind Ras effectors.[11] # Function The MRAS gene is expressed specifically in brain, heart, myoblasts, myotubes, fibroblasts, skeletal muscles, and uterus, suggesting a specific role of M-Ras in these tissue and cells.[12][13] M-Ras is involved in many biological processes by activating a wide variety of proteins. For instance, it is activated by Ras guanine nucleotide exchange factors and can bind/activate some Ras protein effectors.[14] M-Ras also weakly stimulates the mitogen-activated protein kinase (MAPK) activity and ERK2 activity, but modestly stimulates trans-activation from different nuclear response elements which bind transcription factors, such as SRF, ETS/TCF, Jun/Fos, and NF- kB/Rel.[13][15] M-Ras has been found to induce Akt kinase activity in the PI3-K pathway, and it may play a role in cell survival of neural-derived cells.[16] Moreover, M-Ras plays a crucial role in the downregulation of OCT4 and NANOG protein levels upon differentiation and has been demonstrated to modulate cell fate at early steps of development during neurogenesis.[17] M-Ras, induced and activated by BMP-2 signaling, also participates in the osteoblastic determination, differentiation, and transdifferentiation under p38 MAPK and JNK regulation.[18] M-Ras is involved in TNF-alpha-stimulated and Rap1-mediated LFA-1 activation in splenocytes.[19] More generally, cells transfected with M-Ras exhibit dendritic appearances with microspikes, suggesting that M-Ras may participate in reorganization of the actin cytoskeleton.[12] In addition, it is reported that M-Ras forms a complex with SCRIB and SHOC2, a polarity protein with tumor suppressor properties, and may play a key role in tumorigenic growth.[20] # Clinical significance In humans, other members of the Ras subfamilies carry mutations in human cancers.[21] Furthermore, the Ras proteins are not only involved in tumorigenesis but also in many developmental disorders.[21] For instance, the Ras-related proteins appear to be overexpressed in human carcinomas of the oral cavity, esophagus, stomach, skin, and breast, as well as in lymphomas.[22][23][24][25] More currently, Ras family members such as R-RAS, R-RAS2 and also R-RAS3 have also been implicated as main factors in triggering neural transformation, with R-RAS2 as the most significant element.[26] ## Clinical marker A multi-locus genetic risk score study based on a combination of 27 loci, including the MRAS gene, identified individuals at increased risk for both incidence and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[27] # Interactions MRAS has been shown to interact with RASSF5[28] and RALGDS.[1][29]

https://www.wikidoc.org/index.php/MRAS

1f05df0d088099af1a9985fc0b4d2eb035fef6a5

wikidoc

MSDS

MSDS A material safety data sheet (MSDS) is a form containing data regarding the properties of a particular substance. An important component of product stewardship and workplace safety, it is intended to provide workers and emergency personnel with procedures for handling or working with that substance in a safe manner, and includes information such as physical data (melting point, boiling point, flash point, etc.), toxicity, health effects, first aid, reactivity, storage, disposal, protective equipment, and spill handling procedures. The exact format of an MSDS can vary from source to source. MSDS (Material Safety Data Sheets) are a widely used system for cataloging information on chemicals, chemical compounds, and chemical mixtures. MSDS information may include instructions for the safe use and potential hazards associated with a particular material or product. MSDS can be found anywhere chemicals are being used. There is also a duty to properly label substances on the basis of physico-chemical, health and/or environmental risk. Labels include hazard symbols such as the Saint Andrew's Cross (a black diagonal cross on an orange background which is used in the European Union to denote a harmful or irritant substance). An MSDS for a substance is not primarily intended for use by the general consumer, focusing instead on the hazards of working with the material in an occupational setting. For example, an MSDS for a cleaning solution is not highly pertinent to someone who uses a can of the cleaner once a year, but is extremely important to someone who does this in a confined space for 40 hours a week. In some jurisdictions, the MSDS is required to state the chemical's risks, safety and impact on the environment. # Usage by country In the U.S., the Occupational Safety and Health Administration requires that MSDS be available to employees for potentially harmful substances handled in the workplace under the Hazard Communication regulation. The MSDS is also required to be made available to local fire departments and local and state emergency planning officials under Section 311 of the Emergency Planning and Community Right-to-Know Act. In Canada, the program known as the Workplace Hazardous Materials Information System (WHMIS) establishes the requirements for MSDSs in workplaces and is administered federally by Health Canada under the Hazardous Products Act, Part II and the Controlled Products Regulations. WHMIS and MSDS requirements are also enforced by provincial Ministries or Departments of Labour. In the U.K., the Chemicals (Hazard Information and Packaging for Supply) Regulations 2002 - known as CHIP Regulations - impose duties upon suppliers, and importers into the EU, of hazardous materials. The Control of Substances Hazardous to Health (COSHH) Regulations govern the use of hazardous substances in the workplace in the UK and specifically require an assessment of the use of a substance. Regulation 12 requires that an employer provides employees with information, instruction and training for people exposed to hazardous substances. This duty would be very nearly impossible without the data sheet as a starting point. It is important for employers therefore to insist on receiving a data sheet from a supplier of a substance. # Phrases The European Union (EU) requires that Risk and Safety Statements ( R- and S-phrases) and a symbol appear on each label and safety data sheet for hazardous chemicals. - R-phrases consist of the letter R followed by a number. See List of R-phrases. - S-phrases consist of the letter S followed by a number. See List of S-phrases. # Water hazard classes The German Federal Water Management Act requires that substances be evaluated for negative influence on the physical, chemical or biological characteristics of water. These are classified into numeric water hazard classes (WGK or WHC depending whether you use the German or English acronym). - WGK nwg: Non-water polluting substance - WGK 1: Slightly water polluting substance - WGK 2: Water polluting substance - WGK 3: Highly water polluting substance # MSDS authoring Many companies offer the service of collecting, or writing and revising, data sheets to ensure they are up to date and available for their subscribers or users. Some jurisdictions impose an explicit duty of care that each MSDS be regularly updated (usually every three to five years).

MSDS A material safety data sheet (MSDS) is a form containing data regarding the properties of a particular substance. An important component of product stewardship and workplace safety, it is intended to provide workers and emergency personnel with procedures for handling or working with that substance in a safe manner, and includes information such as physical data (melting point, boiling point, flash point, etc.), toxicity, health effects, first aid, reactivity, storage, disposal, protective equipment, and spill handling procedures. The exact format of an MSDS can vary from source to source. MSDS (Material Safety Data Sheets) are a widely used system for cataloging information on chemicals, chemical compounds, and chemical mixtures. MSDS information may include instructions for the safe use and potential hazards associated with a particular material or product. MSDS can be found anywhere chemicals are being used. There is also a duty to properly label substances on the basis of physico-chemical, health and/or environmental risk. Labels include hazard symbols such as the Saint Andrew's Cross (a black diagonal cross on an orange background which is used in the European Union to denote a harmful or irritant substance). An MSDS for a substance is not primarily intended for use by the general consumer, focusing instead on the hazards of working with the material in an occupational setting. For example, an MSDS for a cleaning solution is not highly pertinent to someone who uses a can of the cleaner once a year, but is extremely important to someone who does this in a confined space for 40 hours a week. In some jurisdictions, the MSDS is required to state the chemical's risks, safety and impact on the environment. # Usage by country In the U.S., the Occupational Safety and Health Administration requires that MSDS be available to employees for potentially harmful substances handled in the workplace under the Hazard Communication regulation. The MSDS is also required to be made available to local fire departments and local and state emergency planning officials under Section 311 of the Emergency Planning and Community Right-to-Know Act. In Canada, the program known as the Workplace Hazardous Materials Information System (WHMIS) establishes the requirements for MSDSs in workplaces and is administered federally by Health Canada under the Hazardous Products Act, Part II and the Controlled Products Regulations. WHMIS and MSDS requirements are also enforced by provincial Ministries or Departments of Labour. In the U.K., the Chemicals (Hazard Information and Packaging for Supply) Regulations 2002 - known as CHIP Regulations - impose duties upon suppliers, and importers into the EU, of hazardous materials. The Control of Substances Hazardous to Health (COSHH) Regulations govern the use of hazardous substances in the workplace in the UK and specifically require an assessment of the use of a substance. Regulation 12 requires that an employer provides employees with information, instruction and training for people exposed to hazardous substances. This duty would be very nearly impossible without the data sheet as a starting point. It is important for employers therefore to insist on receiving a data sheet from a supplier of a substance. # Phrases The European Union (EU) requires that Risk and Safety Statements ( R- and S-phrases) and a symbol appear on each label and safety data sheet for hazardous chemicals. - R-phrases consist of the letter R followed by a number. See List of R-phrases. - S-phrases consist of the letter S followed by a number. See List of S-phrases. # Water hazard classes The German Federal Water Management Act requires that substances be evaluated for negative influence on the physical, chemical or biological characteristics of water. These are classified into numeric water hazard classes (WGK or WHC depending whether you use the German or English acronym). - WGK nwg: Non-water polluting substance - WGK 1: Slightly water polluting substance - WGK 2: Water polluting substance - WGK 3: Highly water polluting substance # MSDS authoring Many companies offer the service of collecting, or writing and revising, data sheets to ensure they are up to date and available for their subscribers or users. [1] Some jurisdictions impose an explicit duty of care that each MSDS be regularly updated (usually every three to five years).

https://www.wikidoc.org/index.php/MSDS

ef8612c52bdf49302cadddd4e99f19d7bd8cd770

wikidoc

MSH2

MSH2 DNA mismatch repair protein Msh2 also known as MutS protein homolog 2 or MSH2 is a protein that in humans is encoded by the MSH2 gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair. Mutations in the MSH2 gene are associated with microsatellite instability and some cancers, especially with hereditary nonpolyposis colorectal cancer (HNPCC). # Clinical significance Hereditary nonpolyposis colorectal cancer (HNPCC), sometimes referred to as Lynch syndrome, is inherited in an autosomal dominant fashion, where inheritance of only one copy of a mutated mismatch repair gene is enough to cause disease phenotype. Mutations in the MSH2 gene account for 40% of genetic alterations associated with this disease and is the leading cause, together with MLH1 mutations. Mutations associated with HNPCC are broadly distributed in all domains of MSH2, and hypothetical functions of these mutations based on the crystal structure of the MutSα include protein–protein interactions, stability, allosteric regulation, MSH2-MSH6 interface, and DNA binding. Mutations in MSH2 and other mismatch repair genes cause DNA damage to go unrepaired, resulting in an increase in mutation frequency. These mutations build up over a person's life that otherwise would not have occurred had the DNA been repaired properly. # Microsatellite instability The viability of MMR genes including MSH2 can be tracked via microsatellite instability, a biomarker test that analyzes short sequence repeats which are very difficult for cells to replicate without a functioning mismatch repair system. Because these sequences vary in the population, the actual number of copies of short sequence repeats does not matter, just that the number the patient does have is consistent from tissue to tissue and over time. This phenomenon occurs because these sequences are prone to mistakes by the DNA replication complex, which then need to be fixed by the mismatch repair genes. If these are not working, over time either duplications or deletions of these sequences will occur, leading to different numbers of repeats in the same patient. 71% of HNPCC patients show microsatellite instability. Detection methods for microsatellite instability include polymerase chain reaction (PCR) and immunohistochemical (IHC) methods, polymerase chain checking the DNA and immunohistochemical surveying mismatch repair protein levels. "Currently, there are evidences that universal testing for MSI starting with either IHC or PCR-based MSI testing is cost effective, sensitive, specific and is generally widely accepted." # Role in mismatch repair In eukaryotes from yeast to humans, MSH2 dimerizes with MSH6 to form the MutSα complex, which is involved in base mismatch repair and short insertion/deletion loops. MSH2 heterodimerization stabilizes MSH6, which is not stable because of its N-terminal disordered domain. Conversely, MSH2 does not have a nuclear localization sequence (NLS), so it is believed that MSH2 and MSH6 dimerize in the cytoplasm and then are imported into the nucleus together. In the MutSα dimer, MSH6 interacts with the DNA for mismatch recognition while MSH2 provides the stability that MSH6 requires. MSH2 can be imported into the nucleus without dimerizing to MSH6, in this case, MSH2 is probably dimerized to MSH3 to form MutSβ. MSH2 has two interacting domains with MSH6 in the MutSα heterodimer, a DNA interacting domain, and an ATPase domain. The MutSα dimer scans double stranded DNA in the nucleus, looking for mismatched bases. When the complex finds one, it repairs the mutation in an ATP dependent manner. The MSH2 domain of MutSα prefers ADP to ATP, with the MSH6 domain preferring the opposite. Studies have indicated that MutSα only scans DNA with the MSH2 domain harboring ADP, while the MSH6 domain can contain either ADP or ATP. MutSα then associates with MLH1 to repair the damaged DNA. MutSβ is formed when MSH2 complexes with MSH3 instead of MSH6. This dimer repairs longer insertion/deletion loops than MutSα. Because of the nature of the mutations that this complex repairs, this is probably the state of MSH2 that causes the microsatellite instability phenotype. Large DNA insertions and deletions intrinsically bend the DNA double helix. The MSH2/MSH3 dimer can recognize this topology and initiate repair. The mechanism by which it recognizes mutations is different as well, because it separates the two DNA strands, which MutSα does not. # Interactions MSH2 has been shown to interact with: - ATR, - BRCA1, - CHEK2, - EXO1, - MAX, - MSH3, - MSH6, and - p53. # Epigenetic MSH2 deficiencies in cancer DNA damage appears to be the primary underlying cause of cancer, and deficiencies in expression of DNA repair genes appear to underlie many forms of cancer. If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutations due to error-prone translesion synthesis and error prone repair (see e.g. microhomology-mediated end joining). Elevated DNA damage may also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations may give rise to cancer. Reductions in expression of DNA repair genes (usually caused by epigenetic alterations) are very common in cancers, and are ordinarily much more frequent than mutational defects in DNA repair genes in cancers. (See Frequencies of epimutations in DNA repair genes.) In a study of MSH2 in non-small cell lung cancer (NSCLC), no mutations were found while 29% of NSCLC had epigenetic reduction of MSH2 expression. In acute lymphoblastoid leukemia (ALL), no MSH2 mutations were found while 43% of ALL patients showed MSH2 promoter methylation and 86% of relapsed ALL patients had MSH2 promoter methylation. There were, however, mutations in four other genes in ALL patients that destabilized the MSH2 protein, and these were defective in 11% of children with ALL and 16% of adults with this cancer. Methylation of the promoter region of the MSH2 gene is correlated with the lack of expression of the MSH2 protein in esophageal cancer, in non-small-cell lung cancer, and in colorectal cancer. These correlations suggest that methylation of the promoter region of the MSH2 gene reduces expression of the MSH2 protein. Such promoter methylation would reduce DNA repair in the four pathways in which MSH2 participates: DNA mismatch repair, transcription-coupled repair homologous recombination, and base excision repair. Such reductions in repair likely allow excess DNA damage to accumulate and contribute to carcinogenesis. The frequencies of MSH2 promoter methylation in several different cancers are indicated in the Table.

MSH2 DNA mismatch repair protein Msh2 also known as MutS protein homolog 2 or MSH2 is a protein that in humans is encoded by the MSH2 gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair,[1] homologous recombination,[2] and base excision repair.[3] Mutations in the MSH2 gene are associated with microsatellite instability and some cancers, especially with hereditary nonpolyposis colorectal cancer (HNPCC). # Clinical significance Hereditary nonpolyposis colorectal cancer (HNPCC), sometimes referred to as Lynch syndrome, is inherited in an autosomal dominant fashion, where inheritance of only one copy of a mutated mismatch repair gene is enough to cause disease phenotype. Mutations in the MSH2 gene account for 40% of genetic alterations associated with this disease and is the leading cause, together with MLH1 mutations.[4] Mutations associated with HNPCC are broadly distributed in all domains of MSH2, and hypothetical functions of these mutations based on the crystal structure of the MutSα include protein–protein interactions, stability, allosteric regulation, MSH2-MSH6 interface, and DNA binding.[5] Mutations in MSH2 and other mismatch repair genes cause DNA damage to go unrepaired, resulting in an increase in mutation frequency. These mutations build up over a person's life that otherwise would not have occurred had the DNA been repaired properly. # Microsatellite instability The viability of MMR genes including MSH2 can be tracked via microsatellite instability, a biomarker test that analyzes short sequence repeats which are very difficult for cells to replicate without a functioning mismatch repair system. Because these sequences vary in the population, the actual number of copies of short sequence repeats does not matter, just that the number the patient does have is consistent from tissue to tissue and over time. This phenomenon occurs because these sequences are prone to mistakes by the DNA replication complex, which then need to be fixed by the mismatch repair genes. If these are not working, over time either duplications or deletions of these sequences will occur, leading to different numbers of repeats in the same patient. 71% of HNPCC patients show microsatellite instability.[6] Detection methods for microsatellite instability include polymerase chain reaction (PCR) and immunohistochemical (IHC) methods, polymerase chain checking the DNA and immunohistochemical surveying mismatch repair protein levels. "Currently, there are evidences that universal testing for MSI starting with either IHC or PCR-based MSI testing is cost effective, sensitive, specific and is generally widely accepted."[7] # Role in mismatch repair In eukaryotes from yeast to humans, MSH2 dimerizes with MSH6 to form the MutSα complex,[8] which is involved in base mismatch repair and short insertion/deletion loops.[9] MSH2 heterodimerization stabilizes MSH6, which is not stable because of its N-terminal disordered domain. Conversely, MSH2 does not have a nuclear localization sequence (NLS), so it is believed that MSH2 and MSH6 dimerize in the cytoplasm and then are imported into the nucleus together.[10] In the MutSα dimer, MSH6 interacts with the DNA for mismatch recognition while MSH2 provides the stability that MSH6 requires. MSH2 can be imported into the nucleus without dimerizing to MSH6, in this case, MSH2 is probably dimerized to MSH3 to form MutSβ.[11] MSH2 has two interacting domains with MSH6 in the MutSα heterodimer, a DNA interacting domain, and an ATPase domain.[12] The MutSα dimer scans double stranded DNA in the nucleus, looking for mismatched bases. When the complex finds one, it repairs the mutation in an ATP dependent manner. The MSH2 domain of MutSα prefers ADP to ATP, with the MSH6 domain preferring the opposite. Studies have indicated that MutSα only scans DNA with the MSH2 domain harboring ADP, while the MSH6 domain can contain either ADP or ATP.[13] MutSα then associates with MLH1 to repair the damaged DNA. MutSβ is formed when MSH2 complexes with MSH3 instead of MSH6. This dimer repairs longer insertion/deletion loops than MutSα.[14] Because of the nature of the mutations that this complex repairs, this is probably the state of MSH2 that causes the microsatellite instability phenotype. Large DNA insertions and deletions intrinsically bend the DNA double helix. The MSH2/MSH3 dimer can recognize this topology and initiate repair. The mechanism by which it recognizes mutations is different as well, because it separates the two DNA strands, which MutSα does not.[15] # Interactions MSH2 has been shown to interact with: - ATR,[16][17] - BRCA1,[18] - CHEK2,[19][20] - EXO1,[21][22][23] - MAX,[24] - MSH3,[12][16][25][26] - MSH6,[12][16][18][25][26] and - p53.[27] # Epigenetic MSH2 deficiencies in cancer DNA damage appears to be the primary underlying cause of cancer,[28][29] and deficiencies in expression of DNA repair genes appear to underlie many forms of cancer.[30][31] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutations due to error-prone translesion synthesis and error prone repair (see e.g. microhomology-mediated end joining). Elevated DNA damage may also increase epigenetic alterations due to errors during DNA repair.[32][33] Such mutations and epigenetic alterations may give rise to cancer. Reductions in expression of DNA repair genes (usually caused by epigenetic alterations) are very common in cancers, and are ordinarily much more frequent than mutational defects in DNA repair genes in cancers.[34] (See Frequencies of epimutations in DNA repair genes.) In a study of MSH2 in non-small cell lung cancer (NSCLC), no mutations were found while 29% of NSCLC had epigenetic reduction of MSH2 expression.[35] In acute lymphoblastoid leukemia (ALL), no MSH2 mutations were found[36] while 43% of ALL patients showed MSH2 promoter methylation and 86% of relapsed ALL patients had MSH2 promoter methylation.[37] There were, however, mutations in four other genes in ALL patients that destabilized the MSH2 protein, and these were defective in 11% of children with ALL and 16% of adults with this cancer.[36] Methylation of the promoter region of the MSH2 gene is correlated with the lack of expression of the MSH2 protein in esophageal cancer,[38] in non-small-cell lung cancer,[35][39] and in colorectal cancer.[40] These correlations suggest that methylation of the promoter region of the MSH2 gene reduces expression of the MSH2 protein. Such promoter methylation would reduce DNA repair in the four pathways in which MSH2 participates: DNA mismatch repair, transcription-coupled repair[1] homologous recombination,[2][41][42] and base excision repair.[3] Such reductions in repair likely allow excess DNA damage to accumulate and contribute to carcinogenesis. The frequencies of MSH2 promoter methylation in several different cancers are indicated in the Table.

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MSH3

MSH3 DNA mismatch repair protein, MutS Homolog 3 (MSH3) is a human homologue of the bacterial mismatch repair protein MutS that participates in the mismatch repair (MMR) system. MSH3 typically forms the heterodimer MutSβ with MSH2 in order to correct long insertion/deletion loops and base-base mispairs in microsatellites during DNA synthesis. Deficient capacity for MMR is found in approximately 15% of colorectal cancers, and somatic mutations in the MSH3 gene can be found in nearly 50% of MMR-deficient colorectal cancers. # Gene and Expression In humans, the encoding gene for MSH3 is found on chromosome 5 at location 5q11-q12 upstream of the dihydrofolate reductase (DHFR) gene. MSH3 is encoded by 222,341 base pairs and creates a protein consisting of 1137 amino acids. MSH3 is typically expressed at low levels in several transformed cell lines—including HeLa, K562, HL-60, and CEM—as well as a large range of normal tissues including spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocytes, heart, brain, placenta, lung, liver, skeletal muscle kidney, and pancreas. Although expression levels of MSH3 vary slightly from tissue to tissue, its widespread low-level expression indicates that it is a “housekeeping” gene commonly expressed in all cells. Over-expression of MSH3 decreased capacity for MMR. When MSH3 is over expressed, drastic changes occur in the relative levels of formation of MutSβ at the expense of MutSα. MutSα is responsible for base-base mispairs and short insertion/deletion loops, while MutSβ repairs long insertion/deletion loops in DNA. A drastic shift in the relative levels of these protein complexes can lead to diminished capacity for MMR. In the case of MSH3 overexpression, MSH2 preferentially heterodimerizes with MSH3 leading to high levels of MutSβ and degradation of the partnerless MSH6 protein which normally complexes with MSH2 to form MutSα. # Interactions MSH3 has been shown to interact with MSH2, PCNA, and BRCA1. These interactions form protein complexes that are typically involved in tumor suppression and DNA repair activities. The primary interaction of MSH3 involves forming the MutSβ complex with MSH2. MutSβ forms as a heterodimer of MSH2 and MSH3 with two primary interaction regions: an amino-terminal region and a carboxy-terminal region. The N-terminal region of MSH3 (amino acids 126-250) contact the N-terminal region of MSH2 aa 378-625. The C-terminal regions connect at aa 1050-1128 of MSH3 and aa 875-934 of MSH2. The binding regions on MSH2 are identical when binding to either MSH3 or MSH6. Adenine nucleotide binding regions in MSH3 and MSH2 are not contained in either of the interaction regions involved in dimerization, allowing MutSβ to bind to DNA and perform MMR. Proliferating cell nuclear antigen (PCNA) is a protein involved in post-replication MMR. It has been shown that PCNA binds to the MutSβ heterodimer via a binding motif in the N-terminal domain of MSH3. Bound PCNA then localizes the MutSβ complex to replication foci, indicating that PCNA assists in initiating repair by guiding MutSβ and other repair proteins to free termini in recently replicated DNA. # Function The primary function of MSH3 is to maintain the stability of the genome and enact tumor suppression by forming the heterodimer MutSβ to correct long insertion/deletion loops and base-base mispairs. In the case of long insertion/deletion loops, DNA is severely bent and downstream basepairs can become unpaired and exposed. MutSβ recognizes insertion/deletion loops of 1-15 nucleotides; binding to insertion/deletion loops is achieved by inserting the mismatch-binding domain of MSH3 and part of the mismatch-binding domain of MSH2 into the groove formed by the extreme bend in DNA formed by the insertion/deletion loop. # Role in Cancer The most significant role of MSH3 in cancer is the suppression of tumors by repair of somatic mutations in DNA that occur as the result of base-base mispairs and insertion/deletion loops. Both loss of expression and over expression of MSH3 can lead to carcinogenic effects. Over-expression of MSH3 can lead to drastic changes in the relative e levels of MutSα and MutSβ. Normally, MutSβ is expressed at relatively low levels throughout all cells while MutSα is present at high levels. While both proteins have redundant function in base-base repairs, MutSα typically effects base-base mispair repairs and also performs repairs on the more common short inertion/deletion loops. When MSH3 is heavily overexpressed, it acts as a sequester for MSH2 and the relative levels of MutSβ and MutSα shift dramatically as unpaired MSH6 proteins degrade and MutSα becomes depleted. MutSβ can compensate somewhat for loss of base-base mispair correction functions, but is not suited for repairing many short, 1-2 base pair insertion/deletion loops. This leads to a heightened rate of microsatellite instabilities and increased rates of somatic mutations. This effect is directly related to human cancer in the form of drug resistance. One of the common resistance responses to methotrexate, a drug commonly used to treat childhood acute lymphocytic leukemia and a variety of other tumors, is amplification of the DHFR gene. DHFR amplification leads to overexpression of MSH3 and has been tied drug-resistant recurrence in cancer. In contrast, loss of MSH3 can lead to mismatch repair deficiency and genetic instability which have been identified as particularly common carcinogenic effects in human colorectal cancer. Mutations causing MSH3 knockdown can lead to diminished capacity for cells to repair long insertion/deletion loops causing microsatellite instabilities (MSI) in the genome and allowing an increase in the rates of somatic mutation. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are a type of MSI where loci containing AAAG or ATAG tetranucleotide repeats are particularly unstable. EMAST phenotypes are particularly common, with nearly 60% of sporadic colorectal cancers displaying high levels of EMAST linked to a high-rate of MSH3 deficient cells in tumors.

MSH3 DNA mismatch repair protein, MutS Homolog 3 (MSH3) is a human homologue of the bacterial mismatch repair protein MutS that participates in the mismatch repair (MMR) system. MSH3 typically forms the heterodimer MutSβ with MSH2 in order to correct long insertion/deletion loops and base-base mispairs in microsatellites during DNA synthesis. Deficient capacity for MMR is found in approximately 15% of colorectal cancers, and somatic mutations in the MSH3 gene can be found in nearly 50% of MMR-deficient colorectal cancers.[1] # Gene and Expression In humans, the encoding gene for MSH3 is found on chromosome 5 at location 5q11-q12 upstream of the dihydrofolate reductase (DHFR) gene.[2][3] MSH3 is encoded by 222,341 base pairs and creates a protein consisting of 1137 amino acids.[4] MSH3 is typically expressed at low levels in several transformed cell lines—including HeLa, K562, HL-60, and CEM—as well as a large range of normal tissues including spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocytes, heart, brain, placenta, lung, liver, skeletal muscle kidney, and pancreas. Although expression levels of MSH3 vary slightly from tissue to tissue, its widespread low-level expression indicates that it is a “housekeeping” gene commonly expressed in all cells.[3] Over-expression of MSH3 decreased capacity for MMR. When MSH3 is over expressed, drastic changes occur in the relative levels of formation of MutSβ at the expense of MutSα. MutSα is responsible for base-base mispairs and short insertion/deletion loops, while MutSβ repairs long insertion/deletion loops in DNA. A drastic shift in the relative levels of these protein complexes can lead to diminished capacity for MMR. In the case of MSH3 overexpression, MSH2 preferentially heterodimerizes with MSH3 leading to high levels of MutSβ and degradation of the partnerless MSH6 protein which normally complexes with MSH2 to form MutSα.[5] # Interactions MSH3 has been shown to interact with MSH2, PCNA, and BRCA1. These interactions form protein complexes that are typically involved in tumor suppression and DNA repair activities. The primary interaction of MSH3 involves forming the MutSβ complex with MSH2. MutSβ forms as a heterodimer of MSH2 and MSH3 with two primary interaction regions: an amino-terminal region and a carboxy-terminal region.[6] The N-terminal region of MSH3 (amino acids 126-250) contact the N-terminal region of MSH2 aa 378-625. The C-terminal regions connect at aa 1050-1128 of MSH3 and aa 875-934 of MSH2. The binding regions on MSH2 are identical when binding to either MSH3 or MSH6.[6] Adenine nucleotide binding regions in MSH3 and MSH2 are not contained in either of the interaction regions involved in dimerization, allowing MutSβ to bind to DNA and perform MMR. Proliferating cell nuclear antigen (PCNA) is a protein involved in post-replication MMR. It has been shown that PCNA binds to the MutSβ heterodimer via a binding motif in the N-terminal domain of MSH3. Bound PCNA then localizes the MutSβ complex to replication foci, indicating that PCNA assists in initiating repair by guiding MutSβ and other repair proteins to free termini in recently replicated DNA.[7] # Function The primary function of MSH3 is to maintain the stability of the genome and enact tumor suppression by forming the heterodimer MutSβ to correct long insertion/deletion loops and base-base mispairs. In the case of long insertion/deletion loops, DNA is severely bent and downstream basepairs can become unpaired and exposed. MutSβ recognizes insertion/deletion loops of 1-15 nucleotides; binding to insertion/deletion loops is achieved by inserting the mismatch-binding domain of MSH3 and part of the mismatch-binding domain of MSH2 into the groove formed by the extreme bend in DNA formed by the insertion/deletion loop.[8] # Role in Cancer The most significant role of MSH3 in cancer is the suppression of tumors by repair of somatic mutations in DNA that occur as the result of base-base mispairs and insertion/deletion loops. Both loss of expression and over expression of MSH3 can lead to carcinogenic effects. Over-expression of MSH3 can lead to drastic changes in the relative e levels of MutSα and MutSβ. Normally, MutSβ is expressed at relatively low levels throughout all cells while MutSα is present at high levels. While both proteins have redundant function in base-base repairs, MutSα typically effects base-base mispair repairs and also performs repairs on the more common short inertion/deletion loops. When MSH3 is heavily overexpressed, it acts as a sequester for MSH2 and the relative levels of MutSβ and MutSα shift dramatically as unpaired MSH6 proteins degrade and MutSα becomes depleted. MutSβ can compensate somewhat for loss of base-base mispair correction functions, but is not suited for repairing many short, 1-2 base pair insertion/deletion loops. This leads to a heightened rate of microsatellite instabilities and increased rates of somatic mutations. This effect is directly related to human cancer in the form of drug resistance. One of the common resistance responses to methotrexate, a drug commonly used to treat childhood acute lymphocytic leukemia and a variety of other tumors, is amplification of the DHFR gene. DHFR amplification leads to overexpression of MSH3 and has been tied drug-resistant recurrence in cancer.[5] In contrast, loss of MSH3 can lead to mismatch repair deficiency and genetic instability which have been identified as particularly common carcinogenic effects in human colorectal cancer. Mutations causing MSH3 knockdown can lead to diminished capacity for cells to repair long insertion/deletion loops causing microsatellite instabilities (MSI) in the genome and allowing an increase in the rates of somatic mutation. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are a type of MSI where loci containing AAAG or ATAG tetranucleotide repeats are particularly unstable. EMAST phenotypes are particularly common, with nearly 60% of sporadic colorectal cancers displaying high levels of EMAST linked to a high-rate of MSH3 deficient cells in tumors.[9]

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wikidoc

MSH4

MSH4 MutS protein homolog 4 is a protein that in humans is encoded by the MSH4 gene. # Function The MSH4 and MSH5 proteins form a hetero-oligomeric structure (heterodimer) in yeast and humans. In the yeast Saccharomyces cerevisiae MSH4 and MSH5 act specifically to facilitate crossovers between homologous chromosomes during meiosis. The MSH4/MSH5 complex binds and stabilizes double Holliday junctions and promotes their resolution into crossover products. An MSH4 hypomorphic (partially functional) mutant of S. cerevisiae showed a 30% genome wide reduction in crossover numbers, and a large number of meioses with non exchange chromosomes. Nevertheless this mutant gave rise to spore viability patterns suggesting that segregation of non-exchange chromosomes occurred efficiently. Thus, in S. cerevisiae, proper segregation apparently does not entirely depend on crossovers between homologous pairs. The him-14 gene of the worm Caenorhabditis elegans encodes an ortholog of MSH4. Formation of crossovers during C. elegans meiosis requires the him-14(MSH4) gene. Loss of him-14(MSH-4) function severely reduces crossing over, resulting in lack of chiasmata between homologs and consequent missegregation. Thus, in C. elegans, segregation apparently does depend on crossovers between homologous pairs. Him-14(MSH4) functions during the pachytene stage of meiosis, indicating that it is not needed for establishing the preceding stages of pairing and synapsis of homologous chromosomes. In an MSH4 mutant of rice, chiasma frequency was dramatically decreased to about 10% of the wild-type frequency, although the synaptonemal complex was normally installed. It is likely that MSH4 interacts with MSH5 to promote the majority of crossovers during rice meiosis. In general it appears that MSH4 acts during meiosis to direct the recombinational repair of some DNA double-strand breaks towards the crossover option rather than the non-cross over option (see Homologous recombination). # Interactions MSH4 has been shown to interact with MLH1, MSH5 and MLH3.

MSH4 MutS protein homolog 4 is a protein that in humans is encoded by the MSH4 gene.[1][2] # Function The MSH4 and MSH5 proteins form a hetero-oligomeric structure (heterodimer) in yeast and humans.[3][4][5] In the yeast Saccharomyces cerevisiae MSH4 and MSH5 act specifically to facilitate crossovers between homologous chromosomes during meiosis.[3] The MSH4/MSH5 complex binds and stabilizes double Holliday junctions and promotes their resolution into crossover products. An MSH4 hypomorphic (partially functional) mutant of S. cerevisiae showed a 30% genome wide reduction in crossover numbers, and a large number of meioses with non exchange chromosomes.[6] Nevertheless this mutant gave rise to spore viability patterns suggesting that segregation of non-exchange chromosomes occurred efficiently. Thus, in S. cerevisiae, proper segregation apparently does not entirely depend on crossovers between homologous pairs. The him-14 gene of the worm Caenorhabditis elegans encodes an ortholog of MSH4.[7] Formation of crossovers during C. elegans meiosis requires the him-14(MSH4) gene. Loss of him-14(MSH-4) function severely reduces crossing over, resulting in lack of chiasmata between homologs and consequent missegregation. Thus, in C. elegans, segregation apparently does depend on crossovers between homologous pairs. Him-14(MSH4) functions during the pachytene stage of meiosis, indicating that it is not needed for establishing the preceding stages of pairing and synapsis of homologous chromosomes. In an MSH4 mutant of rice, chiasma frequency was dramatically decreased to about 10% of the wild-type frequency, although the synaptonemal complex was normally installed.[8] It is likely that MSH4 interacts with MSH5 to promote the majority of crossovers during rice meiosis. In general it appears that MSH4 acts during meiosis to direct the recombinational repair of some DNA double-strand breaks towards the crossover option rather than the non-cross over option (see Homologous recombination). # Interactions MSH4 has been shown to interact with MLH1,[9] MSH5[4][5][10] and MLH3.[11]

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wikidoc

MSH5

MSH5 MutS protein homolog 5 is a protein that in humans is encoded by the MSH5 gene. # Function This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair or meiotic recombination processes. This protein is similar to a Saccharomyces cerevisiae protein that participates in meiotic segregation fidelity and crossing-over. This protein forms heterooligomers with another member of this family, mutS homolog 4. Alternative splicing results in four transcript variants encoding three different isoforms. # Mutations Mice homozygous for a null Msh5 mutation (Msh5-/-) are viable but sterile. In these mice, the prophase I stage of meiosis is defective due to the disruption of chromosome pairing. This meiotic failure leads, in male mice, to diminution of testicular size, and in female mice, to a complete loss of ovarian structures. A genetic investigation was performed to test women with premature ovarian failure for mutations in each of four meiotic genes. Among 41 women with premature ovarian failure two were found to be heterozygous for a mutation in the MSH5 gene; among 34 fertile women (controls) no mutations were found in the four tested genes. These findings in mouse and human indicate that the MSH5 protein plays an important role in meiotic recombination. In the worm Caenorhabditis elegans, the MSH5 protein is required during meiosis both for normal spontaneous and for gamma-irradiation induced crossover recombination and chiasma formation. Meiotic recombination is often initiated by double strand breaks. MSH5 mutants retain the competence to repair DNA double-strand breaks that are present during meiosis, but they accomplish this repair in a way that does not lead to crossovers between homologous chromosomes. The known mechanism of non-crossover recombinational repair is called synthesis dependent strand annealing (see homologous recombination; see also Bernstein et al.). MSH5 thus appears to be employed in directing the recombinational repair of some double-strand breaks towards the cross over option rather than the non-cross over option. # Interactions MSH5 has been shown to interact with MSH4.

MSH5 MutS protein homolog 5 is a protein that in humans is encoded by the MSH5 gene.[1][2][3][4] # Function This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair or meiotic recombination processes. This protein is similar to a Saccharomyces cerevisiae protein that participates in meiotic segregation fidelity and crossing-over. This protein forms heterooligomers with another member of this family, mutS homolog 4. Alternative splicing results in four transcript variants encoding three different isoforms.[4] # Mutations Mice homozygous for a null Msh5 mutation (Msh5-/-) are viable but sterile.[5] In these mice, the prophase I stage of meiosis is defective due to the disruption of chromosome pairing. This meiotic failure leads, in male mice, to diminution of testicular size, and in female mice, to a complete loss of ovarian structures. A genetic investigation was performed to test women with premature ovarian failure for mutations in each of four meiotic genes.[6] Among 41 women with premature ovarian failure two were found to be heterozygous for a mutation in the MSH5 gene; among 34 fertile women (controls) no mutations were found in the four tested genes. These findings in mouse and human indicate that the MSH5 protein plays an important role in meiotic recombination. In the worm Caenorhabditis elegans, the MSH5 protein is required during meiosis both for normal spontaneous and for gamma-irradiation induced crossover recombination and chiasma formation.[7] Meiotic recombination is often initiated by double strand breaks. MSH5 mutants retain the competence to repair DNA double-strand breaks that are present during meiosis, but they accomplish this repair in a way that does not lead to crossovers between homologous chromosomes.[7] The known mechanism of non-crossover recombinational repair is called synthesis dependent strand annealing (see homologous recombination; see also Bernstein et al.[8]). MSH5 thus appears to be employed in directing the recombinational repair of some double-strand breaks towards the cross over option rather than the non-cross over option. # Interactions MSH5 has been shown to interact with MSH4.[2][9][10]

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MSH6

MSH6 MSH6 or mutS homolog 6 is a gene that codes for DNA mismatch repair protein Msh6 in the budding yeast Saccharomyces cerevisiae. It is the homologue of the human "G/T binding protein," (GTBP) also called p160 or hMSH6 (human MSH6). The MSH6 protein is a member of the Mutator S (MutS) family of proteins that are involved in DNA damage repair. Defects in hMSH6 are associated with atypical hereditary nonpolyposis colorectal cancer not fulfilling the Amsterdam criteria for HNPCC. hMSH6 mutations have also been linked to endometrial cancer and the development of endometrial carcinomas. # Discovery MSH6 was first identified in the budding yeast S. cerevisiae because of its homology to MSH2. The identification of the human GTBP gene and subsequent amino acid sequence availability showed that yeast MSH6 and human GTBP were more related to each other than any other MutS homolog, with a 26.6% amino acid identity. Thus, GTBP took on the name human MSH6, or hMSH6. # Structure In the human genome, hMSH6 is located on chromosome 2. It contains the Walker-A/B adenine nucleotide binding motif, which is the most highly conserved sequence found in all MutS homologs. As with other MutS homologs, hMSH6 has an intrinsic ATPase activity. It functions exclusively when bound to hMSH2 as a heterodimer, although hMSH2 itself can function as a homomultimer or as a heterodimer with hMSH3. # Function ## Importance of mismatch repair Mismatches commonly occur as a result of DNA replication errors, genetic recombination, or other chemical and physical factors. Recognizing those mismatches and repairing them is extremely important for cells, because failure to do so results in microsatellite instability, an elevated spontaneous mutation rate (mutator phenotype), and susceptibility to HNPCC. hMSH6 combines with hMSH2 to form the active protein complex, hMutS alpha, also called hMSH2-hMSH6. ## Mismatch recognition Mismatch recognition by this complex is regulated by the ADP to ATP transformation, which provides evidence that hMutS alpha complex functions as a molecular switch. In normal DNA, adenine (A) bonds with thymine (T) and cytosine (C) bonds with guanine (G). Sometimes there will be a mismatch where T will bind with G, which is called a G/T mismatch. When a G/T mismatch is recognized, hMutS alpha complex binds and exchanges ADP for ATP. The ADP-->ATP exchange causes a conformational change to convert hMutS alpha into a sliding clamp that can diffuse along the DNA backbone. The ATP induces a release of the complex from the DNA and allows the hMutS alpha to dissociate along the DNA like a sliding clamp. This transformation helps trigger downstream events to repair the damaged DNA. # Cancer Although mutations in hMSH2 cause a strong general mutator phenotype, mutations in hMSH6 cause only a modest mutator phenotype. At the gene level, the mutations were found to cause primarily single-base substitution mutations, which suggests that the role of hMSH6 is primarily for correcting single-base substitution mutations and to a lesser extent single base insertion/deletion mutations. Mutations in the hMSH6 gene cause the protein to be nonfunctional or only partially active, thus reducing its ability to repair mistakes in DNA. The loss of MSH6 function results in instability at mononucleotide repeats. HNPCC is most commonly caused by mutations in hMSH2 and hMLH1, but mutations in hMSH6 are linked to an atypical form of HNPCC. The penetrance of colorectal cancer seems to be lower in these mutations, meaning that a low proportion of hMSH6 mutation carriers present with the disease. Endometrial cancer, on the other hand, seems to be a more important clinical manifestation for female mutation carriers. The onset of endometrial cancer and also colon cancer in families with hMSH6 mutations is about 50 years. This is delayed compared to the age 44 onset of hMSH2-related tumors. # Epigenetic control of MSH6 in cancer Two microRNAs, miR21 and miR-155, target the DNA mismatch repair (MMR) genes hMSH6 and hMSH2, to cause reduced expression of their proteins. If one or the other of these two microRNAs is over-expressed, hMSH2 and hMSH6 proteins are under-expressed, resulting in reduced DNA mismatch repair and increased microsatellite instability. One of these microRNAs, miR21, is regulated by the epigenetic methylation state of the CpG islands in one or the other of its two promoter regions. Hypomethylation of its promoter region is associated with increased expression of an miRNA. High expression of a microRNA causes repression of its target genes (see microRNA silencing of genes). In 66% to 90% of colon cancers, miR-21 was over-expressed, and generally the measured level of hMSH2 was decreased (and hMSH6 is unstable without hMSH2). The other microRNA, miR-155, is regulated both by epigenetic methylation of the CpG islands in its promoter region and by epigenetic acetylation of histones H2A and H3 at the miR-155 promoter (where acetylation increases transcription). Measured by two different methods, miR-155 was over-expressed in sporadic colorectal cancers by either 22% or 50%. When miR-155 was elevated, hMSH2 was under-expressed in 44% to 67% of the same tissues (and hMSH6 is likely under-expressed as well, and also unstable in the absence of hMSH2). # Interactions MSH6 has been shown to interact with MSH2, PCNA and BRCA1.

MSH6 MSH6 or mutS homolog 6 is a gene that codes for DNA mismatch repair protein Msh6 in the budding yeast Saccharomyces cerevisiae. It is the homologue of the human "G/T binding protein," (GTBP) also called p160 or hMSH6 (human MSH6). The MSH6 protein is a member of the Mutator S (MutS) family of proteins that are involved in DNA damage repair. Defects in hMSH6 are associated with atypical hereditary nonpolyposis colorectal cancer not fulfilling the Amsterdam criteria for HNPCC. hMSH6 mutations have also been linked to endometrial cancer and the development of endometrial carcinomas. # Discovery MSH6 was first identified in the budding yeast S. cerevisiae because of its homology to MSH2. The identification of the human GTBP gene and subsequent amino acid sequence availability showed that yeast MSH6 and human GTBP were more related to each other than any other MutS homolog, with a 26.6% amino acid identity.[1] Thus, GTBP took on the name human MSH6, or hMSH6. # Structure In the human genome, hMSH6 is located on chromosome 2. It contains the Walker-A/B adenine nucleotide binding motif, which is the most highly conserved sequence found in all MutS homologs.[2] As with other MutS homologs, hMSH6 has an intrinsic ATPase activity. It functions exclusively when bound to hMSH2 as a heterodimer, although hMSH2 itself can function as a homomultimer or as a heterodimer with hMSH3.[3] # Function ## Importance of mismatch repair Mismatches commonly occur as a result of DNA replication errors, genetic recombination, or other chemical and physical factors.[4] Recognizing those mismatches and repairing them is extremely important for cells, because failure to do so results in microsatellite instability, an elevated spontaneous mutation rate (mutator phenotype), and susceptibility to HNPCC.[2][5] hMSH6 combines with hMSH2 to form the active protein complex, hMutS alpha, also called hMSH2-hMSH6. ## Mismatch recognition Mismatch recognition by this complex is regulated by the ADP to ATP transformation, which provides evidence that hMutS alpha complex functions as a molecular switch.[6] In normal DNA, adenine (A) bonds with thymine (T) and cytosine (C) bonds with guanine (G). Sometimes there will be a mismatch where T will bind with G, which is called a G/T mismatch. When a G/T mismatch is recognized, hMutS alpha complex binds and exchanges ADP for ATP.[5] The ADP-->ATP exchange causes a conformational change to convert hMutS alpha into a sliding clamp that can diffuse along the DNA backbone.[5] The ATP induces a release of the complex from the DNA and allows the hMutS alpha to dissociate along the DNA like a sliding clamp. This transformation helps trigger downstream events to repair the damaged DNA.[5] # Cancer Although mutations in hMSH2 cause a strong general mutator phenotype, mutations in hMSH6 cause only a modest mutator phenotype.[1] At the gene level, the mutations were found to cause primarily single-base substitution mutations, which suggests that the role of hMSH6 is primarily for correcting single-base substitution mutations and to a lesser extent single base insertion/deletion mutations.[1] Mutations in the hMSH6 gene cause the protein to be nonfunctional or only partially active, thus reducing its ability to repair mistakes in DNA. The loss of MSH6 function results in instability at mononucleotide repeats.[1] HNPCC is most commonly caused by mutations in hMSH2 and hMLH1, but mutations in hMSH6 are linked to an atypical form of HNPCC.[7] The penetrance of colorectal cancer seems to be lower in these mutations, meaning that a low proportion of hMSH6 mutation carriers present with the disease. Endometrial cancer, on the other hand, seems to be a more important clinical manifestation for female mutation carriers. The onset of endometrial cancer and also colon cancer in families with hMSH6 mutations is about 50 years. This is delayed compared to the age 44 onset of hMSH2-related tumors.[7] # Epigenetic control of MSH6 in cancer Two microRNAs, miR21 and miR-155, target the DNA mismatch repair (MMR) genes hMSH6 and hMSH2, to cause reduced expression of their proteins.[8][9] If one or the other of these two microRNAs is over-expressed, hMSH2 and hMSH6 proteins are under-expressed, resulting in reduced DNA mismatch repair and increased microsatellite instability. One of these microRNAs, miR21, is regulated by the epigenetic methylation state of the CpG islands in one or the other of its two promoter regions.[10] Hypomethylation of its promoter region is associated with increased expression of an miRNA.[11] High expression of a microRNA causes repression of its target genes (see microRNA silencing of genes). In 66% to 90% of colon cancers, miR-21 was over-expressed,[8] and generally the measured level of hMSH2 was decreased (and hMSH6 is unstable without hMSH2[9]). The other microRNA, miR-155, is regulated both by epigenetic methylation of the CpG islands in its promoter region[12] and by epigenetic acetylation of histones H2A and H3 at the miR-155 promoter (where acetylation increases transcription).[13] Measured by two different methods, miR-155 was over-expressed in sporadic colorectal cancers by either 22% or 50%.[9] When miR-155 was elevated, hMSH2 was under-expressed in 44% to 67% of the same tissues (and hMSH6 is likely under-expressed as well, and also unstable in the absence of hMSH2).[9] # Interactions MSH6 has been shown to interact with MSH2,[14][15][16][17][18] PCNA[19][20][21] and BRCA1.[14][22]

https://www.wikidoc.org/index.php/MSH6

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wikidoc

MSI1

MSI1 RNA-binding protein Musashi homolog 1 also known as Musashi-1 is a protein that in humans is encoded by the MSI1 gene. # Function This gene encodes a protein containing two conserved tandem RNA recognition motifs and functions as an RNA binding protein that is involved in post-transcriptional gene editing. It is a stem cell marker that controls the balance between self-renewal and terminal differentiation. # Clinical significance Over expression of this gene is associated with the grade of the malignancy and proliferative activity in gliomas and melanomas. MSI1 is highly expressed in neural progenitor cells and is required for normal development of the brain. A mutation in these gene is responsible for autosomal recessive primary microcephaly. MSI1 also interacts with the Zika virus genome and may explain why these cells are highly susceptible to Zika virus infection.

MSI1 RNA-binding protein Musashi homolog 1 also known as Musashi-1 is a protein that in humans is encoded by the MSI1 gene.[1][2] # Function This gene encodes a protein containing two conserved tandem RNA recognition motifs and functions as an RNA binding protein that is involved in post-transcriptional gene editing. It is a stem cell marker that controls the balance between self-renewal and terminal differentiation.[3][2] # Clinical significance Over expression of this gene is associated with the grade of the malignancy and proliferative activity in gliomas and melanomas.[3] MSI1 is highly expressed in neural progenitor cells and is required for normal development of the brain. A mutation in these gene is responsible for autosomal recessive primary microcephaly. MSI1 also interacts with the Zika virus genome and may explain why these cells are highly susceptible to Zika virus infection.[4][5]

https://www.wikidoc.org/index.php/MSI1

7dda57e930a55e46c111770c5ae8698825ce839c

wikidoc

MSMB

MSMB Beta-microseminoprotein is a protein that in humans is encoded by the MSMB gene. For historical reasons, the scientific literature may also refer to this protein as Prostate secretory protein 94 (PSP94), microseminoprotein (MSP), microseminoprotein-beta (MSMB), beta-inhibitin, prostatic inhibin peptide (PIP), and inhibitin like material (ILM). # Distribution MSMB is one of the three major proteins secreted by the epithelial cells of the prostate and has a concentration in seminal plasma of 0.5 to 1 mg/mL Two comprehensive studies of beta-microseminoprotein in tissue have shown that it is secreted by epithelial cells in many other organs: liver, lung, breast, kidney, colon, stomach, pancreas, esophagus, duodenum, salivary glands, fallopian tube, corpus uteri, bulbourethral glands and cervix. This list corresponds closely to the sites from which all late onset cancers develop. # Evolution and structure MSMB is a rapidly evolving protein. Solution structures of human and porcine MSMB show remarkable similarity despite having only 51% of amino acids in common. The C-terminus domain of MSMB contains two two-stranded β-sheets; these have no resemblance to other structural motifs. The rapid evolution of MSMB can be attributed to either sexual selection or innate pathogen defense; the wide distribution of MSMB in the body and the fungicidal properties of the C-terminus suggest that innate pathogen defense plays a role in driving this evolution. # Function Beta-microseminoprotein is a member of the immunoglobulin binding factor family. This protein has been reported to have inhibin-like properties, though this finding has been disputed. It may have a role as an autocrine paracrine factor in uterine, breast and other female reproductive tissues. Two alternatively spliced transcript variants encoding different isoforms are described for this gene. Despite having only 4 out of 11 amino acids in common, both the porcine and human fungicidal peptide on MSMB's C-terminus are potently fungicidal in the absence of calcium ions. The protein inhibits growth of cancer cells in an experimental model of prostate cancer, though this property is cell line specific. # Clinical significance Two large genome-wide association studies showed that decreased expression of the MSMB protein caused by the rs10993994 single nucleotide polymorphism is associated with an increased risk of developing prostate cancer (odds ratio for CT allele pair ~1.2x, and for TT allele pair ~1.6x when compared to the low risk CC allele pair). A 2003 study proposed using a truncated form of the MSMB protein called PSP61 as a biomarker for benign prostatic hyperplasia (BPH): this study found PSP61 in the expressed prostatic secretion of 10 out of ten 10 men suffering from BPH, but did not find it in 10 out of 10 age-matched BPH-free men. This truncated form of the MSMB protein lacks the fungicidal peptide identified in 2012. The expression of MSMB is found to be decreased in prostate cancer, so it may be used as a biomarker for prostate cancer. Urinary MSMB has been found to be superior than urinary PSA at differentiating men with prostate cancer at all Gleason grades.

MSMB Beta-microseminoprotein is a protein that in humans is encoded by the MSMB gene.[1][2] For historical reasons, the scientific literature may also refer to this protein as Prostate secretory protein 94 (PSP94), microseminoprotein (MSP), microseminoprotein-beta (MSMB), beta-inhibitin, prostatic inhibin peptide (PIP), and inhibitin like material (ILM). # Distribution MSMB is one of the three major proteins secreted by the epithelial cells of the prostate[3] and has a concentration in seminal plasma of 0.5 to 1 mg/mL[4] Two comprehensive studies of beta-microseminoprotein in tissue have shown that it is secreted by epithelial cells in many other organs: liver, lung, breast, kidney, colon, stomach, pancreas, esophagus, duodenum, salivary glands, fallopian tube, corpus uteri, bulbourethral glands and cervix.[5][6] This list corresponds closely to the sites from which all late onset cancers develop.[citation needed] # Evolution and structure MSMB is a rapidly evolving protein.[7] Solution structures of human and porcine MSMB show remarkable similarity despite having only 51% of amino acids in common.[8] The C-terminus domain of MSMB contains two two-stranded β-sheets; these have no resemblance to other structural motifs.[8] The rapid evolution of MSMB can be attributed to either sexual selection or innate pathogen defense;[9] the wide distribution of MSMB in the body and the fungicidal properties of the C-terminus suggest that innate pathogen defense plays a role in driving this evolution.[10] # Function Beta-microseminoprotein is a member of the immunoglobulin binding factor family. This protein has been reported to have inhibin-like properties,[11] though this finding has been disputed.[12][13] It may have a role as an autocrine paracrine factor in uterine, breast and other female reproductive tissues. Two alternatively spliced transcript variants encoding different isoforms are described for this gene. Despite having only 4 out of 11 amino acids in common, both the porcine and human fungicidal peptide on MSMB's C-terminus are potently fungicidal in the absence of calcium ions.[10] The protein inhibits growth of cancer cells in an experimental model of prostate cancer,[14][15] though this property is cell line specific.[16] # Clinical significance Two large genome-wide association studies showed that decreased expression of the MSMB protein caused by the rs10993994 single nucleotide polymorphism is associated with an increased risk of developing prostate cancer (odds ratio for CT allele pair ~1.2x, and for TT allele pair ~1.6x when compared to the low risk CC allele pair).[17] A 2003 study proposed using a truncated form of the MSMB protein called PSP61 as a biomarker for benign prostatic hyperplasia (BPH): this study found PSP61 in the expressed prostatic secretion of 10 out of ten 10 men suffering from BPH, but did not find it in 10 out of 10 age-matched BPH-free men.[18] This truncated form of the MSMB protein lacks the fungicidal peptide identified in 2012. The expression of MSMB is found to be decreased in prostate cancer, so it may be used as a biomarker for prostate cancer.[19] Urinary MSMB has been found to be superior than urinary PSA at differentiating men with prostate cancer at all Gleason grades.[20]

https://www.wikidoc.org/index.php/MSMB

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wikidoc

MSR1

MSR1 Macrophage scavenger receptor 1, also known as MSR1, is a protein which in humans is encoded by the MSR1 gene. MSR1 has also recently been designated CD204 (cluster of differentiation 204). # Function This gene encodes the class A macrophage scavenger receptors, which include three different types (1, 2, 3) generated by alternative splicing of this gene. These receptors or isoforms are trimeric integral membrane glycoproteins and have been implicated in many macrophage-associated physiological and pathological processes including atherosclerosis, Alzheimer's disease, and host defense. They were thought to be expressed macrophage-specific, but recently shown to be present on different dendritic cells classes, too. The isoforms type 1 and type 2 are functional receptors and are able to mediate the endocytosis of modified low density lipoproteins (LDLs). The isoform type 3 does not internalize modified LDL (acetyl-LDL) despite having the domain shown to mediate this function in the types 1 and 2 isoforms. It has an altered intracellular processing and is trapped within the endoplasmic reticulum, making it unable to perform endocytosis. The isoform type 3 can inhibit the function of isoforms type 1 and type 2 when co-expressed, indicating a dominant negative effect and suggesting a mechanism for regulation of scavenger receptor activity in macrophages. # Biotechnology application Macrophage scavenger receptor has been shown to mediate adhesion of macrophages and other cell lines to tissue culture plastic. # Interactions MSR1 has been shown to interact with HSPA1A.

MSR1 Macrophage scavenger receptor 1, also known as MSR1, is a protein which in humans is encoded by the MSR1 gene.[1][2] MSR1 has also recently been designated CD204 (cluster of differentiation 204). # Function This gene encodes the class A macrophage scavenger receptors, which include three different types (1, 2, 3) generated by alternative splicing of this gene. These receptors or isoforms are trimeric integral membrane glycoproteins and have been implicated in many macrophage-associated physiological and pathological processes including atherosclerosis, Alzheimer's disease, and host defense. They were thought to be expressed macrophage-specific, but recently shown to be present on different dendritic cells classes, too.[3] The isoforms type 1 and type 2 are functional receptors and are able to mediate the endocytosis of modified low density lipoproteins (LDLs). The isoform type 3 does not internalize modified LDL (acetyl-LDL) despite having the domain shown to mediate this function in the types 1 and 2 isoforms. It has an altered intracellular processing and is trapped within the endoplasmic reticulum, making it unable to perform endocytosis. The isoform type 3 can inhibit the function of isoforms type 1 and type 2 when co-expressed, indicating a dominant negative effect and suggesting a mechanism for regulation of scavenger receptor activity in macrophages.[1] # Biotechnology application Macrophage scavenger receptor has been shown to mediate adhesion of macrophages and other cell lines to tissue culture plastic.[4] # Interactions MSR1 has been shown to interact with HSPA1A.[5]

https://www.wikidoc.org/index.php/MSR1

46e17f125d464fc761862f7f384387d6ac2eac40

wikidoc

MSX1

MSX1 Msh homeobox 1, also known as MSX1, is a protein that in humans is encoded by the MSX1 gene. MSX1 transcripts are not only found in thyrotrope-derived TSH cells, but also in the TtT97 thyrotropic tumor, which is a well differentiated hyperplastic tissue that produces both TSHß- and a-subunits and is responsive to thyroid hormone. MSX1 is also expressed in highly differentiated pituitary cells which until recently was thought to be expressed exclusively during embryogenesis. There is a highly conserved structural organization of the members of the MSX family of genes and their abundant expression at sites of inductive cell–cell interactions in the embryo suggest that they have a pivotal role during early development. # Function This gene encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, in particular, odontogenesis, and tumor growth inhibition. There is also strong evidence from sequencing studies of candidate genes involved in clefting that mutations in the MSX1 gene may be associated in the pathogenesis of cleft lip and palate. Mutations in this gene, which was once known as homeobox 7, have also been associated with Witkop syndrome, Wolf-Hirschhorn syndrome, and autosomal dominant hypodontia. Haploinsufficiency of MSX1 protein affects the development of all teeth, preferentially third molars and second premolars. The effect of haploinsufficiency of PAX9 on the development of incisors and premolars is probably caused by a deficiency of MSX1 protein. Phenotypes caused by deficiency of MSX1 protein might depend on the localization of mutations and their effect on the protein structure and function. Two substitution mutations, Arg196Pro and Met61Lys cause only familial non-syndromic tooth agenesis. Frameshift mutations, Ser202Stop mutation, resulting in a protein that lacks the C-terminal end of the homeodomain, impairs not only teeth but also nail formation, while Ser105Stop mutation, causing complete absence of the MSX1 homeodomain, is responsible for the most severe phenotype, which includes orofacial clefts with accompanied tooth agenesis. MSX1 is one of the strongest candidate genes for specific forms of tooth agenesis, mutations in this gene was detected only in some affected individuals. Genes expressed in the early dental epithelium in mice such as Bmp4, Bmp7, Dlx2, Dlx5, Fgf1, Fgf2, Fgf4, Fgf8, Lef1, Gli2, and Gli3 are also potential candidates. Based on existing evidence, it seems possible that both hypodontia and oligodontia are heterogeneous traits, caused by several independent defective genes, which act along or in combination with other genes and lead to specific phenotypes. MSX1 is found to have a linkage with Witkop syndrome, also known as “tooth and nail syndrome” or “nail dysgenesis and hypodontia” since mutations in MSX1 were shown to be associated with tooth agenesis. There is a linkage found between TNS and markers surrounding the MSX1 locus and it showed that a nonsense mutation (S202X) in MSX1 cosegregated with the TNS phenotype in a three-generation family. # Interactions MSX1 has been shown to interact with DLX5, CREB binding protein, Sp1 transcription factor, DLX2, TATA binding protein and Msh homeobox 2. LHX2, a LIMtype homeoprotein, is a protein partner for MSX1 in vitro and in cellular extracts. The interaction between MSX1 and LHX2 is mediated through the homeodomain-containing regions of both proteins. MSX1 and LHX2 form a protein complex in the absence of DNA, and that DNA binding by either protein alone can occur at the expense of protein complex formation.

MSX1 Msh homeobox 1, also known as MSX1, is a protein that in humans is encoded by the MSX1 gene.[1][2] MSX1 transcripts are not only found in thyrotrope-derived TSH cells, but also in the TtT97 thyrotropic tumor, which is a well differentiated hyperplastic tissue that produces both TSHß- and a-subunits and is responsive to thyroid hormone. MSX1 is also expressed in highly differentiated pituitary cells which until recently was thought to be expressed exclusively during embryogenesis.[3] There is a highly conserved structural organization of the members of the MSX family of genes and their abundant expression at sites of inductive cell–cell interactions in the embryo suggest that they have a pivotal role during early development.[4] # Function This gene encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, in particular, odontogenesis, and tumor growth inhibition. There is also strong evidence from sequencing studies of candidate genes involved in clefting that mutations in the MSX1 gene may be associated in the pathogenesis of cleft lip and palate.[5][6][7][8] Mutations in this gene, which was once known as homeobox 7, have also been associated with Witkop syndrome, Wolf-Hirschhorn syndrome, and autosomal dominant hypodontia.[9] Haploinsufficiency of MSX1 protein affects the development of all teeth, preferentially third molars and second premolars. The effect of haploinsufficiency of PAX9 on the development of incisors and premolars is probably caused by a deficiency of MSX1 protein.[10] Phenotypes caused by deficiency of MSX1 protein might depend on the localization of mutations and their effect on the protein structure and function. Two substitution mutations, Arg196Pro and Met61Lys cause only familial non-syndromic tooth agenesis. Frameshift mutations, Ser202Stop mutation, resulting in a protein that lacks the C-terminal end of the homeodomain, impairs not only teeth but also nail formation, while Ser105Stop mutation, causing complete absence of the MSX1 homeodomain, is responsible for the most severe phenotype, which includes orofacial clefts with accompanied tooth agenesis.[10] MSX1 is one of the strongest candidate genes for specific forms of tooth agenesis, mutations in this gene was detected only in some affected individuals. Genes expressed in the early dental epithelium in mice such as Bmp4, Bmp7, Dlx2, Dlx5, Fgf1, Fgf2, Fgf4, Fgf8, Lef1, Gli2, and Gli3 are also potential candidates. Based on existing evidence, it seems possible that both hypodontia and oligodontia are heterogeneous traits, caused by several independent defective genes, which act along or in combination with other genes and lead to specific phenotypes.[10] MSX1 is found to have a linkage with Witkop syndrome, also known as “tooth and nail syndrome” or “nail dysgenesis and hypodontia” since mutations in MSX1 were shown to be associated with tooth agenesis. There is a linkage found between TNS and markers surrounding the MSX1 locus and it showed that a nonsense mutation (S202X) in MSX1 cosegregated with the TNS phenotype in a three-generation family.[11] # Interactions MSX1 has been shown to interact with DLX5,[12] CREB binding protein,[4] Sp1 transcription factor,[4] DLX2,[12] TATA binding protein[4][12][13] and Msh homeobox 2.[12] LHX2, a LIMtype homeoprotein, is a protein partner for MSX1 in vitro and in cellular extracts. The interaction between MSX1 and LHX2 is mediated through the homeodomain-containing regions of both proteins. MSX1 and LHX2 form a protein complex in the absence of DNA, and that DNA binding by either protein alone can occur at the expense of protein complex formation.[14]

https://www.wikidoc.org/index.php/MSX1

b91524954d4393e9452e4918f3bb840428609f65

wikidoc

MTA1

MTA1 Metastasis-associated protein MTA1 is a protein that in humans is encoded by the MTA1 gene. MTA1 is the founding member of the MTA family of genes. MTA1 is primarily localized in the nucleus but also found to be distributed in the extra-nuclear compartments. MTA1 is a component of several chromatin remodeling complexes including the nucleosome remodeling and deacetylation complex (NuRD). MTA1 regulates gene expression by functioning as a coregulator to integrate DNA-interacting factors to gene activity. MTA1 participates in physiological functions in the normal and cancer cells. MTA1 is one of the most upregulated proteins in human cancer and associates with cancer progression, aggressive phenotypes, and poor prognosis of cancer patients. # Discovery MTA1 was first cloned by Toh, Pencil and Nicholson in 1994 as a differentially expressed gene in a highly metastatic rat breast cancer cell line. The role in MTA1 in chromatin remodeling was deduced due to the presence of MTA1 polypeptides in the NuRD complex. The first direct target of the MTA1-NuRD complex was ERα. # Gene and spliced variants The MTA1 is 715/703 amino acids long, coded by one of three genes of the MTA family and localized on chromosome 14q32 in human and on chromosome 12F in mouse. There are 21 exons spread over a region of about 51-kb in human MTA1. Alternative splicing from 21 exons generates 20 transcripts, ranging from 416-bp to 2.9-kb long. However, open-reading frames are present only in eight spliced transcripts which code six proteins and two polypeptides and remaining transcripts are non-coding long RNAs some of which retain intron sequences. Murine Mta1 contains three protein coding transcripts and three non-coding RNA transcripts. Among human MTA1 variants, only two spliced variants are characterized: ZG29p variant is derived from the c-terminal MTA1, with 251 amino acids and 29-kDa molecular weight; and MTA1s variant generated from alternative splicing of a middle exon followed by a frame-shift, is 430 amino acids and 47-kDa molecular weight. # Protein domains The conserved domains of MTA1 include a BAH (Bromo-Adjacent Homology), a ELM2 (egl-27 and MTA1 homology), a SANT (SWI, ADA2, N-CoR, TFIIIB-B) and a GATA-like zinc finger. The C-terminal divergent region of MTA1 has an Src homology 3-binding domain, acidic regions, and nuclear localization signals. The presence of these domains revealed the role of MTA1 in interactions with modified or unmodified histone and non-histone proteins, chromatin remodeling, and modulation of gene transcription. MTA1 undergoes multiple post-translation modifications: acetylation on lysine 626, ubiquitination on lysine 182 and lysine 626, sumoylation on lysine 509, and methylation on lysine 532. The structural insights of MTA1 domains are deduced from studies involving complexes with HDAC1 or RbAp48 subunits of the NuRD complexes. The MTA1s variant is an N-terminal portion of MTA1 without nuclear localization sequence but contains a novel sequence of 33 amino acids in its C-terminal region. The novel sequence harbors a nuclear receptor binding motif LXXLL which confers MTA1 with an ability to interact with estrogen receptor alpha or other type I nuclear receptors. The ZG29p variant represents the c-terminal MTA1 with two proline-rich SH3 binding sites. # Regulation Expression of MTA1 is influenced by transcription and non-transcriptional mechanisms. MTA1 expression is regulated by growth factors, growth factor receptors, oncogenes, environmental stress, ionizing radiation, inflammation, and hypoxia. The transcription of MTA1 is stimulated by transcriptional factors including, c-Myc, SP1, CUTL1 homeodomain, NF-ḵB, HSF1, HIF-1a, and Clock/BMAL1 complex, and inhibited by p53. Non-genomic mechanisms of MTA1 expression include post-transcriptional regulations such as ubiquitination by RING-finger ubiquitin-protein ligase COP1 or interaction with tumor suppressor ARF or micro-RNAs such as miR-30c, miR-661 and miR-125a-3p. # Targets Functions of MTA1 are regulated by its post-translational modifications, modulating the roles of effector molecules, interacting with other regulatory proteins and chromatin remodeling machinery, and modulating the expression of target genes via interacting with the components of the NuRD complex including HDACs. MTA1 suppresses transcription of breast cancer type 1 susceptibility gene, PTEN, p21WAF, guanine nucleotide-binding protein G(i) subunit alpha-2, SMAD family member 7, nuclear receptor subfamily 4 group A member 1, and homeobox protein SIX3, and represses BCL11B as well as E-cadherin expression. MTA1 is a dual coregulatory as it stimulates the transcription of Stat3, breast cancer-amplified sequence 3, FosB, paired box gene 5, transglutaminase 2, myeloid differentiation primary response 88, tumor suppressorp14/p19ARF, tyrosine hydroxylase, clock gene CRY1, SUMO2, and Wnt1 and rhodopsin due to release of their transcriptional inhibition by homeodomain protein Six3, MTA1 interacts with ERα and coregulatory factors such as MAT1, MICoA, NRIF3 and LMO4， , which inhibits ER transactivation activity. MTA1 also deacetylate its target proteins such as p53 and HIF and modulates their transactivation functions. Furthermore, MTA1 could potentially modulate the expression of target genes through the microRNA network as MTA1 knockdown results modulation of miR-210, miR-125b, miR-194, miR-103, and miR-500. # Cellular functions MTA1 modulates the expression of target genes due to its ability to act as a corepressor or coactivator. MTA1 targets and/or effector pathways regulate pathways with cellular functions in both normal and cancer cells. Physiological functions of MTA1 include: its role in the brain due to MTA1 interactions with DJ1 and endophilin-3; regulation of Rhodopsin expression in the murine eye; modifier of circadian rhythm due to MTA1 interactions with the CLOCK-BMAL1 complex and stimulation of Cry-transcription; in heart development due to MTA1-FOG2 interaction; in mammary gland development as MTA1 depletion leads to ductal hypobranching, in spermatogenesis; in immunomodulation due to differential effects on the expression of cytokines in the resting and activated macrophage; in liver regeneration following hepatic injury; differentiation of mesenchymal stem cells into osteogenic axis; and a component of DNA-damage response. In cancer cells, MTA1 and its downstream effectors regulate genes and/or pathways with roles in transformation, invasion, survival, angiogenesis, epithelial-to-mesenchymal transition, metastasis, DNA damage response, and hormone-independence of breast cancer. # Notes

MTA1 Metastasis-associated protein MTA1 is a protein that in humans is encoded by the MTA1 gene. MTA1 is the founding member of the MTA family of genes.[1][2] MTA1 is primarily localized in the nucleus but also found to be distributed in the extra-nuclear compartments.[3][4] MTA1 is a component of several chromatin remodeling complexes including the nucleosome remodeling and deacetylation complex (NuRD).[5][6] MTA1 regulates gene expression by functioning as a coregulator to integrate DNA-interacting factors to gene activity.[7] MTA1 participates in physiological functions in the normal and cancer cells.[8][9] MTA1 is one of the most upregulated proteins in human cancer and associates with cancer progression, aggressive phenotypes, and poor prognosis of cancer patients.[6][10] # Discovery MTA1 was first cloned by Toh, Pencil and Nicholson in 1994 as a differentially expressed gene in a highly metastatic rat breast cancer cell line.[1][2] The role in MTA1 in chromatin remodeling was deduced due to the presence of MTA1 polypeptides in the NuRD complex.[5] The first direct target of the MTA1-NuRD complex was ERα.[11] # Gene and spliced variants The MTA1 is 715/703 amino acids long, coded by one of three genes of the MTA family and localized on chromosome 14q32 in human and on chromosome 12F in mouse. There are 21 exons spread over a region of about 51-kb in human MTA1. Alternative splicing from 21 exons generates 20 transcripts, ranging from 416-bp to 2.9-kb long.[12] However, open-reading frames are present only in eight spliced transcripts which code six proteins and two polypeptides and remaining transcripts are non-coding long RNAs some of which retain intron sequences. Murine Mta1 contains three protein coding transcripts and three non-coding RNA transcripts.[12] Among human MTA1 variants, only two spliced variants are characterized: ZG29p variant is derived from the c-terminal MTA1, with 251 amino acids and 29-kDa molecular weight;[13] and MTA1s variant generated from alternative splicing of a middle exon followed by a frame-shift, is 430 amino acids and 47-kDa molecular weight.[14] # Protein domains The conserved domains of MTA1 include a BAH (Bromo-Adjacent Homology), a ELM2 (egl-27 and MTA1 homology), a SANT (SWI, ADA2, N-CoR, TFIIIB-B) and a GATA-like zinc finger. The C-terminal divergent region of MTA1 has an Src homology 3-binding domain, acidic regions, and nuclear localization signals. The presence of these domains revealed the role of MTA1 in interactions with modified or unmodified histone and non-histone proteins, chromatin remodeling, and modulation of gene transcription.[6][15][16][17] MTA1 undergoes multiple post-translation modifications: acetylation on lysine 626, ubiquitination on lysine 182 and lysine 626, sumoylation on lysine 509, and methylation on lysine 532.[18][18][19][20] The structural insights of MTA1 domains are deduced from studies involving complexes with HDAC1 or RbAp48 subunits of the NuRD complexes.[15][16] The MTA1s variant is an N-terminal portion of MTA1 without nuclear localization sequence but contains a novel sequence of 33 amino acids in its C-terminal region. The novel sequence harbors a nuclear receptor binding motif LXXLL which confers MTA1 with an ability to interact with estrogen receptor alpha or other type I nuclear receptors.[14] The ZG29p variant represents the c-terminal MTA1 with two proline-rich SH3 binding sites.[13][21] # Regulation Expression of MTA1 is influenced by transcription and non-transcriptional mechanisms. MTA1 expression is regulated by growth factors, growth factor receptors, oncogenes, environmental stress, ionizing radiation, inflammation, and hypoxia.[6][9] The transcription of MTA1 is stimulated by transcriptional factors including, c-Myc,[22] SP1,[23] CUTL1 homeodomain,[24] NF-ḵB,[25] HSF1,[26] HIF-1a,[27] and Clock/BMAL1 complex,[28] and inhibited by p53.[29] Non-genomic mechanisms of MTA1 expression include post-transcriptional regulations such as ubiquitination by RING-finger ubiquitin-protein ligase COP1 [30] or interaction with tumor suppressor ARF [24] or micro-RNAs such as miR-30c, miR-661 and miR-125a-3p.[31][32][33][34] # Targets Functions of MTA1 are regulated by its post-translational modifications, modulating the roles of effector molecules, interacting with other regulatory proteins and chromatin remodeling machinery, and modulating the expression of target genes via interacting with the components of the NuRD complex including HDACs.[6][15][16] MTA1 suppresses transcription of breast cancer type 1 susceptibility gene,[35] PTEN,[36] p21WAF,[37] guanine nucleotide-binding protein G(i) subunit alpha-2,[18] SMAD family member 7,[38] nuclear receptor subfamily 4 group A member 1,[39] and homeobox protein SIX3,[40] and represses BCL11B[41] as well as E-cadherin expression.[42][43] MTA1 is a dual coregulatory as it stimulates the transcription of Stat3,[44] breast cancer-amplified sequence 3,[45] FosB,[24] paired box gene 5,[46] transglutaminase 2,[47] myeloid differentiation primary response 88,[48] tumor suppressorp14/p19ARF,[23][49] tyrosine hydroxylase,[50] clock gene CRY1,[28] SUMO2,[19] and Wnt1 and rhodopsin due to release of their transcriptional inhibition by homeodomain protein Six3,[40][51] MTA1 interacts with ERα and coregulatory factors such as MAT1,[52] MICoA,[53] NRIF3 [55][54] and LMO4， [56],[55] which inhibits ER transactivation activity.[11] MTA1 also deacetylate its target proteins such as p53 and HIF and modulates their transactivation functions.[56][57] Furthermore, MTA1 could potentially modulate the expression of target genes through the microRNA network as MTA1 knockdown results modulation of miR-210, miR-125b, miR-194, miR-103, and miR-500.[58][59] # Cellular functions MTA1 modulates the expression of target genes due to its ability to act as a corepressor or coactivator. MTA1 targets and/or effector pathways regulate pathways with cellular functions in both normal and cancer cells.[8][9] Physiological functions of MTA1 include: its role in the brain due to MTA1 interactions with DJ1[49] and endophilin-3;[60] regulation of Rhodopsin expression in the murine eye; modifier of circadian rhythm due to MTA1 interactions with the CLOCK-BMAL1 complex and stimulation of Cry-transcription; in heart development due to MTA1-FOG2 interaction; in mammary gland development as MTA1 depletion leads to ductal hypobranching, in spermatogenesis; in immunomodulation due to differential effects on the expression of cytokines in the resting and activated macrophage; in liver regeneration following hepatic injury; differentiation of mesenchymal stem cells into osteogenic axis; and a component of DNA-damage response.[8] In cancer cells, MTA1 and its downstream effectors regulate genes and/or pathways with roles in transformation, invasion, survival, angiogenesis, epithelial-to-mesenchymal transition, metastasis, DNA damage response, and hormone-independence of breast cancer.[6][9] # Notes

https://www.wikidoc.org/index.php/MTA1

1254008c1fd91afa52c9dc990177a4018929691b

wikidoc

MTA2

MTA2 Metastasis-associated protein MTA2 is a protein that in humans is encoded by the MTA2 gene. MTA2 is the second member of the MTA family of genes. MTA2 protein localizes in the nucleus and is a component of the nucleosome remodeling and the deacetylation complex (NuRD). Similar to the founding family member MTA1, MTA2 functions as a chromatin remodeling factor and regulates gene expression. MTA2 is overexpressed in human cancer and its dysregulated level correlates well with cancer invasiveness and aggressive phenotypes. # Discovery MTA2 was initially recognized as an MTA1 like 1 gene, named MTA1-L1, from a large scale sequencing of randomly selected clones from human cDNA libraries in 1999. Clues about the role of MTA2 in gene expression came from the association of MTA2 polypeptides in the NuRD complex in a proteomic study This was followed by targeted cloning of murine Mta2 in 2001. # Gene and spliced variants MTA2 is localized on chromosome 11q12-q13.1 in human and on 19B in mice. The 8.6-kb long human MTA2 gene contains 20 exons and seven transcripts inclusive of three protein-coding transcripts but predicted to code for two polypeptides of 688 amino acids and 495 amino acids. The remaining four MTA2 transcripts are non-coding RNA transcripts ranging from 532-bp to 627-bp. The murine Mta2 consists of a 3.1-kb protein-coding transcript to code a protein of 668 amino acids, and five non-coding RNAs transcripts, ranging from 620-bp to 839-bp. # Structure Amino acid sequence of MTA2 shares 68.2% homology with MTA1’s sequence. MTA2 domains include, a BAH (Bromo-Adjacent Homology), a ELM2 (egl-27 and MTA1 homology), a SANT domain (SWI, ADA2, N-CoR, TFIIIB-B), and a GATA-like zinc finger. MTA2 is acetylated at lysine 152 within the BAH domain # Function This gene encodes a protein that has been identified as a component of NuRD, a nucleosome remodeling deacetylase complex identified in the nucleus of human cells. It shows a very broad expression pattern and is strongly expressed in many tissues. It may represent one member of a small gene family that encode different but related proteins involved either directly or indirectly in transcriptional regulation. Their indirect effects on transcriptional regulation may include chromatin remodeling. MTA2 inhibits estrogen receptor-transactivation functions, and participates in the development of hormones independent of breast cancer cells. The MTA2 participate in the circadian rhythm through CLOCK-BMAL1 complex. MTA2 inhibits the expression of target genes owing to its ability to interact with chromatin remodeling complexes, and modulates pathways involved in cellular functions, including invasion, apoptosis, epithelial-to-mesenchymal transition, and growth of normal and cancer cells # Regulation Expression of MTA2 is stimulated by Sp1 transcription factor and repressed by Kaiso. Growth regulatory activity of MTA2 is modulated through its acetylation by histone acetylase p300 . The expression of MTA2 is inhibited by the Rho GDIa in breast cancer cells and by human β-defensins in colon cancer cells. MicroRNAs-146a and miR-34a also regulate the levels of MTA2 mRNA through post-transcriptional mechanism. # Targets MTA2 deacetylates the estrogen receptor alpha and p53 and inhibits their transactivation functions. MTA2 represses the expression of E-cadherin in non-small-cell lung cancer cells. but stimulates the expression of IL-11 in gastric cancer cells. The MTA2-containing chromatin remodeling complex targets CLOCK-BMAL1 complex. # Interactions MTA2 has been shown to interact with: - CHD4, - HDAC1, - HDAC2, - MBD3 - MTA1, - RBBP4, - RBBP7, and - SATB1. # Notes

MTA2 Metastasis-associated protein MTA2 is a protein that in humans is encoded by the MTA2 gene.[1][2] MTA2 is the second member of the MTA family of genes.[1][3][4] MTA2 protein localizes in the nucleus and is a component of the nucleosome remodeling and the deacetylation complex (NuRD).[4] Similar to the founding family member MTA1, MTA2 functions as a chromatin remodeling factor and regulates gene expression.[5][6] MTA2 is overexpressed in human cancer and its dysregulated level correlates well with cancer invasiveness and aggressive phenotypes.[7] # Discovery MTA2 was initially recognized as an MTA1 like 1 gene, named MTA1-L1, from a large scale sequencing of randomly selected clones from human cDNA libraries in 1999.[1] Clues about the role of MTA2 in gene expression came from the association of MTA2 polypeptides in the NuRD complex in a proteomic study[3] This was followed by targeted cloning of murine Mta2 in 2001.[8] # Gene and spliced variants MTA2 is localized on chromosome 11q12-q13.1 in human and on 19B in mice. The 8.6-kb long human MTA2 gene contains 20 exons and seven transcripts inclusive of three protein-coding transcripts but predicted to code for two polypeptides of 688 amino acids and 495 amino acids.[9] The remaining four MTA2 transcripts are non-coding RNA transcripts ranging from 532-bp to 627-bp. The murine Mta2 consists of a 3.1-kb protein-coding transcript to code a protein of 668 amino acids, and five non-coding RNAs transcripts, ranging from 620-bp to 839-bp. # Structure Amino acid sequence of MTA2 shares 68.2% homology with MTA1’s sequence. MTA2 domains include, a BAH (Bromo-Adjacent Homology), a ELM2 (egl-27 and MTA1 homology), a SANT domain (SWI, ADA2, N-CoR, TFIIIB-B), and a GATA-like zinc finger.[10][11][12] MTA2 is acetylated at lysine 152 within the BAH domain[13] # Function This gene encodes a protein that has been identified as a component of NuRD, a nucleosome remodeling deacetylase complex identified in the nucleus of human cells. It shows a very broad expression pattern and is strongly expressed in many tissues. It may represent one member of a small gene family that encode different but related proteins involved either directly or indirectly in transcriptional regulation. Their indirect effects on transcriptional regulation may include chromatin remodeling.[2] MTA2 inhibits estrogen receptor-transactivation functions, and participates in the development of hormones independent of breast cancer cells.[7] The MTA2 participate in the circadian rhythm through CLOCK-BMAL1 complex. MTA2 inhibits the expression of target genes owing to its ability to interact with chromatin remodeling complexes, and modulates pathways involved in cellular functions, including invasion, apoptosis, epithelial-to-mesenchymal transition, and growth of normal and cancer cells[5][7] # Regulation Expression of MTA2 is stimulated by Sp1 transcription factor [8][14] and repressed by Kaiso.[15] Growth regulatory activity of MTA2 is modulated through its acetylation by histone acetylase p300 [12]. The expression of MTA2 is inhibited by the Rho GDIa in breast cancer cells[16] and by human β-defensins in colon cancer cells.[17] MicroRNAs-146a and miR-34a also regulate the levels of MTA2 mRNA through post-transcriptional mechanism.[18][19][20] # Targets MTA2 deacetylates the estrogen receptor alpha and p53 and inhibits their transactivation functions.[21][22] MTA2 represses the expression of E-cadherin in non-small-cell lung cancer cells.[23] but stimulates the expression of IL-11 in gastric cancer cells.[24] The MTA2-containing chromatin remodeling complex targets CLOCK-BMAL1 complex.[25] # Interactions MTA2 has been shown to interact with: - CHD4,[26] - HDAC1,[26][27][28][29] - HDAC2,[26][28][30] - MBD3[28][31][32] - MTA1,[26] - RBBP4,[26][28] - RBBP7,[26][28] and - SATB1.[29] # Notes

https://www.wikidoc.org/index.php/MTA2

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wikidoc

MTA3

MTA3 Metastasis-associated protein MTA3 is a protein that in humans is encoded by the MTA3 gene. MTA3 protein localizes in the nucleus as well as in other cellular compartments MTA3 is a component of the nucleosome remodeling and deacetylate (NuRD) complex and participates in gene expression. The expression pattern of MTA3 is opposite to that of MTA1 and MTA2 during mammary gland tumorigenesis. However, MTA3 is also overexpressed in a variety of human cancers. # Discovery Mouse Mta3 was initially identified as a partial cDNA with open reading frames in screening of a mouse keratinocyte cDNA library with a human MTA1 partial fragment by My G. Mahoney's research team. The full length Mta3 cDNA was cloned through 5'-RACE methodology using RNA from C57B1/6J mouse skin. The deduced amino acids and its comparison with the sequences in the GeneBank established MTA3 as the third MTA family member. # Gene and spliced variants The Mta3 is localized on chromosome 12p in mice and MTA3 on 2p21 in human. The human MTA3 gene contains 20 exons, and 19 alternative spliced transcripts. Of these, nine MTA3 transcripts are predicted to code six proteins of 392, 514, 515, 537, 590 and 594 amino acids long, two MTA3 transcripts code 18 amino acids and 91 amino acids polypeptides. The remaining 10 transcripts are non-coding RNAs. The murine Mta3 gene contains nine transcripts, six of which are predicted to code proteins ranging from 251 amino acids to 591 amino acids while one transcript codes for 40 amino acids polypeptide. The murine Mta3 gene contains two predicted non-coding RNAs. # Structure The overall organization of MTA3 protein domains is similar to the other two family members with a BAH (Bromo-Adjacent Homology), a ELM2 (egl-27 and MTA1 homology), a SANT (SWI, ADA2, N-CoR, TFIIIB-B), a GATA-like zinc finger, and one predicted bipartite nuclear localization signal (NLS). The SH3 motif of Mta3 allows it to interact with Fyn and Grb2 – both SH3 containing signaling proteins. # Function Functions of MTA3 are believed to be differentially regulated in the context of cancer-types. For example, MTA3 expression is downregulated in breast cancer and endometrioid adenocarcinomas. MTA3 is overexpressed in non-small cell lung cancer and human placenta and chorionic carcinoma cells. In breast cancer, loss of MTA3 promotes EMT and invasiveness of breast cancer cells via upregulating Snail, which in turn represses E-cadherin adhesion molecule. In the mammary epithelium and breast cancer cells, MTA3 is an estrogen regulated gene and part of a larger regulatory network involving MTA1 and MTAs, all modifiers of hormone response, and participate in the processes involved in growth and differentiation. Accordingly, the MTA3-NuRD complex regulates the expression of Wnt4 in mammary epithelial cells and mice, and controls Wnt4-dependent ductal morphogenesis. In contrast to its repressive actions, MTA3 also stimulates the expression of HIF1α as well as its target genes under hypoxic conditions in trophoblasts and is thought to be involved in differentiation during pregnancy. MTA3-NuRD complex and downstream targets have been shown to participate in primitive hematopoietic and angiogenesis in a zebrafish model system As a part of BCL6 corepressor complex, MTA3 regulates BCL6-dependent repression of target genes, including PRDM1, and modulates the differentiation of B-cells. # Regulation The estrogen receptor-stimulates the expression of MTA3 in breast cancer cells. The SP1 transcription factor stimulates the transcription of MTA3. MicroRNA-495 inhibits the level of MTA3 mRNA as well as the growth and migration of non-small cell lung cancer cells. The β-elemene - a traditional Chinese medicine, upregulates MTA3’s expression in breast cancer cells # Targets The MTA3-NuRD complex represses Snail, a master regulator of epithelial-to-mesenchymal transition (EMT), Wnt4 expression in mammary epithelial cells, and BCL6-corepressor target genes The MTA3-NuRD complex interacts with GATA3 to regulate the expression of GATA3 downstream targets. In addition, MTA3 upregulates HIF1 and its transactivation activity in hypoxic conditions. # Notes

MTA3 Metastasis-associated protein MTA3 is a protein that in humans is encoded by the MTA3 gene.[1][2][3][4] MTA3 protein localizes in the nucleus as well as in other cellular compartments[5] MTA3 is a component of the nucleosome remodeling and deacetylate (NuRD) complex and participates in gene expression.[6][7][8] The expression pattern of MTA3 is opposite to that of MTA1 and MTA2 during mammary gland tumorigenesis.[9][10] However, MTA3 is also overexpressed in a variety of human cancers.[11][12][13] # Discovery Mouse Mta3 was initially identified as a partial cDNA with open reading frames in screening of a mouse keratinocyte cDNA library with a human MTA1 partial fragment by My G. Mahoney's research team.[1] The full length Mta3 cDNA was cloned through 5'-RACE methodology using RNA from C57B1/6J mouse skin.[1] The deduced amino acids and its comparison with the sequences in the GeneBank established MTA3 as the third MTA family member. # Gene and spliced variants The Mta3 is localized on chromosome 12p in mice and MTA3 on 2p21 in human. The human MTA3 gene contains 20 exons, and 19 alternative spliced transcripts. Of these, nine MTA3 transcripts are predicted to code six proteins of 392, 514, 515, 537, 590 and 594 amino acids long, two MTA3 transcripts code 18 amino acids and 91 amino acids polypeptides.[14] The remaining 10 transcripts are non-coding RNAs. The murine Mta3 gene contains nine transcripts, six of which are predicted to code proteins ranging from 251 amino acids to 591 amino acids while one transcript codes for 40 amino acids polypeptide. The murine Mta3 gene contains two predicted non-coding RNAs. # Structure The overall organization of MTA3 protein domains is similar to the other two family members with a BAH (Bromo-Adjacent Homology), a ELM2 (egl-27 and MTA1 homology), a SANT (SWI, ADA2, N-CoR, TFIIIB-B), a GATA-like zinc finger, and one predicted bipartite nuclear localization signal (NLS).[1][6][13] The SH3 motif of Mta3 allows it to interact with Fyn and Grb2 – both SH3 containing signaling proteins.[1] # Function Functions of MTA3 are believed to be differentially regulated in the context of cancer-types. For example, MTA3 expression is downregulated in breast cancer[9][10] and endometrioid adenocarcinomas.[13] MTA3 is overexpressed in non-small cell lung cancer[11] and human placenta and chorionic carcinoma cells.[12] In breast cancer, loss of MTA3 promotes EMT and invasiveness of breast cancer cells via upregulating Snail, which in turn represses E-cadherin adhesion molecule.[15] In the mammary epithelium and breast cancer cells, MTA3 is an estrogen regulated gene and part of a larger regulatory network involving MTA1 and MTAs, all modifiers of hormone response, and participate in the processes involved in growth and differentiation.[15][16][17][18] Accordingly, the MTA3-NuRD complex regulates the expression of Wnt4 in mammary epithelial cells and mice, and controls Wnt4-dependent ductal morphogenesis.[19] In contrast to its repressive actions, MTA3 also stimulates the expression of HIF1α as well as its target genes under hypoxic conditions in trophoblasts and is thought to be involved in differentiation during pregnancy.[20] MTA3-NuRD complex and downstream targets have been shown to participate in primitive hematopoietic and angiogenesis in a zebrafish model system[7][21] As a part of BCL6 corepressor complex, MTA3 regulates BCL6-dependent repression of target genes, including PRDM1, and modulates the differentiation of B-cells.[22][23] # Regulation The estrogen receptor-stimulates the expression of MTA3 in breast cancer cells.[15][16][17] The SP1 transcription factor stimulates the transcription of MTA3.[17] MicroRNA-495 inhibits the level of MTA3 mRNA as well as the growth and migration of non-small cell lung cancer cells.[24] The β-elemene - a traditional Chinese medicine, upregulates MTA3’s expression in breast cancer cells[25] # Targets The MTA3-NuRD complex represses Snail, a master regulator of epithelial-to-mesenchymal transition (EMT),[15] Wnt4 expression in mammary epithelial cells,[19] and BCL6-corepressor target genes[22][23] The MTA3-NuRD complex interacts with GATA3 to regulate the expression of GATA3 downstream targets.[10] In addition, MTA3 upregulates HIF1 and its transactivation activity in hypoxic conditions.[20] # Notes

https://www.wikidoc.org/index.php/MTA3

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wikidoc

MTDH

MTDH Metadherin, also known as protein LYRIC or astrocyte elevated gene-1 protein (AEG-1) is a protein that in humans is encoded by the MTDH gene. # Function AEG-1 is involved in HIF-1alpha mediated angiogenesis. AEG-1 also interacts with SND1 and involved in RNA-induced silencing complex (RISC) and plays very important role in RISC and miRNA functions. AEG-1 induces an oncogene called Late SV40 factor (LSF/TFCP2) which is involved in thymidylate synthase (TS) induction and DNA biosynthesis synthesis. Late SV40 factor (LSF/TFCP2) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9). # Clinical significance AEG-1 acts as an oncogene in melanoma, malignant glioma, breast cancer and hepatocellular carcinoma. It is highly expressed in these cancers and helps in progression and development of these cancers. It is induced by c-Myc oncogene and plays very important role in anchorage independent growth of cancer cells. Elevated expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers, is associated with poor clinical outcomes. MTDH has a dual role in promoting metastatic seeding and enhancing chemoresistance. MTDH is therefore a potential therapeutic target for enhancing chemotherapy and reducing metastasis. LSF/TFCP2 plays multifaceted role in chemo resistance, EMT, allergic response, inflammation and Alzheimer’s disease. AEG-1 controls many hallmarks of oncogenes and cancer. AEG-1/MTDH induces hepato steatosis in mouse liver. The MTDH knockdown by artificial microRNA interference functions as a potential tumor suppressor in breast cancer. Astrocyte elevated gene-1/MTDH undergoes palmitoylation in normal and abnormal physiology of the cell.The microgrooved biomaterial titanium substrata can alter the expression of AEG-1 in human primary cells.

MTDH Metadherin, also known as protein LYRIC or astrocyte elevated gene-1 protein (AEG-1) is a protein that in humans is encoded by the MTDH gene.[1][2][3] # Function AEG-1 is involved in HIF-1alpha mediated angiogenesis. AEG-1 also interacts with SND1 and involved in RNA-induced silencing complex (RISC) and plays very important role in RISC and miRNA functions.[4][5] AEG-1 induces an oncogene called Late SV40 factor (LSF/TFCP2) which is involved in thymidylate synthase (TS) induction and DNA biosynthesis synthesis.[6] Late SV40 factor (LSF/TFCP2) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9).[7] # Clinical significance AEG-1 acts as an oncogene in melanoma, malignant glioma, breast cancer and hepatocellular carcinoma.[8] It is highly expressed in these cancers and helps in progression and development of these cancers. It is induced by c-Myc oncogene and plays very important role in anchorage independent growth of cancer cells. Elevated expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers, is associated with poor clinical outcomes. MTDH has a dual role in promoting metastatic seeding and enhancing chemoresistance. MTDH is therefore a potential therapeutic target for enhancing chemotherapy and reducing metastasis.[9] LSF/TFCP2 plays multifaceted role in chemo resistance, EMT, allergic response, inflammation and Alzheimer’s disease.[10] AEG-1 controls many hallmarks of oncogenes and cancer. AEG-1/MTDH induces hepato steatosis in mouse liver.[11] The MTDH knockdown by artificial microRNA interference functions as a potential tumor suppressor in breast cancer.[12] Astrocyte elevated gene-1/MTDH undergoes palmitoylation in normal and abnormal physiology of the cell.[13]The microgrooved biomaterial titanium substrata can alter the expression of AEG-1 in human primary cells.[14]

https://www.wikidoc.org/index.php/MTDH

24ed1b38d68256d70a821120446542a4624c9d56

wikidoc

mTOR

mTOR The mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases. mTOR links with other proteins and serves as a core component of two distinct protein complexes, mTOR complex 1 and mTOR complex 2, which regulate different cellular processes. In particular, as a core component of both complexes, mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin-like growth factor 1 receptors. mTORC2 has also been implicated in the control and maintenance of the actin cytoskeleton. # Discovery ## Rapa Nui (Easter Island - Chile) The study of TOR originated in the 1960s with an expedition to Easter Island (known by the island inhabitants as Rapa Nui), with the goal of identifying natural products from plants and soil with possible therapeutic potential. In 1972, Suren Sehgal identified a small molecule, from a soil bacterium Streptomyces hygroscopicus, that he purified and initially reported to possess potent antifungal activity. He appropriately named it rapamycin, noting its original source and activity (Sehgal et al., 1975). However, early testing revealed that rapamycin also had potent immunosuppressive and cytostatic anti-cancer activity. Unfortunately, rapamycin did not initially receive significant interest from the pharmaceutical industry until the 1980s, when Wyeth-Ayerst supported Sehgal's efforts to further investigate rapamycin's effect on the immune system. This eventually led to its FDA approval as an immunosuppressant following kidney transplantation. However, prior to its FDA approval, how rapamycin worked remained completely unknown. The discovery of TOR and mTOR stemmed from independent studies of the natural product rapamycin by Joseph Heitman, Rao Movva, and Michael N. Hall, and by Stuart L. Schreiber, David M. Sabatini, and Robert T. Abraham. In 1993, George Livi and Michael N. Hall independently cloned genes that mediate the toxicity of rapamycin in fungi, known as the TOR/DRR genes. However, the molecular target of the FKBP12-rapamycin complex in mammals was not known. In 1994, Stuart L. Schreiber, David M. Sabatini and Robert T. Abraham independently discovered a protein that directly interacts with FKBP12-rapamycin, which became known as mTOR due to its homology to the yeast TOR/DRR genes. Rapamycin arrests fungal activity at the G1 phase of the cell cycle. In mammals, it suppresses the immune system by blocking the G1 to S phase transition in T-lymphocytes. Thus, it is used as an immunosuppressant following organ transplantation. Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product FK506 in 1987. In 1989–90, FK506 and rapamycin were determined to inhibit T-cell receptor (TCR) and IL-2 receptor signaling pathways, respectively. The two natural products were used to discover the FK506- and rapamycin-binding proteins, including FKBP12, and to provide evidence that FKBP12–FK506 and FKBP12–rapamycin might act through gain-of-function mechanisms that target distinct cellular functions. These investigations included key studies by Francis Dumont and Nolan Sigal at Merck contributing to show that FK506 and rapamycin behave as reciprocal antagonists. These studies implicated FKBP12 as a possible target of rapamycin, but suggested that the complex might interact with another element of the mechanistic cascade. In 1991, calcineurin was identified as the target of FKBP12-FK506. That of FKBP12-rapamycin remained mysterious until genetic and molecular studies in yeast established FKBP12 as the target of rapamycin, and implicated TOR1 and TOR2 as the targets of FKBP12-rapamycin in 1991 and 1993, followed by studies in 1994 when several groups, working independently, discovered the mTOR kinase as its direct target in mammalian tissues. Sequence analysis of mTOR revealed it to be the direct ortholog of proteins encoded by the yeast target of rapamycin 1 and 2 (TOR1 and TOR2) genes, which Joseph Heitman, Rao Movva, and Michael N. Hall had identified in August 1991 and May 1993. Independently, George Livi and colleagues later reported the same genes, which they called dominant rapamycin resistance 1 and 2 (DRR1 and DRR2), in studies published in October 1993. The protein now called mTOR was originally named FRAP by Stuart L. Schreiber and RAFT1 by David M. Sabatini; FRAP1 was used as its official gene symbol in humans. Because of these different names, mTOR, which had been first used by Robert T. Abraham, was increasingly adopted by the community of scientists working on the mTOR pathway to refer to the protein and in homage to the original discovery of the TOR protein in yeast that was named TOR, the Target of Rapamycin, by Joe Heitman, Rao Movva, and Mike Hall. TOR was originally discovered at the Biozentrum and Sandoz Pharmaceuticals in 1991 in Basel, Switzerland, and the name TOR pays further homage to this discovery, as TOR means doorway or gate in German, and the city of Basel was once ringed by a wall punctuated with gates into the city, including the iconic Spalentor. Similarly, with subsequent discoveries the zebra fish TOR was named zTOR, the Arabidopsis thaliana TOR was named AtTOR, and the Drosophila TOR was named dTOR. In 2009 the FRAP1 gene name was officially changed by the HUGO Gene Nomenclature Committee (HGNC) to mTOR, which stands for mechanistic target of rapamycin. The discovery of TOR and the subsequent identification of mTOR opened the door to the molecular and physiological study of what is now called the mTOR pathway and had a catalytic effect on the growth of the field of chemical biology, where small molecules are used as probes of biology. # Function mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids. mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers. Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12. The FKBP12–rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity. # Complexes mTOR is the catalytic subunit of two structurally distinct complexes: mTORC1 and mTORC2. Both complexes localize to different subcellular compartments, thus affecting their activation and function. Upon activation by Rheb, mTORC1 localizes to the Ragulator-Rag complex on the lysosome surface where it then becomes active in the presence of sufficient amino acids. ## mTORC1 mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (mLST8) and the non-core components PRAS40 and DEPTOR. This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress. ## mTORC2 mTOR Complex 2 (mTORC2) is composed of MTOR, rapamycin-insensitive companion of MTOR (RICTOR), MLST8, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1). mTORC2 has been shown to function as an important regulator of the actin cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα). mTORC2 also phosphorylates the serine/threonine protein kinase Akt/PKB on serine residue Ser473, thus affecting metabolism and survival. Phosphorylation of Akt's serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by PDK1 and leads to full Akt activation. In addition, mTORC2 exhibits tyrosine protein kinase activity and phosphorylates the insulin-like growth factor 1 receptor (IGF-IR) and insulin receptor (InsR) on the tyrosine residues Tyr1131/1136 and Tyr1146/1151, respectively, leading to full activation of IGF-IR and InsR. ## Inhibition by rapamycin Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Rapamycin has a more complex effect on mTORC2, inhibiting it only in certain cell types under prolonged exposure. Disruption of mTORC2 produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin. # Gene deletion experiments The mTORC2 signaling pathway is less defined than the mTORC1 signaling pathway. The functions of the components of the mTORC complexes have been studied using knockdowns and knockouts and were found to produce the following phenotypes: - NIP7: Knockdown reduced mTORC2 activity that is indicated by decreased phosphorylation of mTORC2 substrates. - RICTOR: Overexpression leads to metastasis and knockdown inhibits growth factor-induced PKC-phosphorylation. Constitutive deletion of Rictor in mice leads to embryonic lethality, while tissue specific deletion leads to a variety of phenotypes; a common phenotype of Rictor deletion in liver, white adipose tissue, and pancreatic beta cells is systemic glucose intolerance and insulin resistance in one or more tissues. Decreased Rictor expression in mice decreases male, but not female, lifespan. - mTOR: Inhibition of mTORC1 and mTORC2 by PP242 pyrimidin-3-yl)-1H-indol-5-ol] leads to autophagy or apoptosis; inhibition of mTORC2 alone by PP242 prevents phosphorylation of Ser-473 site on AKT and arrests the cells in G1 phase of the cell cycle. Genetic reduction of mTOR expression in mice significantly increases lifespan. - PDK1: Knockout is lethal; hypomorphic allele results in smaller organ volume and organism size but normal AKT activation. - AKT: Knockout mice experience spontaneous apoptosis (AKT1), severe diabetes (AKT2), small brains (AKT3), and growth deficiency (AKT1/AKT2). Mice heterozygous for AKT1 have increased lifespan. - TOR1, the S. cerevisiae orthologue of mTORC1, is a regulator of both carbon and nitrogen metabolism; TOR1 KO strains regulate response to nitrogen as well as carbon availability, indicating that it is a key nutritional transducer in yeast. # Clinical significance ## Aging Decreased TOR activity has been found to increase life span in S. cerevisiae, C. elegans, and D. melanogaster. The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice. It is hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity. Some studies have suggested that mTOR signaling may increase during aging, at least in specific tissues like adipose tissue, and rapamycin may act in part by blocking this increase. An alternative theory is mTOR signaling is an example of antagonistic pleiotropy, and while high mTOR signaling is good during early life, it is maintained at an inappropriately high level in old age. Calorie restriction and methionine restriction may act in part by limiting levels of essential amino acids including leucine and methionine, which are potent activators of mTOR. The administration of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway in the hypothalamus. According to the free radical theory of aging, reactive oxygen species cause damage of mitochondrial proteins and decrease ATP production. Subsequently, via ATP sensitive AMPK, the mTOR pathway is inhibited and ATP consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the ribosome. Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration. These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates glycolysis and removal of dysfunctional cellular components via autophagy. ## Cancer Over-activation of mTOR signaling significantly contributes to the initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas. Reasons for constitutive activation are several. Among the most common are mutations in tumor suppressor PTEN gene. PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of PI3K, an upstream effector of mTOR. Additionally, mTOR activity is deregulated in many cancers as a result of increased activity of PI3K or Akt. Similarly, overexpression of downstream mTOR effectors 4E-BP1, S6K and eIF4E leads to poor cancer prognosis. Also, mutations in TSC proteins that inhibit the activity of mTOR may lead to a condition named tuberous sclerosis complex, which exhibits as benign lesions and increases the risk of renal cell carcinoma. Increasing mTOR activity was shown to drive cell cycle progression and increase cell proliferation mainly thanks to its effect on protein synthesis. Moreover, active mTOR supports tumor growth also indirectly by inhibiting autophagy. Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of HIF1A and supporting angiogenesis. mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate—activation of glycolytic metabolism. Akt2, a substrate of mTOR, specifically of mTORC2, upregulates expression of the glycolytic enzyme PKM2 thus contributing to the Warburg effect. ## Central nervous system disorders / Brain function ### Autism MTOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in autism spectrum disorders. ### Alzheimer's disease mTOR signaling intersects with Alzheimer's disease (AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression. In general, findings demonstrate mTOR signaling hyperactivity in AD brains. For example, postmortem studies of human AD brain reveal dysregulation in PTEN, Akt, S6K, and mTOR. mTOR signaling appears to be closely related to the presence of soluble amyloid beta (Aβ) and tau proteins, which aggregate and form two hallmarks of the disease, Aβ plaques and neurofibrillary tangles, respectively. In vitro studies have shown Aβ to be an activator of the PI3K/AKT pathway, which in turn activates mTOR. In addition, applying Aβ to N2K cells increases the expression of p70S6K, a downstream target of mTOR known to have higher expression in neurons that eventually develop neurofibrillary tangles. Chinese hamster ovary cells transfected with the 7PA2 familial AD mutation also exhibit increased mTOR activity compared to controls, and the hyperactivity is blocked using a gamma-secretase inhibitor. These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling. Consistent with data observed in vitro, mTOR activity and activated p70S6K have been shown to be significantly increased in the cortex and hippocampus of animal models of AD compared to controls. Pharmacologic or genetic removal of the Aβ in animal models of AD eliminates the disruption in normal mTOR activity, pointing to the direct involvement of Aβ in mTOR signaling. In addition, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed. Cognitive impairments characteristic of AD appear to be mediated by the phosphorylation of PRAS-40, which detaches from and allows for the mTOR hyperactivity when it is phosphorylated; inhibiting PRAS-40 phosphorylation prevents Aβ-induced mTOR hyperactivity. Given these findings, the mTOR signaling pathway appears to be one mechanism of Aβ-induced toxicity in AD. The hyperphosphorylation of tau proteins into neurofibrillary tangles is one hallmark of AD. p70S6K activation has been shown to promote tangle formation as well as mTOR hyperactivity through increased phosphorylation and reduced dephosphorylation. It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins. Synaptic plasticity is a key contributor to learning and memory, two processes that are severely impaired in AD patients. Translational control, or the maintenance of protein homeostasis, has been shown to be essential for neural plasticity and is regulated by mTOR. Both protein over- and under-production via mTOR activity seem to contribute to impaired learning and memory. Furthermore, given that deficits resulting from mTOR overactivity can be alleviated through treatment with rapamycin, it is possible that mTOR plays an important role in affecting cognitive functioning through synaptic plasticity. Further evidence for mTOR activity in neurodegeneration comes from recent findings demonstrating that eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition. Some evidence points to mTOR's role in reduced Aβ clearance as well. mTOR is a negative regulator of autophagy; therefore, hyperactivity in mTOR signaling should reduce Aβ clearance in the AD brain. Disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, including AD. Studies using mouse models of Huntington's disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates. Perhaps the same treatment may be useful in clearing Aβ deposits as well. ## Protein synthesis and cell growth mTORC1 activation is required for myofibrillar muscle protein synthesis and skeletal muscle hypertrophy in humans in response to both physical exercise and ingestion of certain amino acids or amino acid derivatives. Persistent inactivation of mTORC1 signaling in skeletal muscle facilitates the loss of muscle mass and strength during muscle wasting in old age, cancer cachexia, and muscle atrophy from physical inactivity. mTORC2 activation appears to mediate neurite outgrowth in differentiated mouse neuro2a cells. Intermittent mTOR activation in prefrontal neurons by β-hydroxy β-methylbutyrate inhibits age-related cognitive decline associated with dendritic pruning in animals, which is a phenomenon also observed in humans. ## Lysosomal damage inhibits mTOR and induces autophagy Active mTORC1 is positioned on lysosomes. mTOR is inhibited when lysosomal membrane is damaged by various exogenous or endogenous agents, such as invading bacteria, membrane-permeant chemicals yielding osmotically active products (this type of injury can be modeled using membrane-permeant dipeptide precursors that polymerize in lysosomes), amyloid protein aggregates (see above section on Alzheimer's disease) and cytoplasmic organic or inorganic inclusions including urate crystals and crystalline silica. The process of mTOR inactivation following lysosomal/endomembrane is mediated by the protein complex termed GALTOR. At the heart of GALTOR is galectin-8, a member of β-galactoside binding superfamily of cytosolic lectins termed galectins, which recognizes lysosomal membrane damage by binding to the exposed glycans on the lumenal side of the delimiting endomembrane. Following membrane damage, galectin-8, which normally associates with mTOR under homeostatic conditions, no longer interacts with mTOR but now instead binds to SLC38A9, RRAGA/RRAGB, and LAMTOR1, inhibiting Ragulator's (LAMTOR1-5 complex) guanine nucleotide exchange function- TOR is a negative regulator of autophagy in general, best studied during response to starvation, which is a metabolic response. During lysosomal damage however, mTOR inhibition activates autophagy response in its quality control function, leading to the process termed lysophagy that removes damaged lysosomes. At this stage another galectin, galectin-3, interacts with TRIM16 to guide selective autophagy of damaged lysosomes. TRIM16 gathers ULK1 and principal components (Beclin 1 and ATG16L1) of other complexes (Beclin 1-VPS34-ATG14 and ATG16L1-ATG5-ATG12) initiating autophagy, many of them being under negative control of mTOR directly such as the ULK1-ATG13 complex, or indirectly, such as components of the class III PI3K (Beclin 1, ATG14 and VPS34) since they depend on activating phosphorylations by ULK1 when it is not inhibited by mTOR. These autophagy-driving components physically and functionally link up with each other integrating all processes necessary for autophagosomal formation: (i) the ULK1-ATG13-FIP200/RB1CC1 complex associates with the LC3B/GABARAP conjugation machinery through direct interactions between FIP200/RB1CC1 and ATG16L1, (ii) ULK1-ATG13-FIP200/RB1CC1 complex associates with the Beclin 1-VPS34-ATG14 via direct interactions between ATG13's HORMA domain and ATG14, (iii) ATG16L1 interacts with WIPI2, which binds to PI3P, the enzymatic product of the class III PI3K Beclin 1-VPS34-ATG14. Thus, mTOR inactivation, initiated through GALTOR upon lysosomal damage, plus a simultaneous activation via galectin-9 (which also recognizes lysosomal membrane breach) of AMPK that directly phosphorylates and activates key components (ULK1, Beclin 1) of the autophagy systems listed above and further inactivates mTORC1, allows for strong autophagy induction and autophagic removal of damaged lysosomes. Additionally, several types of ubiquitination events parallel and complement the galectin-driven processes: Ubiquitination of TRIM16-ULK1-Beclin-1 stabilizes these complexes to promote autophagy activation as described above. ATG16L1 has an intrinsic binding affinity for ubiquitin); whereas ubiqutination by a glycioprotein-specific FBXO27-endowed ubiquitin ligase of several damage-exposed glycosylated lysosomal membrane proteins such as LAMP1, LAMP2, GNS/N-acetylglucosamine-6-sulfatase, TSPAN6/tetraspanin-6, PSAP/prosaposin, and TMEM192/transmembrane protein 192 may contribute to the execution of lysophagy via autophagic receptors such as p62/SQSTM1, which is recruited during lysophagy, or other to be determined functions. ## Scleroderma Scleroderma, also known as systemic sclerosis, is a chronic systemic autoimmune disease characterised by hardening (sclero) of the skin (derma) that affects internal organs in its more severe forms. mTOR plays a role in fibrotic diseases and autoimmunity, and blockade of the mTORC pathway is under investigation as a treatment for scleroderma. # mTOR inhibitors as therapies ## Transplantation mTOR inhibitors, e.g. rapamycin, are already used to prevent transplant rejection. Rapamycin is also related to the therapy of glycogen storage disease (GSD). ## Glycogen storage disease Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS (glycogen synthase) can be increased in skeletal muscle. This discovery represents a potential novel therapeutic approach for glycogen storage diseases that involve glycogen accumulation in muscle. Various natural compounds, including epigallocatechin gallate (EGCG), caffeine, curcumin, and resveratrol, have also been reported to inhibit mTOR when applied to isolated cells in culture. As yet no evidence exists that these substances inhibit mTOR signaling when taken as dietary supplements. However, a natural substance Berberine is available as a dietary supplement. In live cells it localizes in mitochondria, inhibits complex I of respiratory chain thereby decreasing ATP (increasing AMP/ATP ratio) which leads to activation of AMPK and suppression of mTOR signaling, consistent with its potential anti-aging properties. ## Anti-cancer There are two primary mTOR inhibitors used in the treatment of human cancers, temsirolimus and everolimus. mTOR inhibitors have found use in the treatment of a variety of malignancies, including renal cell carcinoma (temsirolimus) and pancreatic cancer, breast cancer, and renal cell carcinoma (everolimus). The complete mechanism of these agents is not clear, but they are thought to function by imparing tumour angiogenesis and causing impariment of the G1/S transition. ## Anti-aging mTOR inhibitors may be useful for treating/preventing several age-associated conditions, including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. After a short-term treatment with mTor inhibitors, in elderly (65 and older), treated subjects had a reduced number of infections, over the course of a year. # Interactions Mechanistic target of rapamycin has been shown to interact with: - ABL1, - AKT1, - IGF-IR, - InsR, - CLIP1, - EIF3F - EIF4EBP1, - FKBP1A, - GPHN, - KIAA1303, - PRKCD, - RHEB, - RICTOR, - RPS6KB1, - STAT1, - STAT3, - Two-pore channels: TPCN1; TPCN2, and - UBQLN1.

mTOR The mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene.[1][2][3] mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.[4] mTOR links with other proteins and serves as a core component of two distinct protein complexes, mTOR complex 1 and mTOR complex 2, which regulate different cellular processes.[5] In particular, as a core component of both complexes, mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription.[5][6] As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin-like growth factor 1 receptors.[7] mTORC2 has also been implicated in the control and maintenance of the actin cytoskeleton.[5][8] # Discovery ## Rapa Nui (Easter Island - Chile) The study of TOR originated in the 1960s with an expedition to Easter Island (known by the island inhabitants as Rapa Nui), with the goal of identifying natural products from plants and soil with possible therapeutic potential. In 1972, Suren Sehgal identified a small molecule, from a soil bacterium Streptomyces hygroscopicus, that he purified and initially reported to possess potent antifungal activity. He appropriately named it rapamycin, noting its original source and activity (Sehgal et al., 1975). However, early testing revealed that rapamycin also had potent immunosuppressive and cytostatic anti-cancer activity. Unfortunately, rapamycin did not initially receive significant interest from the pharmaceutical industry until the 1980s, when Wyeth-Ayerst supported Sehgal's efforts to further investigate rapamycin's effect on the immune system. This eventually led to its FDA approval as an immunosuppressant following kidney transplantation. However, prior to its FDA approval, how rapamycin worked remained completely unknown. The discovery of TOR and mTOR stemmed from independent studies of the natural product rapamycin by Joseph Heitman, Rao Movva, and Michael N. Hall, and by Stuart L. Schreiber, David M. Sabatini, and Robert T. Abraham.[9][2][3] In 1993, George Livi and Michael N. Hall independently cloned genes that mediate the toxicity of rapamycin in fungi, known as the TOR/DRR genes.[10][11] However, the molecular target of the FKBP12-rapamycin complex in mammals was not known. In 1994, Stuart L. Schreiber, David M. Sabatini and Robert T. Abraham independently discovered a protein that directly interacts with FKBP12-rapamycin, which became known as mTOR due to its homology to the yeast TOR/DRR genes.[1][2][3] Rapamycin arrests fungal activity at the G1 phase of the cell cycle. In mammals, it suppresses the immune system by blocking the G1 to S phase transition in T-lymphocytes.[12] Thus, it is used as an immunosuppressant following organ transplantation.[13] Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product FK506 in 1987. In 1989–90, FK506 and rapamycin were determined to inhibit T-cell receptor (TCR) and IL-2 receptor signaling pathways, respectively.[14][15] The two natural products were used to discover the FK506- and rapamycin-binding proteins, including FKBP12, and to provide evidence that FKBP12–FK506 and FKBP12–rapamycin might act through gain-of-function mechanisms that target distinct cellular functions. These investigations included key studies by Francis Dumont and Nolan Sigal at Merck contributing to show that FK506 and rapamycin behave as reciprocal antagonists.[16][17] These studies implicated FKBP12 as a possible target of rapamycin, but suggested that the complex might interact with another element of the mechanistic cascade.[18][19] In 1991, calcineurin was identified as the target of FKBP12-FK506.[20] That of FKBP12-rapamycin remained mysterious until genetic and molecular studies in yeast established FKBP12 as the target of rapamycin, and implicated TOR1 and TOR2 as the targets of FKBP12-rapamycin in 1991 and 1993,[9][21] followed by studies in 1994 when several groups, working independently, discovered the mTOR kinase as its direct target in mammalian tissues.[1][2][13] Sequence analysis of mTOR revealed it to be the direct ortholog of proteins encoded by the yeast target of rapamycin 1 and 2 (TOR1 and TOR2) genes, which Joseph Heitman, Rao Movva, and Michael N. Hall had identified in August 1991 and May 1993. Independently, George Livi and colleagues later reported the same genes, which they called dominant rapamycin resistance 1 and 2 (DRR1 and DRR2), in studies published in October 1993. The protein now called mTOR was originally named FRAP by Stuart L. Schreiber and RAFT1 by David M. Sabatini;[1][2] FRAP1 was used as its official gene symbol in humans. Because of these different names, mTOR, which had been first used by Robert T. Abraham,[1] was increasingly adopted by the community of scientists working on the mTOR pathway to refer to the protein and in homage to the original discovery of the TOR protein in yeast that was named TOR, the Target of Rapamycin, by Joe Heitman, Rao Movva, and Mike Hall. TOR was originally discovered at the Biozentrum and Sandoz Pharmaceuticals in 1991 in Basel, Switzerland, and the name TOR pays further homage to this discovery, as TOR means doorway or gate in German, and the city of Basel was once ringed by a wall punctuated with gates into the city, including the iconic Spalentor.[22] Similarly, with subsequent discoveries the zebra fish TOR was named zTOR, the Arabidopsis thaliana TOR was named AtTOR, and the Drosophila TOR was named dTOR. In 2009 the FRAP1 gene name was officially changed by the HUGO Gene Nomenclature Committee (HGNC) to mTOR, which stands for mechanistic target of rapamycin. The discovery of TOR and the subsequent identification of mTOR opened the door to the molecular and physiological study of what is now called the mTOR pathway and had a catalytic effect on the growth of the field of chemical biology, where small molecules are used as probes of biology. # Function mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids.[6] mTOR also senses cellular nutrient, oxygen, and energy levels.[23] The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.[24][25] Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12.[26][27] The FKBP12–rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.[27] # Complexes mTOR is the catalytic subunit of two structurally distinct complexes: mTORC1 and mTORC2.[28] Both complexes localize to different subcellular compartments, thus affecting their activation and function.[29] Upon activation by Rheb, mTORC1 localizes to the Ragulator-Rag complex on the lysosome surface where it then becomes active in the presence of sufficient amino acids.[30][31] ## mTORC1 mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (mLST8) and the non-core components PRAS40 and DEPTOR.[32][33] This complex functions as a nutrient/energy/redox sensor and controls protein synthesis.[6][32] The activity of mTORC1 is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress.[32][34][35] ## mTORC2 mTOR Complex 2 (mTORC2) is composed of MTOR, rapamycin-insensitive companion of MTOR (RICTOR), MLST8, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1).[36][37] mTORC2 has been shown to function as an important regulator of the actin cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα).[37] mTORC2 also phosphorylates the serine/threonine protein kinase Akt/PKB on serine residue Ser473, thus affecting metabolism and survival.[38] Phosphorylation of Akt's serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by PDK1 and leads to full Akt activation.[39][40] In addition, mTORC2 exhibits tyrosine protein kinase activity and phosphorylates the insulin-like growth factor 1 receptor (IGF-IR) and insulin receptor (InsR) on the tyrosine residues Tyr1131/1136 and Tyr1146/1151, respectively, leading to full activation of IGF-IR and InsR.[7] ## Inhibition by rapamycin Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Rapamycin has a more complex effect on mTORC2, inhibiting it only in certain cell types under prolonged exposure. Disruption of mTORC2 produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin.[41] # Gene deletion experiments The mTORC2 signaling pathway is less defined than the mTORC1 signaling pathway. The functions of the components of the mTORC complexes have been studied using knockdowns and knockouts and were found to produce the following phenotypes: - NIP7: Knockdown reduced mTORC2 activity that is indicated by decreased phosphorylation of mTORC2 substrates.[42] - RICTOR: Overexpression leads to metastasis and knockdown inhibits growth factor-induced PKC-phosphorylation.[43] Constitutive deletion of Rictor in mice leads to embryonic lethality,[44] while tissue specific deletion leads to a variety of phenotypes; a common phenotype of Rictor deletion in liver, white adipose tissue, and pancreatic beta cells is systemic glucose intolerance and insulin resistance in one or more tissues.[41][45][46][47] Decreased Rictor expression in mice decreases male, but not female, lifespan.[48] - mTOR: Inhibition of mTORC1 and mTORC2 by PP242 [2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol] leads to autophagy or apoptosis; inhibition of mTORC2 alone by PP242 prevents phosphorylation of Ser-473 site on AKT and arrests the cells in G1 phase of the cell cycle.[49] Genetic reduction of mTOR expression in mice significantly increases lifespan.[50] - PDK1: Knockout is lethal; hypomorphic allele results in smaller organ volume and organism size but normal AKT activation.[51] - AKT: Knockout mice experience spontaneous apoptosis (AKT1), severe diabetes (AKT2), small brains (AKT3), and growth deficiency (AKT1/AKT2).[52] Mice heterozygous for AKT1 have increased lifespan.[53] - TOR1, the S. cerevisiae orthologue of mTORC1, is a regulator of both carbon and nitrogen metabolism; TOR1 KO strains regulate response to nitrogen as well as carbon availability, indicating that it is a key nutritional transducer in yeast.[54][55] # Clinical significance ## Aging Decreased TOR activity has been found to increase life span in S. cerevisiae, C. elegans, and D. melanogaster.[56][57][58][59] The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice.[60][61][62][63][64] It is hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity.[56][57] Some studies have suggested that mTOR signaling may increase during aging, at least in specific tissues like adipose tissue, and rapamycin may act in part by blocking this increase.[65] An alternative theory is mTOR signaling is an example of antagonistic pleiotropy, and while high mTOR signaling is good during early life, it is maintained at an inappropriately high level in old age. Calorie restriction and methionine restriction may act in part by limiting levels of essential amino acids including leucine and methionine, which are potent activators of mTOR.[66] The administration of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway in the hypothalamus.[67] According to the free radical theory of aging,[68] reactive oxygen species cause damage of mitochondrial proteins and decrease ATP production. Subsequently, via ATP sensitive AMPK, the mTOR pathway is inhibited and ATP consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the ribosome.[12] Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration.[69] These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates glycolysis[69] and removal of dysfunctional cellular components via autophagy.[68] ## Cancer Over-activation of mTOR signaling significantly contributes to the initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas.[70] Reasons for constitutive activation are several. Among the most common are mutations in tumor suppressor PTEN gene. PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of PI3K, an upstream effector of mTOR. Additionally, mTOR activity is deregulated in many cancers as a result of increased activity of PI3K or Akt.[71] Similarly, overexpression of downstream mTOR effectors 4E-BP1, S6K and eIF4E leads to poor cancer prognosis.[72] Also, mutations in TSC proteins that inhibit the activity of mTOR may lead to a condition named tuberous sclerosis complex, which exhibits as benign lesions and increases the risk of renal cell carcinoma.[73] Increasing mTOR activity was shown to drive cell cycle progression and increase cell proliferation mainly thanks to its effect on protein synthesis. Moreover, active mTOR supports tumor growth also indirectly by inhibiting autophagy.[74] Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of HIF1A and supporting angiogenesis.[75] mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate—activation of glycolytic metabolism. Akt2, a substrate of mTOR, specifically of mTORC2, upregulates expression of the glycolytic enzyme PKM2 thus contributing to the Warburg effect.[76] ## Central nervous system disorders / Brain function ### Autism MTOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in autism spectrum disorders.[77] ### Alzheimer's disease mTOR signaling intersects with Alzheimer's disease (AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression. In general, findings demonstrate mTOR signaling hyperactivity in AD brains. For example, postmortem studies of human AD brain reveal dysregulation in PTEN, Akt, S6K, and mTOR.[78][79][80] mTOR signaling appears to be closely related to the presence of soluble amyloid beta (Aβ) and tau proteins, which aggregate and form two hallmarks of the disease, Aβ plaques and neurofibrillary tangles, respectively.[81] In vitro studies have shown Aβ to be an activator of the PI3K/AKT pathway, which in turn activates mTOR.[82] In addition, applying Aβ to N2K cells increases the expression of p70S6K, a downstream target of mTOR known to have higher expression in neurons that eventually develop neurofibrillary tangles.[83][84] Chinese hamster ovary cells transfected with the 7PA2 familial AD mutation also exhibit increased mTOR activity compared to controls, and the hyperactivity is blocked using a gamma-secretase inhibitor.[85][86] These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling.[87] Consistent with data observed in vitro, mTOR activity and activated p70S6K have been shown to be significantly increased in the cortex and hippocampus of animal models of AD compared to controls.[86][88] Pharmacologic or genetic removal of the Aβ in animal models of AD eliminates the disruption in normal mTOR activity, pointing to the direct involvement of Aβ in mTOR signaling.[88] In addition, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed.[88] Cognitive impairments characteristic of AD appear to be mediated by the phosphorylation of PRAS-40, which detaches from and allows for the mTOR hyperactivity when it is phosphorylated; inhibiting PRAS-40 phosphorylation prevents Aβ-induced mTOR hyperactivity.[88][89][90] Given these findings, the mTOR signaling pathway appears to be one mechanism of Aβ-induced toxicity in AD. The hyperphosphorylation of tau proteins into neurofibrillary tangles is one hallmark of AD. p70S6K activation has been shown to promote tangle formation as well as mTOR hyperactivity through increased phosphorylation and reduced dephosphorylation.[83][91][92][93] It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins.[94] Synaptic plasticity is a key contributor to learning and memory, two processes that are severely impaired in AD patients. Translational control, or the maintenance of protein homeostasis, has been shown to be essential for neural plasticity and is regulated by mTOR.[86][95][96][97][98] Both protein over- and under-production via mTOR activity seem to contribute to impaired learning and memory. Furthermore, given that deficits resulting from mTOR overactivity can be alleviated through treatment with rapamycin, it is possible that mTOR plays an important role in affecting cognitive functioning through synaptic plasticity.[82][99] Further evidence for mTOR activity in neurodegeneration comes from recent findings demonstrating that eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition.[100] Some evidence points to mTOR's role in reduced Aβ clearance as well. mTOR is a negative regulator of autophagy;[101] therefore, hyperactivity in mTOR signaling should reduce Aβ clearance in the AD brain. Disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, including AD.[102][103][104][105][106][107] Studies using mouse models of Huntington's disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates.[108][109] Perhaps the same treatment may be useful in clearing Aβ deposits as well. ## Protein synthesis and cell growth mTORC1 activation is required for myofibrillar muscle protein synthesis and skeletal muscle hypertrophy in humans in response to both physical exercise and ingestion of certain amino acids or amino acid derivatives.[110][111] Persistent inactivation of mTORC1 signaling in skeletal muscle facilitates the loss of muscle mass and strength during muscle wasting in old age, cancer cachexia, and muscle atrophy from physical inactivity.[110][111][112] mTORC2 activation appears to mediate neurite outgrowth in differentiated mouse neuro2a cells.[113] Intermittent mTOR activation in prefrontal neurons by β-hydroxy β-methylbutyrate inhibits age-related cognitive decline associated with dendritic pruning in animals, which is a phenomenon also observed in humans.[114] ## Lysosomal damage inhibits mTOR and induces autophagy Active mTORC1 is positioned on lysosomes. mTOR is inhibited [116] when lysosomal membrane is damaged by various exogenous or endogenous agents, such as invading bacteria, membrane-permeant chemicals yielding osmotically active products (this type of injury can be modeled using membrane-permeant dipeptide precursors that polymerize in lysosomes), amyloid protein aggregates (see above section on Alzheimer's disease) and cytoplasmic organic or inorganic inclusions including urate crystals and crystalline silica.[116] The process of mTOR inactivation following lysosomal/endomembrane is mediated by the protein complex termed GALTOR.[116] At the heart of GALTOR[116] is galectin-8, a member of β-galactoside binding superfamily of cytosolic lectins termed galectins, which recognizes lysosomal membrane damage by binding to the exposed glycans on the lumenal side of the delimiting endomembrane. Following membrane damage, galectin-8, which normally associates with mTOR under homeostatic conditions, no longer interacts with mTOR but now instead binds to SLC38A9, RRAGA/RRAGB, and LAMTOR1, inhibiting Ragulator's (LAMTOR1-5 complex) guanine nucleotide exchange function-[116] TOR is a negative regulator of autophagy in general, best studied during response to starvation,[117][118][119][120][121] which is a metabolic response. During lysosomal damage however, mTOR inhibition activates autophagy response in its quality control function, leading to the process termed lysophagy[122] that removes damaged lysosomes. At this stage another galectin, galectin-3, interacts with TRIM16 to guide selective autophagy of damaged lysosomes.[123][124] TRIM16 gathers ULK1 and principal components (Beclin 1 and ATG16L1) of other complexes (Beclin 1-VPS34-ATG14 and ATG16L1-ATG5-ATG12) initiating autophagy,[124] many of them being under negative control of mTOR directly such as the ULK1-ATG13 complex,[119][120][121] or indirectly, such as components of the class III PI3K (Beclin 1, ATG14 and VPS34) since they depend on activating phosphorylations by ULK1 when it is not inhibited by mTOR. These autophagy-driving components physically and functionally link up with each other integrating all processes necessary for autophagosomal formation: (i) the ULK1-ATG13-FIP200/RB1CC1 complex associates with the LC3B/GABARAP conjugation machinery through direct interactions between FIP200/RB1CC1 and ATG16L1,[125][126][127] (ii) ULK1-ATG13-FIP200/RB1CC1 complex associates with the Beclin 1-VPS34-ATG14 via direct interactions between ATG13's HORMA domain and ATG14,[128] (iii) ATG16L1 interacts with WIPI2, which binds to PI3P, the enzymatic product of the class III PI3K Beclin 1-VPS34-ATG14.[129] Thus, mTOR inactivation, initiated through GALTOR[116] upon lysosomal damage, plus a simultaneous activation via galectin-9 (which also recognizes lysosomal membrane breach) of AMPK [116] that directly phosphorylates and activates key components (ULK1,[130] Beclin 1[131]) of the autophagy systems listed above and further inactivates mTORC1,[132][133] allows for strong autophagy induction and autophagic removal of damaged lysosomes. Additionally, several types of ubiquitination events parallel and complement the galectin-driven processes: Ubiquitination of TRIM16-ULK1-Beclin-1 stabilizes these complexes to promote autophagy activation as described above.[124] ATG16L1 has an intrinsic binding affinity for ubiquitin[127]); whereas ubiqutination by a glycioprotein-specific FBXO27-endowed ubiquitin ligase of several damage-exposed glycosylated lysosomal membrane proteins such as LAMP1, LAMP2, GNS/N-acetylglucosamine-6-sulfatase, TSPAN6/tetraspanin-6, PSAP/prosaposin, and TMEM192/transmembrane protein 192 [134] may contribute to the execution of lysophagy via autophagic receptors such as p62/SQSTM1, which is recruited during lysophagy,[127] or other to be determined functions. ## Scleroderma Scleroderma, also known as systemic sclerosis, is a chronic systemic autoimmune disease characterised by hardening (sclero) of the skin (derma) that affects internal organs in its more severe forms.[135][136] mTOR plays a role in fibrotic diseases and autoimmunity, and blockade of the mTORC pathway is under investigation as a treatment for scleroderma.[4] # mTOR inhibitors as therapies ## Transplantation mTOR inhibitors, e.g. rapamycin, are already used to prevent transplant rejection. Rapamycin is also related to the therapy of glycogen storage disease (GSD). ## Glycogen storage disease Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS (glycogen synthase) can be increased in skeletal muscle. This discovery represents a potential novel therapeutic approach for glycogen storage diseases that involve glycogen accumulation in muscle. Various natural compounds, including epigallocatechin gallate (EGCG), caffeine, curcumin, and resveratrol, have also been reported to inhibit mTOR when applied to isolated cells in culture.[24][137] As yet no evidence exists that these substances inhibit mTOR signaling when taken as dietary supplements. However, a natural substance Berberine is available as a dietary supplement. In live cells it localizes in mitochondria, inhibits complex I of respiratory chain thereby decreasing ATP (increasing AMP/ATP ratio) which leads to activation of AMPK and suppression of mTOR signaling, consistent with its potential anti-aging properties.[138] ## Anti-cancer There are two primary mTOR inhibitors used in the treatment of human cancers, temsirolimus and everolimus. mTOR inhibitors have found use in the treatment of a variety of malignancies, including renal cell carcinoma (temsirolimus) and pancreatic cancer, breast cancer, and renal cell carcinoma (everolimus).[139] The complete mechanism of these agents is not clear, but they are thought to function by imparing tumour angiogenesis and causing impariment of the G1/S transition.[140] ## Anti-aging mTOR inhibitors may be useful for treating/preventing several age-associated conditions,[141] including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.[142] After a short-term treatment with mTor inhibitors, in elderly (65 and older), treated subjects had a reduced number of infections, over the course of a year.[143] # Interactions Mechanistic target of rapamycin has been shown to interact with:[144] - ABL1,[145] - AKT1,[39][146][147] - IGF-IR,[7] - InsR,[7] - CLIP1,[148] - EIF3F[149] - EIF4EBP1,[32][150][151][152][153][154][155][156] - FKBP1A,[8][37][157][158][159][160] - GPHN,[161] - KIAA1303,[8][32][36][37][69][150][151][152][162][163][164][165][166][167][168][169][170][171][172][173] - PRKCD,[174] - RHEB,[153][175][176][177] - RICTOR,[8][36][37][164][170][172][173] - RPS6KB1,[32][151][153][154][155][169][172][178][179][180][181][182][183][183][184][185] - STAT1,[186] - STAT3,[187][188] - Two-pore channels: TPCN1; TPCN2,[189] and - UBQLN1.[190]

https://www.wikidoc.org/index.php/MTOR

5193008feb20cb2b46b705cc67c973d4f5a37221

wikidoc

MUC1

MUC1 Mucin 1, cell surface associated (MUC1) or polymorphic epithelial mucin (PEM) is a mucin encoded by the MUC1 gene in humans. MUC1 is a glycoprotein with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and several other organs. Mucins protect the body from infection by pathogen binding to oligosaccharides in the extracellular domain, preventing the pathogen from reaching the cell surface. Overexpression of MUC1 is often associated with colon, breast, ovarian, lung and pancreatic cancers. Joyce Taylor-Papadimitriou identified and characterised the antigen during her work with breast and ovarian tumors. # Structure MUC1 is a member of the mucin family and encodes a membrane bound, glycosylated phosphoprotein. MUC1 has a core protein mass of 120-225 kDa which increases to 250-500 kDa with glycosylation. It extends 200-500 nm beyond the surface of the cell. The protein is anchored to the apical surface of many epithelia by a transmembrane domain. Beyond the transmembrane domain is a SEA domain that contains a cleavage site for release of the large extracellular domain. The release of mucins is performed by sheddases. The extracellular domain includes a 20 amino acid variable number tandem repeat (VNTR) domain, with the number of repeats varying from 20 to 120 in different individuals. These repeats are rich in serine, threonine and proline residues which permits heavy o-glycosylation. Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length nature of only some has been determined. MUC1 is cleaved in the endoplasmic reticulum into two pieces, the cytoplasmic tail including the transmembrane domain and the extracellular domain. These domains tightly associate in a non-covalent fashion. This tight, non-covalent association is not broken by treatment with urea, low pH, high salt or boiling. Treatment with sodium dodecyl sulfate triggers dissociation of the subunits. The cytoplasmic tail of MUC1 is 72 amino acids long and contains several phosphorylation sites. # Function The protein serves a protective function by binding to pathogens and also functions in a cell signaling capacity. Overexpression, aberrant intracellular localization, and changes in glycosylation of this protein have been associated with carcinomas. e.g. The CanAg tumour antigen is a novel glycoform of MUC1. In the cell nucleus, the protein MUC1 regulates the activity of transcription factor complexes that have a documented role in tumor-induced changes of host immunity. ## Diagnostic utility In histopathology, the product of the MUC-1 gene is commonly referred to as epithelial membrane antigen or EMA. Using immunohistochemistry, it can be identified in a wide range of secretory epithelia and their neoplastic equivalents. It can also be used for the identification of mesenchymal tumours, such as synovial sarcoma and ovarian granulosa cell tumours. Although other antibodies, such as cytokeratins, are more commonly used for the identification of metastatic carcinoma deposits, EMA can be used to distinguish mesothelioma, in which it is restricted to the cell membranes and associated micovilli, from adenocarcinoma, in which it is diffusely spread through the cytoplasm. # Interactions MUC1 has been shown to interact with: - CTNND1, - ERBB2, - GRB2, - JUP, and - SOS1. # Role in cancer The ability of chemotherapeutic drugs to access the cancer cells is inhibited by the heavy glycosylation in the extracellular domain of MUC1. The glycosylation creates a highly hydrophilic region which prevents hydrophobic chemotherapeutic drugs from passing through. This prevents the drugs from reaching their targets which usually reside within the cell. Similarly, the glycosylation has been shown to bind to growth factors. This allows cancer cells which produce a large amount of MUC1 to concentrate growth factors near their receptors, increasing receptor activity and the growth of cancer cells. MUC1 also prevents the interaction of immune cells with receptors on the cancer cell surface through steric hindrance. This inhibits an anti-tumor immune response. ## Preventing cell death MUC1 cytoplasmic tail has been shown to bind to p53. This interaction is increased by genotoxic stress. MUC1 and p53 were found to be associated with the p53 response element of the p21 gene promoter. This results in activation of p21 which results in cell cycle arrest. Association of MUC1 with p53 in cancer results in inhibition of p53-mediated apoptosis and promotion of p53-mediated cell cycle arrest. Overexpression of MUC1 in fibroblasts increased the phosphorylation of Akt. Phosphorylation of Akt results in phosphorylation of Bcl-2-associated death promoter. This results in dissociation of Bcl-2-associated death promoter with Bcl-2 and Bcl-xL. Activation was shown to be dependent on the upstream activation of PI3K. Additionally, MUC1 was shown to increase expression of Bcl-xL. Overexpression of MUC1 in cancer. The presence of free Bcl-2 and Bcl-xL prevents the release of cytochrome c from mitochondria, thereby preventing apoptosis. MUC1 cytoplasmic tail is shuttled to the mitochondria through interaction with hsp90. This interaction is induced through phosphorylation of the MUC1 cytoplasmic tail by Src (gene). Src is activated by the EGF receptor family ligand Neuregulin. The cytoplasmic tail is then inserted into the mitochondrial outer membrane. Localization of MUC1 to the mitochondria prevents the activation of apoptotic mechanisms. ## Promoting tumor invasion MUC1 cytoplasmic tail was shown to interact with Beta-catenin. A SXXXXXSSL motif was identified in MUC1 that is conserved with other beta-catenin binding partners. This interaction was shown to be dependent on cell adhesion. Studies have demonstrated that MUC1 is phosphorylated on a YEKV motif. Phosphorylation of this site has been demonstrated by LYN through mediation of interleukin 7, Src through mediation of EGFR, and PRKCD. This interaction is antagonized by degradation of beta-catenin by GSK3B. MUC1 blocks the phosphorylation-dependent degradation of beta-catenin by GSK3B. The end result is that increased expression of MUC1 in cancer increases stabilized beta-catenin. This promotes the expression of vimentin and CDH2. These proteins are associated with a mesenchymal phenotype, characterized by increased motility and invasiveness. In cancer cells, increased expression of MUC1 promotes cancer cell invasion through beta-catenin, resulting in the initiation of epithelial-mesenchymal transition which promotes the formation of metastases. # Cancer Antigens (CA) 27.29 and 15-3 CA 27.29 (aka BR 27.29) and CA 15-3 measure different epitopes of the same protein antigen product of the MUC1 gene seen in breast cancer. CA 27.29 has enhanced sensitivity and specificity compared to CA 15-3 and is elevated in 30% of patients with low-stage disease and 60 to 70% of patients with advanced-stage breast cancer. CA 27.29 levels over 100 U/mL and CA 15-3 levels over 25 U/mL are rare in benign conditions and suggest malignancy. # Diagnostic use in clinical pathology - Epithelial marker - breast micropapillary carcinoma - bladder micropapillary carcinoma - Distinguish systemic anaplastic large-cell lymphoma (MUC1+) from cutaneous anaplastic large-cell lymphoma (usually MUC1-) ## Positive tumoral cells - Adenocarcinomas (breast, colorectal, pancreatic, other) - Carcinoid tumor - Chordoma - Choriocarcinoma - Desmoplastic small round cell tumor (DSRCT) - Epithelioid sarcoma - Follicular dendritic cell sarcoma, interdigitating dendritic cell / reticulum cell sarcoma - Lung: type II pneumocyte lesions (type II cell hyperplasia, dysplastic type II cells, apical alveolar hyperplasia) - Anaplastic large-cell lymphoma, diffuse large B cell lymphoma (variable), plasmablastic lymphoma, primary effusion lymphoma - Epithelioid mesotheliomas () - Myeloma, Plasmacytomas - Perineurioma - Renal cell carcinoma - Synovial sarcoma (epithelial areas) - Thymic carcinoma (often) - Meningioma - Paget’s disease ## Negative tumoral cells - Adrenal cell carcinoma - Hepatocellular carcinoma - Germ cell tumors (except choriocarcinoma) - Acquired cystic disease-associated renal cell carcinoma - Leiomyosarcomas (usually) - Liposarcomas - Melanoma - Neuroblastoma - Paraganglioma - Solitary fibrous tumor (SFT) - Myoepithelial cells # As a therapeutic drug target Using MUC1, vaccines are being tested against a type of blood cancer called multiple myeloma. The technology could in theory be applied to 90 percent of all known cancers, including prostate and breast cancer, solid and non-solid tumors. This method would activate the immune system by training T-cells to search out and destroy cells that display a specific molecule (or marker) of MUC1. MUC1 is found on nearly all epithelial cells, but it is over expressed in cancer cells, and its associated glycans are shorter than those of non-tumor-associated MUC1. Because MUC1 is overexpressed (and differently glycosylated) in many cancers it has been investigated as a drug target, eg for the MUC1 vaccine ONT-10, which has had a phase 1 clinical study.

MUC1 Mucin 1, cell surface associated (MUC1) or polymorphic epithelial mucin (PEM) is a mucin encoded by the MUC1 gene in humans.[1] MUC1 is a glycoprotein with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and several other organs.[2] Mucins protect the body from infection by pathogen binding to oligosaccharides in the extracellular domain, preventing the pathogen from reaching the cell surface.[3] Overexpression of MUC1 is often associated with colon, breast, ovarian, lung and pancreatic cancers.[4] Joyce Taylor-Papadimitriou identified and characterised the antigen during her work with breast and ovarian tumors. # Structure MUC1 is a member of the mucin family and encodes a membrane bound, glycosylated phosphoprotein. MUC1 has a core protein mass of 120-225 kDa which increases to 250-500 kDa with glycosylation. It extends 200-500 nm beyond the surface of the cell.[5] The protein is anchored to the apical surface of many epithelia by a transmembrane domain. Beyond the transmembrane domain is a SEA domain that contains a cleavage site for release of the large extracellular domain. The release of mucins is performed by sheddases.[6] The extracellular domain includes a 20 amino acid variable number tandem repeat (VNTR) domain, with the number of repeats varying from 20 to 120 in different individuals. These repeats are rich in serine, threonine and proline residues which permits heavy o-glycosylation.[5] Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length nature of only some has been determined.[7] MUC1 is cleaved in the endoplasmic reticulum into two pieces, the cytoplasmic tail including the transmembrane domain and the extracellular domain. These domains tightly associate in a non-covalent fashion.[8] This tight, non-covalent association is not broken by treatment with urea, low pH, high salt or boiling. Treatment with sodium dodecyl sulfate triggers dissociation of the subunits.[9] The cytoplasmic tail of MUC1 is 72 amino acids long and contains several phosphorylation sites.[10] # Function The protein serves a protective function by binding to pathogens[11] and also functions in a cell signaling capacity.[10] Overexpression, aberrant intracellular localization, and changes in glycosylation of this protein have been associated with carcinomas. e.g. The CanAg tumour antigen is a novel glycoform of MUC1.[12] In the cell nucleus, the protein MUC1 regulates the activity of transcription factor complexes that have a documented role in tumor-induced changes of host immunity.[13] ## Diagnostic utility In histopathology, the product of the MUC-1 gene is commonly referred to as epithelial membrane antigen or EMA. Using immunohistochemistry, it can be identified in a wide range of secretory epithelia and their neoplastic equivalents. It can also be used for the identification of mesenchymal tumours, such as synovial sarcoma and ovarian granulosa cell tumours. Although other antibodies, such as cytokeratins, are more commonly used for the identification of metastatic carcinoma deposits, EMA can be used to distinguish mesothelioma, in which it is restricted to the cell membranes and associated micovilli, from adenocarcinoma, in which it is diffusely spread through the cytoplasm.[14] # Interactions MUC1 has been shown to interact with: - CTNND1,[15] - ERBB2,[16][17] - GRB2,[18] - JUP,[16] and - SOS1.[17][18] # Role in cancer The ability of chemotherapeutic drugs to access the cancer cells is inhibited by the heavy glycosylation in the extracellular domain of MUC1. The glycosylation creates a highly hydrophilic region which prevents hydrophobic chemotherapeutic drugs from passing through. This prevents the drugs from reaching their targets which usually reside within the cell. Similarly, the glycosylation has been shown to bind to growth factors. This allows cancer cells which produce a large amount of MUC1 to concentrate growth factors near their receptors, increasing receptor activity and the growth of cancer cells. MUC1 also prevents the interaction of immune cells with receptors on the cancer cell surface through steric hindrance. This inhibits an anti-tumor immune response.[2] ## Preventing cell death MUC1 cytoplasmic tail has been shown to bind to p53. This interaction is increased by genotoxic stress. MUC1 and p53 were found to be associated with the p53 response element of the p21 gene promoter. This results in activation of p21 which results in cell cycle arrest. Association of MUC1 with p53 in cancer results in inhibition of p53-mediated apoptosis and promotion of p53-mediated cell cycle arrest.[19] Overexpression of MUC1 in fibroblasts increased the phosphorylation of Akt. Phosphorylation of Akt results in phosphorylation of Bcl-2-associated death promoter. This results in dissociation of Bcl-2-associated death promoter with Bcl-2 and Bcl-xL. Activation was shown to be dependent on the upstream activation of PI3K. Additionally, MUC1 was shown to increase expression of Bcl-xL. Overexpression of MUC1 in cancer. The presence of free Bcl-2 and Bcl-xL prevents the release of cytochrome c from mitochondria, thereby preventing apoptosis.[20] MUC1 cytoplasmic tail is shuttled to the mitochondria through interaction with hsp90. This interaction is induced through phosphorylation of the MUC1 cytoplasmic tail by Src (gene). Src is activated by the EGF receptor family ligand Neuregulin. The cytoplasmic tail is then inserted into the mitochondrial outer membrane. Localization of MUC1 to the mitochondria prevents the activation of apoptotic mechanisms.[21] ## Promoting tumor invasion MUC1 cytoplasmic tail was shown to interact with Beta-catenin. A SXXXXXSSL motif was identified in MUC1 that is conserved with other beta-catenin binding partners. This interaction was shown to be dependent on cell adhesion.[22] Studies have demonstrated that MUC1 is phosphorylated on a YEKV motif. Phosphorylation of this site has been demonstrated by LYN through mediation of interleukin 7,[23] Src through mediation of EGFR,[24][25] and PRKCD.[26] This interaction is antagonized by degradation of beta-catenin by GSK3B. MUC1 blocks the phosphorylation-dependent degradation of beta-catenin by GSK3B.[27][28] The end result is that increased expression of MUC1 in cancer increases stabilized beta-catenin. This promotes the expression of vimentin and CDH2. These proteins are associated with a mesenchymal phenotype, characterized by increased motility and invasiveness. In cancer cells, increased expression of MUC1 promotes cancer cell invasion through beta-catenin, resulting in the initiation of epithelial-mesenchymal transition which promotes the formation of metastases.[29][30] # Cancer Antigens (CA) 27.29 and 15-3 CA 27.29 (aka BR 27.29) and CA 15-3 measure different epitopes of the same protein antigen product of the MUC1 gene seen in breast cancer. CA 27.29 has enhanced sensitivity and specificity compared to CA 15-3 and is elevated in 30% of patients with low-stage disease and 60 to 70% of patients with advanced-stage breast cancer. CA 27.29 levels over 100 U/mL and CA 15-3 levels over 25 U/mL are rare in benign conditions and suggest malignancy. # Diagnostic use in clinical pathology - Epithelial marker - breast micropapillary carcinoma - bladder micropapillary carcinoma - Distinguish systemic anaplastic large-cell lymphoma (MUC1+) from cutaneous anaplastic large-cell lymphoma (usually MUC1-) ## Positive tumoral cells - Adenocarcinomas (breast, colorectal, pancreatic, other) - Carcinoid tumor - Chordoma - Choriocarcinoma - Desmoplastic small round cell tumor (DSRCT) - Epithelioid sarcoma - Follicular dendritic cell sarcoma, interdigitating dendritic cell / reticulum cell sarcoma - Lung: type II pneumocyte lesions (type II cell hyperplasia, dysplastic type II cells, apical alveolar hyperplasia) - Anaplastic large-cell lymphoma, diffuse large B cell lymphoma (variable), plasmablastic lymphoma, primary effusion lymphoma - Epithelioid mesotheliomas () - Myeloma, Plasmacytomas - Perineurioma - Renal cell carcinoma - Synovial sarcoma (epithelial areas) - Thymic carcinoma (often) - Meningioma - Paget’s disease ## Negative tumoral cells - Adrenal cell carcinoma - Hepatocellular carcinoma - Germ cell tumors (except choriocarcinoma) - Acquired cystic disease-associated renal cell carcinoma - Leiomyosarcomas (usually) - Liposarcomas - Melanoma - Neuroblastoma - Paraganglioma - Solitary fibrous tumor (SFT) - Myoepithelial cells # As a therapeutic drug target Using MUC1, vaccines are being tested against a type of blood cancer called multiple myeloma. The technology could in theory be applied to 90 percent of all known cancers, including prostate and breast cancer, solid and non-solid tumors. This method would activate the immune system by training T-cells to search out and destroy cells that display a specific molecule (or marker) of MUC1. MUC1 is found on nearly all epithelial cells, but it is over expressed in cancer cells, and its associated glycans are shorter than those of non-tumor-associated MUC1.[31] Because MUC1 is overexpressed (and differently glycosylated) in many cancers it has been investigated as a drug target, eg for the MUC1 vaccine ONT-10, which has had a phase 1 clinical study.[32]

https://www.wikidoc.org/index.php/MUC1

113bb7bade2f5af0cb51379f0dc4bafcab1dbd1e

wikidoc

MUL1

MUL1 Mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is an enzyme that in humans is encoded by the MUL1 gene on chromosome 1. This enzyme localizes to the outer mitochondrial membrane, where it regulates mitochondrial morphology and apoptosis through multiple pathways, including the Akt, JNK, and NF-κB. Its proapopototic function thus implicates it in cancer and Parkinson’s disease. # Structure ## Gene The gene MUL1 encodes one of the E3 ubiquitin ligases. The human gene MUL1 has 5 exons and is located at chromosome band 1p36.12. ## Protein The human protein Mitochondrial E3 ubiquitin protein ligase 1 is ~40 kDa in size and composed of 352 amino acids. The calculated theoretical pI of this protein is 7.28. MUL1 contains Ring domains at both its N-terminal and C-terminal, which are both exposed to the cytosol. The C-terminal Ring finger domain is homologous to that found in the IAP family members and responsible for its E3 ligase activity. In addition to these Ring domains, MUL1 is predicted to have two mitochondrial transmembrane helices, with the first domain serving as the primary anchor for the rest of the exposed protein. Though it lacks a conserved N-terminal signal peptide or mitochondrial targeting sequence, its transmembrane domains have been observed to influence its trafficking and insertion into the mitochondrial membrane. # Function Exhibits weak E3 ubiquitin-protein ligase activity. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. Can ubiquitinate AKT1 preferentially at 'Lys-284' involving 'Lys-48'-linked polyubiquitination and seems to be involved in regulation of Akt signaling by targeting phosphorylated Akt to proteosomal degradation. Proposed to preferentially act as a SUMO E3 ligase at physiological concentrations. Is anchored in the outer mitochondrial membrane. Plays a role in the control of mitochondrial morphology. Promotes mitochondrial fragmentation and influences mitochondrial localization. The function may implicate its ability to sumoylate DNM1L. Has been observed to shuttle between the mitochondria and peroxisome, where it may also help regulate peroxisome fission. Inhibits cell growth. When overexpressed, activates JNK through MAP3K7/TAK1 and induces caspase-dependent apoptosis. Involved in the modulation of innate immune defense against viruses by inhibiting DDX58-dependent antiviral response. Can mediate DDX58 sumoylation and disrupt its polyubiquitination. Can also activate NF-κB to initiate mitochondria-to-nucleus signaling under stress. # Clinical significance As aforementioned, MUL1 encodes for an enzyme which is located on outer mitochondrial membrane, where it regulates mitochondrial morphology and apoptosis. Specifically, this enzyme has pro-apoptotic functions. An apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells. Though MUL1 is highly expressed in most human tissues during normal conditions, it is found to be missing in cancer cells derived from lung, liver, colon, and kidney. This observation suggests that the antiapoptotic MUL1 serves as a tumor suppressor and is thus downregulated in cancer cells. Experiments in drosophila and mammalian systems reveal that MUL1 binds and ubiquitinylates mitofusin, which then allows it to indirectly regulate the PINK1/parkin pathway. Thus, this protein can rescue the phenotypes of PINK1 or parkin knockout mice display, which elucidates why only subtle dopaminergic neuronal degeneration or mitochondrial morphology changes have been observed. MUL1 is then a promising therapeutic target for treating Parkinson’s disease. Mul1 has also been implicated as a modulator of antiviral signaling. MUL1 is localized to the mitochondria where it interacts with mitochondrial antiviral signaling and catalyzes RIG-I post-translational modifications that inhibit RIG-I-dependent cell signaling. Accordingly, depletion of MUL1 potentiates RIG-I mediated nuclear factor-kappa B (NF-κB) and interferon (IFN) β reporter activity. Moreover, depletion of MUL1 boosts the antiviral response and increased pro inflammatory cytokines following challenge with the RNA mimetic poly I:C and Sendai virus. It is therefore submitted that MUL1 is a novel regulator of the RIG-I-like receptor-dependent antiviral response, that otherwise functions to limit inflammation. In addition, as a regulator of viral-induced interferon production and proinflammatory cytokine induction, MUL1 functions through mitochondrial antiviral signaling proteins to inhibit RIG-1-induced signaling and mediate the cell’s antiviral and inflammatory response. # Interactions MUL1 is known to interact with: - MUL1, - DNM1L, - TAK1, and - Mitofusin.

MUL1 Mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is an enzyme that in humans is encoded by the MUL1 gene on chromosome 1. This enzyme localizes to the outer mitochondrial membrane, where it regulates mitochondrial morphology and apoptosis through multiple pathways, including the Akt, JNK, and NF-κB.[1][2][3] Its proapopototic function thus implicates it in cancer and Parkinson’s disease.[3][4] # Structure ## Gene The gene MUL1 encodes one of the E3 ubiquitin ligases. The human gene MUL1 has 5 exons and is located at chromosome band 1p36.12.[5] ## Protein The human protein Mitochondrial E3 ubiquitin protein ligase 1 is ~40 kDa in size and composed of 352 amino acids.[3][6][7] The calculated theoretical pI of this protein is 7.28.[8] MUL1 contains Ring domains at both its N-terminal and C-terminal, which are both exposed to the cytosol.[2] The C-terminal Ring finger domain is homologous to that found in the IAP family members and responsible for its E3 ligase activity.[3] In addition to these Ring domains, MUL1 is predicted to have two mitochondrial transmembrane helices, with the first domain serving as the primary anchor for the rest of the exposed protein.[2][9] Though it lacks a conserved N-terminal signal peptide or mitochondrial targeting sequence, its transmembrane domains have been observed to influence its trafficking and insertion into the mitochondrial membrane.[6][9] # Function Exhibits weak E3 ubiquitin-protein ligase activity. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. Can ubiquitinate AKT1 preferentially at 'Lys-284' involving 'Lys-48'-linked polyubiquitination and seems to be involved in regulation of Akt signaling by targeting phosphorylated Akt to proteosomal degradation.[10] Proposed to preferentially act as a SUMO E3 ligase at physiological concentrations.[1] Is anchored in the outer mitochondrial membrane.[2] Plays a role in the control of mitochondrial morphology. Promotes mitochondrial fragmentation and influences mitochondrial localization.[1][2] The function may implicate its ability to sumoylate DNM1L.[1] Has been observed to shuttle between the mitochondria and peroxisome, where it may also help regulate peroxisome fission.[2] Inhibits cell growth.[3] When overexpressed, activates JNK through MAP3K7/TAK1 and induces caspase-dependent apoptosis.[3] Involved in the modulation of innate immune defense against viruses by inhibiting DDX58-dependent antiviral response. Can mediate DDX58 sumoylation and disrupt its polyubiquitination.[7][9] Can also activate NF-κB to initiate mitochondria-to-nucleus signaling under stress.[3] # Clinical significance As aforementioned, MUL1 encodes for an enzyme which is located on outer mitochondrial membrane, where it regulates mitochondrial morphology and apoptosis.[1][2][3] Specifically, this enzyme has pro-apoptotic functions. An apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[11] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells. Though MUL1 is highly expressed in most human tissues during normal conditions, it is found to be missing in cancer cells derived from lung, liver, colon, and kidney. This observation suggests that the antiapoptotic MUL1 serves as a tumor suppressor and is thus downregulated in cancer cells.[3] Experiments in drosophila and mammalian systems reveal that MUL1 binds and ubiquitinylates mitofusin, which then allows it to indirectly regulate the PINK1/parkin pathway. Thus, this protein can rescue the phenotypes of PINK1 or parkin knockout mice display, which elucidates why only subtle dopaminergic neuronal degeneration or mitochondrial morphology changes have been observed. MUL1 is then a promising therapeutic target for treating Parkinson’s disease.[4] Mul1 has also been implicated as a modulator of antiviral signaling.[9] MUL1 is localized to the mitochondria where it interacts with mitochondrial antiviral signaling and catalyzes RIG-I post-translational modifications that inhibit RIG-I-dependent cell signaling. Accordingly, depletion of MUL1 potentiates RIG-I mediated nuclear factor-kappa B (NF-κB) and interferon (IFN) β reporter activity. Moreover, depletion of MUL1 boosts the antiviral response and increased pro inflammatory cytokines following challenge with the RNA mimetic poly I:C and Sendai virus. It is therefore submitted that MUL1 is a novel regulator of the RIG-I-like receptor-dependent antiviral response, that otherwise functions to limit inflammation.[9] In addition, as a regulator of viral-induced interferon production and proinflammatory cytokine induction, MUL1 functions through mitochondrial antiviral signaling proteins to inhibit RIG-1-induced signaling and mediate the cell’s antiviral and inflammatory response.[9] # Interactions MUL1 is known to interact with: - MUL1,[3] - DNM1L,[1] - TAK1,[3] and - Mitofusin.[4]

https://www.wikidoc.org/index.php/MUL1

f925f798ccd8e38c16d83917dda54ce1ff972fb2

wikidoc

MXD1

MXD1 MAD protein is a protein that in humans is encoded by the MXD1 gene. MAD-MAX dimerization protein belongs to a subfamily of MAX-interacting proteins. This protein competes with MYC for binding to MAX to form a sequence-specific DNA-binding complex, acts as a transcriptional repressor (while MYC appears to function as an activator) and is a candidate tumor suppressor. The MAD-MAX protein dimer may be a reference to the popular cult classic film Mad Max (1979). # Interactions MXD1 has been shown to interact with Histone deacetylase 2, SMC3, MLX, SIN3A and MAX.

MXD1 MAD protein is a protein that in humans is encoded by the MXD1 gene.[1][2] MAD-MAX dimerization protein belongs to a subfamily of MAX-interacting proteins. This protein competes with MYC for binding to MAX to form a sequence-specific DNA-binding complex, acts as a transcriptional repressor (while MYC appears to function as an activator) and is a candidate tumor suppressor.[2] The MAD-MAX protein dimer may be a reference to the popular cult classic film Mad Max (1979). # Interactions MXD1 has been shown to interact with Histone deacetylase 2,[3][4] SMC3,[5] MLX,[6][7] SIN3A[8][9][10] and MAX.[5][11][12][13]

https://www.wikidoc.org/index.php/MXD1

18f2d4bd220db04f8a4fa5a19bc419af0bc2c57c

wikidoc

MYF5

MYF5 Myogenic factor 5 is a protein that in humans is encoded by the MYF5 gene. It is a protein with a key role in regulating muscle differentiation or myogenesis, specifically the development of skeletal muscle. Myf5 belongs to a family of proteins known as myogenic regulatory factors (MRFs). These basic helix loop helix transcription factors act sequentially in myogenic differentiation. MRF family members include Myf5, MyoD (Myf3), myogenin, and MRF4 (Myf6). This transcription factor is the earliest of all MRFs to be expressed in the embryo, where it is only markedly expressed for a few days (specifically around 8 days post-somite formation and lasting until day 14 post-somite in mice). It functions during that time to commit myogenic precursor cells to become skeletal muscle. In fact, its expression in proliferating myoblasts has led to its classification as a determination factor. Furthermore, Myf5 is a master regulator of muscle development, possessing the ability to induce a muscle phenotype upon its forced expression in fibroblastic cells. # Expression Myf5 is expressed in the dermomyotome of the early somites, pushing the myogenic precursors to undergo determination and differentiate into myoblasts. Specifically, it is first seen in the dorsomedial portion of the dermomyotome, which develops into the epaxial myotome. Although it is expressed in both the epaxial (to become muscles of the back) and hypaxial (body wall and limb muscles) portions of the myotome, it is regulated differently in these tissue lines, providing part of their alternative differentiation. Most notably, while Myf5 is activated by Sonic hedgehog in the epaxial lineage, it is instead directly activated by the transcription factor Pax3 in hypaxial cells. The limb myogenic precursors (derived from the hypaxial myotome) do not begin expressing Myf5 or any MRFs, in fact, until after migration to the limb buds. Alternatively, during its brief window of expression in the embryo it is also expressed in nonsomitic paraxial mesoderm that goes on to form the muscles of the head, according to studies done on zebrafish. While the product of this gene is capable of directing cells towards the skeletal muscle lineage, it is not absolutely required for this process. Numerous studies have shown redundancy with two other MRFs, MyoD and MRF4. The absence of all three of these factors results in a phenotype with no skeletal muscle. These studies were performed after it was shown that Myf5 knockouts had no clear abnormality in their skeletal muscle. The high redundancy of this system shows how crucial the development of skeletal muscle is to the viability of the fetus. Some evidence shows that Myf5 and MyoD are responsible for the development of separate muscle lineages, and are not expressed concurrently in the same cell. Specifically, while Myf5 plays a large role in the initiation of epaxial development, MyoD directs the initiation of hypaxial development, and these separate lineages can compensate for the absence of one or the other. This has led some to claim that they are not indeed redundant, though this depends on the definition of the word. Still, the existence of these separate “MyoD-dependent” and “Myf5-dependent” subpopulations has been disputed, with some claiming that these MRFs are indeed coexpressed in muscle progenitor cells. This debate is ongoing. Although Myf5 is mainly associated with myogenesis, it is expressed in other tissues, as well. Firstly, it is expressed in brown adipose precursors. However, its expression is limited to brown and not white adipose precursors, providing part of the developmental separation between these two lineages. Furthermore, Myf5 is expressed in portions of the neural tube (that go on to form neurons) a few days after it is seen in the somites. This expression is eventually repressed to prevent extraneous muscle formation. Although the specific roles and dependency of Myf5 in adipogenesis and neurogenesis have remained to be explored, these findings show that Myf5 plays roles outside of myogenesis. Myf5 also has an indirect role controlling proximal rib development. Although Myf5 knockouts have normal skeletal muscle, they die due to abnormalities in their proximal ribs that make it difficult to breathe. Despite only being present for a few days during embryonic development, Myf5 is still expressed in certain adult cells. As one of the key cell markers of satellite cells (the stem cell pool for skeletal muscles), it plays an important role in the regeneration of adult muscle. Specifically, it allows a brief pulse of proliferation of these satellite cells in response to injury. Differentiation begins (regulated by other genes) after this initial proliferation. In fact, if Myf5 is not downregulated, differentiation does not occur. # Regulation The regulation of Myf5 is dictated by a large number of enhancer elements that allow a complex system of regulation. Although most events throughout myogenesis that involve Myf5 are controlled through the interaction of multiple enhancers, there is one important early enhancer that initiates expression. Termed the early epaxial enhancer, its activation provides the "go" signal for expression of Myf5 in the epaxial dermomyotome, where it is first seen. Sonic hedgehog from the neural tube acts at this enhancer to activate it. Following that, the chromosome contains different enhancers for regulation of Myf5 expression in the hypaxial region, cranial region, limbs, etc. This early expression of Myf5 in the epaxial dermamyotome is involved with the very formation of myotome, but nothing beyond that. After its initial expression, other enhancer elements dictate where and how long it is expressed. It remains clear that each population of myogenic progenitor cells (for different locations in the embryo) is regulated by a different set of enhancers. # Clinical significance As for its clinical significance, the aberration of this transcription factor provides part of the mechanism for how hypoxia (lack of oxygen) can influence muscle development. Hypoxia has the ability to impede muscle differentiation in part by inhibiting the expression of Myf5 (as well as other MRFs). This prevents the muscle precursors from becoming post-mitotic muscle fibers. Although hypoxia is a teratogen, this inhibition of expression is reversible, therefore it remains unclear if there is a connection between hypoxia and birth defects in the fetus.

MYF5 Myogenic factor 5 is a protein that in humans is encoded by the MYF5 gene. [1] It is a protein with a key role in regulating muscle differentiation or myogenesis, specifically the development of skeletal muscle. Myf5 belongs to a family of proteins known as myogenic regulatory factors (MRFs). These basic helix loop helix transcription factors act sequentially in myogenic differentiation. MRF family members include Myf5, MyoD (Myf3), myogenin, and MRF4 (Myf6).[2] This transcription factor is the earliest of all MRFs to be expressed in the embryo, where it is only markedly expressed for a few days (specifically around 8 days post-somite formation and lasting until day 14 post-somite in mice).[3] It functions during that time to commit myogenic precursor cells to become skeletal muscle. In fact, its expression in proliferating myoblasts has led to its classification as a determination factor. Furthermore, Myf5 is a master regulator of muscle development, possessing the ability to induce a muscle phenotype upon its forced expression in fibroblastic cells.[4] # Expression Myf5 is expressed in the dermomyotome of the early somites, pushing the myogenic precursors to undergo determination and differentiate into myoblasts.[3] Specifically, it is first seen in the dorsomedial portion of the dermomyotome, which develops into the epaxial myotome.[3] Although it is expressed in both the epaxial (to become muscles of the back) and hypaxial (body wall and limb muscles) portions of the myotome, it is regulated differently in these tissue lines, providing part of their alternative differentiation. Most notably, while Myf5 is activated by Sonic hedgehog in the epaxial lineage,[5] it is instead directly activated by the transcription factor Pax3 in hypaxial cells.[6] The limb myogenic precursors (derived from the hypaxial myotome) do not begin expressing Myf5 or any MRFs, in fact, until after migration to the limb buds.[7] Alternatively, during its brief window of expression in the embryo it is also expressed in nonsomitic paraxial mesoderm that goes on to form the muscles of the head, according to studies done on zebrafish.[8] While the product of this gene is capable of directing cells towards the skeletal muscle lineage, it is not absolutely required for this process. Numerous studies have shown redundancy with two other MRFs, MyoD and MRF4. The absence of all three of these factors results in a phenotype with no skeletal muscle.[9] These studies were performed after it was shown that Myf5 knockouts had no clear abnormality in their skeletal muscle.[10] The high redundancy of this system shows how crucial the development of skeletal muscle is to the viability of the fetus. Some evidence shows that Myf5 and MyoD are responsible for the development of separate muscle lineages, and are not expressed concurrently in the same cell.[11] Specifically, while Myf5 plays a large role in the initiation of epaxial development, MyoD directs the initiation of hypaxial development, and these separate lineages can compensate for the absence of one or the other. This has led some to claim that they are not indeed redundant, though this depends on the definition of the word. Still, the existence of these separate “MyoD-dependent” and “Myf5-dependent” subpopulations has been disputed, with some claiming that these MRFs are indeed coexpressed in muscle progenitor cells.[6] This debate is ongoing. Although Myf5 is mainly associated with myogenesis, it is expressed in other tissues, as well. Firstly, it is expressed in brown adipose precursors. However, its expression is limited to brown and not white adipose precursors, providing part of the developmental separation between these two lineages.[12] Furthermore, Myf5 is expressed in portions of the neural tube (that go on to form neurons) a few days after it is seen in the somites. This expression is eventually repressed to prevent extraneous muscle formation.[13] Although the specific roles and dependency of Myf5 in adipogenesis and neurogenesis have remained to be explored, these findings show that Myf5 plays roles outside of myogenesis. Myf5 also has an indirect role controlling proximal rib development. Although Myf5 knockouts have normal skeletal muscle, they die due to abnormalities in their proximal ribs that make it difficult to breathe.[11] Despite only being present for a few days during embryonic development, Myf5 is still expressed in certain adult cells. As one of the key cell markers of satellite cells (the stem cell pool for skeletal muscles), it plays an important role in the regeneration of adult muscle.[14] Specifically, it allows a brief pulse of proliferation of these satellite cells in response to injury. Differentiation begins (regulated by other genes) after this initial proliferation. In fact, if Myf5 is not downregulated, differentiation does not occur.[15] # Regulation The regulation of Myf5 is dictated by a large number of enhancer elements that allow a complex system of regulation. Although most events throughout myogenesis that involve Myf5 are controlled through the interaction of multiple enhancers, there is one important early enhancer that initiates expression. Termed the early epaxial enhancer, its activation provides the "go" signal for expression of Myf5 in the epaxial dermomyotome, where it is first seen.[16] Sonic hedgehog from the neural tube acts at this enhancer to activate it.[5] Following that, the chromosome contains different enhancers for regulation of Myf5 expression in the hypaxial region, cranial region, limbs, etc.[16] This early expression of Myf5 in the epaxial dermamyotome is involved with the very formation of myotome, but nothing beyond that. After its initial expression, other enhancer elements dictate where and how long it is expressed. It remains clear that each population of myogenic progenitor cells (for different locations in the embryo) is regulated by a different set of enhancers.[17] # Clinical significance As for its clinical significance, the aberration of this transcription factor provides part of the mechanism for how hypoxia (lack of oxygen) can influence muscle development. Hypoxia has the ability to impede muscle differentiation in part by inhibiting the expression of Myf5 (as well as other MRFs). This prevents the muscle precursors from becoming post-mitotic muscle fibers. Although hypoxia is a teratogen, this inhibition of expression is reversible, therefore it remains unclear if there is a connection between hypoxia and birth defects in the fetus.[18]

https://www.wikidoc.org/index.php/MYF5

ab796efe30c45823314cdd36e3a1ec148b4600c9

wikidoc

MYF6

MYF6 Myogenic factor 6 (herculin) is a protein that in humans is encoded by the MYF6 gene. Also known in the medical literature as MRF4 and herculin), MYF6 is a myogenic regulatory factor (MRF) in the process known as myogenesis. # Function MYF6 is a member of the myogenic factors (MYF) family that regulate myogenesis and muscle regeneration. Myogenics factor are basic helix-loop-helix (bHLH) transcription factors. MYF-6 is a gene that encodes a protein involved in the regulation of myogenesis. Specifically, it induces the maturation of myotubes into myofibers. The portion of the protein integral to myogenesis regulation is a basic helix-loop-helix (bHLH) domain that is conserved among all of the genes in the MRF family. MYF-6 is expressed exclusively in skeletal muscle, and it is expressed at a higher levels in adult skeletal muscle than all of the other genes in the muscle regulatory factor factor gene family. MYF-6 is different from the other myogenic regulatory factor genes due to its two-phase expression. Initially, MYF-6 is transiently expressed along with MYF-5 in the somites during the early stages of myogenesis. However, it is primarily expressed postnatally. This suggests that it serves an important role in the maintenance and repair of adult skeletal muscle. The role of MYF-6 expression in the somites during embryogenesis is currently unknown. The MYF-6 gene is physically linked to the MYF-5 gene on chromosome 12, and mutations in the MYF-6 gene typically exhibit reduced levels of MYF-5. Despite reductions in muscle mass of the back, MYF6 mutants still exhibit fairly normal skeletal muscle. While this demonstrates that MYF-6 might not be essential for the formation of myofibers, it is thought that myogenin compensates for the absence of functional MYF-6. # Clinical significance Mutations in the MYF6 gene are associated with autosomal dominant centronuclear myopathy (ADCNM) and Becker's muscular dystrophy.

MYF6 Myogenic factor 6 (herculin) is a protein that in humans is encoded by the MYF6 gene. [1] Also known in the medical literature as MRF4 and herculin), MYF6 is a myogenic regulatory factor (MRF) in the process known as myogenesis.[2][3] # Function MYF6 is a member of the myogenic factors (MYF) family that regulate myogenesis and muscle regeneration. Myogenics factor are basic helix-loop-helix (bHLH) transcription factors. MYF-6 is a gene that encodes a protein involved in the regulation of myogenesis. Specifically, it induces the maturation of myotubes into myofibers. The portion of the protein integral to myogenesis regulation is a basic helix-loop-helix (bHLH) domain that is conserved among all of the genes in the MRF family. MYF-6 is expressed exclusively in skeletal muscle, and it is expressed at a higher levels in adult skeletal muscle than all of the other genes in the muscle regulatory factor factor gene family. MYF-6 is different from the other myogenic regulatory factor genes due to its two-phase expression. Initially, MYF-6 is transiently expressed along with MYF-5 in the somites during the early stages of myogenesis.[4] However, it is primarily expressed postnatally. This suggests that it serves an important role in the maintenance and repair of adult skeletal muscle.[4] The role of MYF-6 expression in the somites during embryogenesis is currently unknown. The MYF-6 gene is physically linked to the MYF-5 gene on chromosome 12, and mutations in the MYF-6 gene typically exhibit reduced levels of MYF-5.[5] Despite reductions in muscle mass of the back, MYF6 mutants still exhibit fairly normal skeletal muscle. While this demonstrates that MYF-6 might not be essential for the formation of myofibers, it is thought that myogenin compensates for the absence of functional MYF-6.[6] # Clinical significance Mutations in the MYF6 gene are associated with autosomal dominant centronuclear myopathy (ADCNM) and Becker's muscular dystrophy.[7]

https://www.wikidoc.org/index.php/MYF6

7e7eb9564bd9b8d350145abf5a298130249edb5d

wikidoc

MYH6

MYH6 Myosin heavy chain, α isoform (MHC-α) is a protein that in humans is encoded by the MYH6 gene. This isoform is distinct from the ventricular/slow myosin heavy chain isoform, MYH7, referred to as MHC-β. MHC-α isoform is expressed predominantly in human cardiac atria, exhibiting only minor expression in human cardiac ventricles. It is the major protein comprising the cardiac muscle thick filament, and functions in cardiac muscle contraction. Mutations in MYH6 have been associated with late-onset hypertrophic cardiomyopathy, atrial septal defects and sick sinus syndrome. # Structure MHC-α is a 224 kDa protein composed of 1939 amino acids. The MYH6 gene is located on chromosome 14q12, approximately ~4kb downstream of the MYH7 gene encoding the other major cardiac muscle isoform of myosin heavy chain, MHC-β. MHC-α is a hexameric, asymmetric motor forming the bulk of the thick filament in cardiac muscle; it is the predominant isoform expressed in human cardiac atria, and the lesser expressed isoform (7%) expressed in human cardiac ventricles. MHC-α is composed of N-terminal globular heads (20 nm) that project laterally, and alpha helical tails (130 nm) that dimerize and multimerize into a coiled-coil motif to form the light meromyosin (LMM), thick filament rod. The 9 nm alpha-helical neck region of each MHC-α head non-covalently binds two light chains, atrial essential light chain (MYL4) and atrial regulatory light chain (MYL7). Approximately 300 myosin molecules constitute one thick filament. # Function MHC-α isoform is abundantly expressed in both cardiac atria and cardiac ventricles during embryonic development. Following birth, cardiac ventricles predominantly express the MHC-β isoform and cardiac atria predominantly express the MHC-α isoform. The two isoforms of cardiac MHC, α and β, display 93% homology. MHC-α and MHC-β display significantly different enzymatic properties, with α having 150-300% the contractile velocity and 60-70% actin attachment time as that of β. It is the enzymatic activity of the ATPase in the myosin head that cyclically hydrolyzes ATP, fueling the myosin power stroke. This process converts chemical to mechanical energy, and propels shortening of the sarcomeres in order to generate intraventricular pressure and power. An accepted mechanism for this process is that ADP-bound myosin attaches to actin while thrusting tropomyosin inwards, then the S1-S2 myosin lever arm rotates ~70° about the converter domain and drives actin filaments towards the M-line. # Clinical significance The first mutation identified in MYH6 by Niimura et al. was found in a patient population with late-onset hypertrophic cardiomyopathy. An Arg to Gln variant was found at position 795 (Arg795Gln). This mutation was located in a region of MHC-α shown to be important for binding essential light chain. Subsequent studies have also found additional mutations in MYH6 linked to both hypertrophic cardiomyopathy and dilated cardiomyopathy. Mutations in MYH6 cause atrial septal defect. One underlying mutation is a missense substitution at Ile820Asn, which alters the association of alpha-myosin heavy chain with regulatory light chain. MYH6 has been shown to be the predominant sarcomeric disease gene for secundum-type atrial septal defects. Additional studies unveiled an association between MYH6 mutations and a wide array of cardiac malformations in addition to atrial septal defect, including one non-sense mutation, one splicing site mutation and seven non-synonymous coding mutations. MYH6 has also been identified as a susceptibility gene for sick sinus syndrome. A missense mutation at Arg721Trp was identified as conferring a lifetime risk of 50% for carriers. An in-frame 3-bp deletion mutation in MYH6, in which one residue in MHC-α is removed, enhances the binding of MHC-α to myosin binding protein-C and disrupts normal sarcomere function and cardiac atrial conduction velocity. # Cardiomyopathy from mutation R403Q Hypertrophic cardiomyopathy (HCM) is a cardiac disease that has some characteristic abnormalities including hypertrophy of the septal wall, disorganized cardiac myocytes, and increase fibrosis within the myocardium. The majority of familial HCM cases have been linked to a mutation in beta-myosin heavy chains converting a single amino acid from an arginine to a glutamine at the 403rd position. More than half of affected people die by the age of 40 because of HCM due to R403Q. The R403Q mutation interferes with the beta-myosin heavy chain and therefore greatly hinders the functionality of the heart muscle. Specifically, the affected muscle cells have slower contractile velocities, have depressed actin-activated ATPase rates, and have increased stiffness. Due to the fact that the cause of the R403Q mutation lies within the region that encodes for the globular myosin head, alterations in the myosin head structure greatly impairs its ability to strongly interact with actin and form a stable cross-bridge. The development of HCM is multifaceted, but the R403Q mutation is one of the most influential risk factors. Of the hundreds of pathogenic mutations that give rise to HCM, R403Q mutations in myosin heavy chain genes are present in over half of them. Since HCM is such a debilitating disease, investigation into possible therapeutic approaches to treat some of the causes of HCM- or at the very least provide palliative care for people affected by this condition- is of extreme importance. # Myh6 knockdown as a therapy for HCM HCM is an autosomal dominant disease and conventional treatments are ineffective. Gene therapy is currently being investigated as a possible treatment option. Myh6 gene is a possible target for gene therapy. Infected with adeno-associated vectors carrying the siRNA to silence the mutant Mhy6 gene, inhibited expression of R403Q myosin postponed development of HCM for 6 months. Without the dysfunctional myosin protein the heart functioned more efficiently and this prevents the development of myocyte hypertrophy as a compensatory mechanism. Not only was there an absence of HCM, but fibrosis and myocyte disorganization was greatly reduced in the knockdown mice. The proposed mechanism for this is the expression of a more normalized ratio of α-myosin chain to β-myosin chain proteins. This enables proper assembly of myofibrils and thus, more organized sarcomeres. It should be noted, however, that all of the mice in the study developed HCM after 11 months and that the gene therapy was only temporarily therapeutic.

MYH6 Myosin heavy chain, α isoform (MHC-α) is a protein that in humans is encoded by the MYH6 gene.[1][2] This isoform is distinct from the ventricular/slow myosin heavy chain isoform, MYH7, referred to as MHC-β. MHC-α isoform is expressed predominantly in human cardiac atria, exhibiting only minor expression in human cardiac ventricles. It is the major protein comprising the cardiac muscle thick filament, and functions in cardiac muscle contraction. Mutations in MYH6 have been associated with late-onset hypertrophic cardiomyopathy, atrial septal defects and sick sinus syndrome. # Structure MHC-α is a 224 kDa protein composed of 1939 amino acids.[3][4] The MYH6 gene is located on chromosome 14q12, approximately ~4kb downstream of the MYH7 gene encoding the other major cardiac muscle isoform of myosin heavy chain, MHC-β. MHC-α is a hexameric, asymmetric motor forming the bulk of the thick filament in cardiac muscle; it is the predominant isoform expressed in human cardiac atria,[5] and the lesser expressed isoform (7%) expressed in human cardiac ventricles.[6] MHC-α is composed of N-terminal globular heads (20 nm) that project laterally, and alpha helical tails (130 nm) that dimerize and multimerize into a coiled-coil motif to form the light meromyosin (LMM), thick filament rod. The 9 nm alpha-helical neck region of each MHC-α head non-covalently binds two light chains, atrial essential light chain (MYL4) and atrial regulatory light chain (MYL7).[7] Approximately 300 myosin molecules constitute one thick filament.[8] # Function MHC-α isoform is abundantly expressed in both cardiac atria and cardiac ventricles during embryonic development. Following birth, cardiac ventricles predominantly express the MHC-β isoform and cardiac atria predominantly express the MHC-α isoform.[5] The two isoforms of cardiac MHC, α and β, display 93% homology. MHC-α and MHC-β display significantly different enzymatic properties, with α having 150-300% the contractile velocity and 60-70% actin attachment time as that of β.[7][9] It is the enzymatic activity of the ATPase in the myosin head that cyclically hydrolyzes ATP, fueling the myosin power stroke. This process converts chemical to mechanical energy, and propels shortening of the sarcomeres in order to generate intraventricular pressure and power. An accepted mechanism for this process is that ADP-bound myosin attaches to actin while thrusting tropomyosin inwards,[10] then the S1-S2 myosin lever arm rotates ~70° about the converter domain and drives actin filaments towards the M-line.[11] # Clinical significance The first mutation identified in MYH6 by Niimura et al. was found in a patient population with late-onset hypertrophic cardiomyopathy. An Arg to Gln variant was found at position 795 (Arg795Gln). This mutation was located in a region of MHC-α shown to be important for binding essential light chain.[12] Subsequent studies have also found additional mutations in MYH6 linked to both hypertrophic cardiomyopathy and dilated cardiomyopathy.[13] Mutations in MYH6 cause atrial septal defect.[14] One underlying mutation is a missense substitution at Ile820Asn, which alters the association of alpha-myosin heavy chain with regulatory light chain. MYH6 has been shown to be the predominant sarcomeric disease gene for secundum-type atrial septal defects.[15] Additional studies unveiled an association between MYH6 mutations and a wide array of cardiac malformations in addition to atrial septal defect, including one non-sense mutation, one splicing site mutation and seven non-synonymous coding mutations.[16] MYH6 has also been identified as a susceptibility gene for sick sinus syndrome. A missense mutation at Arg721Trp was identified as conferring a lifetime risk of 50% for carriers.[17] An in-frame 3-bp deletion mutation in MYH6, in which one residue in MHC-α is removed, enhances the binding of MHC-α to myosin binding protein-C and disrupts normal sarcomere function and cardiac atrial conduction velocity.[18] # Cardiomyopathy from mutation R403Q Hypertrophic cardiomyopathy (HCM) is a cardiac disease that has some characteristic abnormalities including hypertrophy of the septal wall, disorganized cardiac myocytes, and increase fibrosis within the myocardium. The majority of familial HCM cases have been linked to a mutation in beta-myosin heavy chains converting a single amino acid from an arginine to a glutamine at the 403rd position.[19] More than half of affected people die by the age of 40 because of HCM due to R403Q.[19] The R403Q mutation interferes with the beta-myosin heavy chain and therefore greatly hinders the functionality of the heart muscle.[20] Specifically, the affected muscle cells have slower contractile velocities, have depressed actin-activated ATPase rates, and have increased stiffness.[20] Due to the fact that the cause of the R403Q mutation lies within the region that encodes for the globular myosin head, alterations in the myosin head structure greatly impairs its ability to strongly interact with actin and form a stable cross-bridge.[20] The development of HCM is multifaceted, but the R403Q mutation is one of the most influential risk factors. Of the hundreds of pathogenic mutations that give rise to HCM, R403Q mutations in myosin heavy chain genes are present in over half of them.[19][20] Since HCM is such a debilitating disease, investigation into possible therapeutic approaches to treat some of the causes of HCM- or at the very least provide palliative care for people affected by this condition- is of extreme importance. # Myh6 knockdown as a therapy for HCM HCM is an autosomal dominant disease and conventional treatments are ineffective.[21] Gene therapy is currently being investigated as a possible treatment option. Myh6 gene is a possible target for gene therapy.[21] Infected with adeno-associated vectors carrying the siRNA to silence the mutant Mhy6 gene, inhibited expression of R403Q myosin postponed development of HCM for 6 months. Without the dysfunctional myosin protein the heart functioned more efficiently and this prevents the development of myocyte hypertrophy as a compensatory mechanism. Not only was there an absence of HCM, but fibrosis and myocyte disorganization was greatly reduced in the knockdown mice.[21] The proposed mechanism for this is the expression of a more normalized ratio of α-myosin chain to β-myosin chain proteins.[20] This enables proper assembly of myofibrils and thus, more organized sarcomeres.[20] It should be noted, however, that all of the mice in the study developed HCM after 11 months and that the gene therapy was only temporarily therapeutic.

https://www.wikidoc.org/index.php/MYH6

7c28b219988c186297871cea1cee700321095677

wikidoc

MYH7

MYH7 MYH7 is a gene encoding a myosin heavy chain beta (MHC-β) isoform (slow twitch) expressed primarily in the heart, but also in skeletal muscles (type I fibers). This isoform is distinct from the fast isoform of cardiac myosin heavy chain, MYH6, referred to as MHC-α. MHC-β is the major protein comprising the thick filament in cardiac muscle and plays a major role in cardiac muscle contraction. # Structure MHC-β is a 223 kDa protein composed of 1935 amino acids. MHC-β is a hexameric, asymmetric motor forming the bulk of the thick filament in cardiac muscle. MHC-β is composed of N-terminal globular heads (20 nm) that project laterally, and alpha helical tails (130 nm) that dimerize and multimerize into a coiled-coil motif to form the light meromyosin (LMM), thick filament rod. The 9 nm alpha-helical neck region of each MHC-β head non-covalently binds two light chains, essential light chain (MYL3) and regulatory light chain (MYL2). Approximately 300 myosin molecules constitute one thick filament. There are two isoforms of cardiac MHC, α and β, which display 93% homology. MHC-α and MHC-β display significantly different enzymatic properties, with α having 150-300% the contractile velocity and 60-70% actin attachment time as that of β. MHC-β is predominately expressed in the human ventricle, while MHC-α is predominantly expressed in human atria. # Function It is the enzymatic activity of the ATPase in the myosin head that cyclically hydrolyzes ATP, fueling the myosin power stroke. This process converts chemical to mechanical energy, and propels shortening of the sarcomeres in order to generate intraventricular pressure and power. An accepted mechanism for this process is that ADP-bound myosin attaches to actin while thrusting tropomyosin inwards, then the S1-S2 myosin lever arm rotates ~70° about the converter domain and drives actin filaments towards the M-line. # Clinical significance Several mutations in MYH7 have been associated with inherited cardiomyopathies. Lowrance et al. were the first to identify the causative mutation Arg403Gln for hypertrophic cardiomyopathy (HCM) in the MYH7 gene. Studies have since identified several more MYH7 mutations, that are estimated to be causal in approximately 40% of HCM cases. This condition is an autosomal-dominant disease, in which a single copy of the variant gene causes enlargement of the left ventricle of the heart. Disease onset usually occurs later in life, perhaps triggered by changes in thyroid hormone function and/or physical stress. Another condition associated to mutations in this gene is paraspinal and proximal muscle atrophy.

MYH7 MYH7 is a gene encoding a myosin heavy chain beta (MHC-β) isoform (slow twitch) expressed primarily in the heart, but also in skeletal muscles (type I fibers).[1] This isoform is distinct from the fast isoform of cardiac myosin heavy chain, MYH6, referred to as MHC-α. MHC-β is the major protein comprising the thick filament in cardiac muscle and plays a major role in cardiac muscle contraction. # Structure MHC-β is a 223 kDa protein composed of 1935 amino acids.[2][3] MHC-β is a hexameric, asymmetric motor forming the bulk of the thick filament in cardiac muscle. MHC-β is composed of N-terminal globular heads (20 nm) that project laterally, and alpha helical tails (130 nm) that dimerize and multimerize into a coiled-coil motif to form the light meromyosin (LMM), thick filament rod. The 9 nm alpha-helical neck region of each MHC-β head non-covalently binds two light chains, essential light chain (MYL3) and regulatory light chain (MYL2).[4] Approximately 300 myosin molecules constitute one thick filament.[5] There are two isoforms of cardiac MHC, α and β, which display 93% homology. MHC-α and MHC-β display significantly different enzymatic properties, with α having 150-300% the contractile velocity and 60-70% actin attachment time as that of β.[6][7] MHC-β is predominately expressed in the human ventricle, while MHC-α is predominantly expressed in human atria.[citation needed] # Function It is the enzymatic activity of the ATPase in the myosin head that cyclically hydrolyzes ATP, fueling the myosin power stroke. This process converts chemical to mechanical energy, and propels shortening of the sarcomeres in order to generate intraventricular pressure and power. An accepted mechanism for this process is that ADP-bound myosin attaches to actin while thrusting tropomyosin inwards,[8] then the S1-S2 myosin lever arm rotates ~70° about the converter domain and drives actin filaments towards the M-line.[9] # Clinical significance Several mutations in MYH7 have been associated with inherited cardiomyopathies. Lowrance et al. were the first to identify the causative mutation Arg403Gln for hypertrophic cardiomyopathy (HCM) in the MYH7 gene.[10] Studies have since identified several more MYH7 mutations, that are estimated to be causal in approximately 40% of HCM cases. This condition is an autosomal-dominant disease, in which a single copy of the variant gene causes enlargement of the left ventricle of the heart. Disease onset usually occurs later in life, perhaps triggered by changes in thyroid hormone function and/or physical stress. Another condition associated to mutations in this gene is paraspinal and proximal muscle atrophy.[11]

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64431ba98097b836822502a9d4aada54b1d5054b

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MYH9

MYH9 Myosin-9 also known as myosin, heavy chain 9, non-muscle or non-muscle myosin heavy chain IIa (NMMHC-IIA) is a protein which in humans is encoded by the MYH9 gene. Non-muscle myosin IIA (NM IIA) is expressed in most cells and tissues where it participates in a variety of processes requiring contractile force, such as cytokinesis, cell migration, polarization and adhesion, maintenance of cell shape, and signal transduction. Myosin IIs are motor proteins that are part of a superfamily composed of more than 30 classes. Class II myosins include muscle and non-muscle myosins that are organized as hexameric molecules consisting of two heavy chains (230 kDa), two regulatory light chains (20 KDa) controlling the myosin activity, and two essential light chains (17 kDa), which stabilize the heavy chain structure. # Gene and protein structure MYH9 is a large gene spanning more than 106 kilo base pairs on chromosome 22q12.3. It is composed of 41 exons with the first ATG of the open reading frame localized in exon 2 and the stop codon in exon 41. It encodes non-muscle myosin heavy chain IIA (NMHC IIA), a protein of 1,960 amino acids. Consistent with its wide expression in cells and tissues, the promoter region of MYH9 is typical of housekeeping genes having no TATA box but high GC content, with multiple GC boxes. MYH9 is a well-conserved gene through evolution. The mouse ortholog (Myh9) is localized in a syntenic region on chromosome 15 and has the same genomic organization as that of the human gene. It encodes a protein of the same length, with 97.1% amino acid identity with the human MYH9 protein. Like all class II myosins, the two NMHC IIAs dimerize producing an asymmetric molecular structure recognizable by two heads and a tail domain: the N-terminal half of each heavy chain generates the head domain, which consists of the globular motor domain and the neck domain, and the C-terminal halves of the two heavy chains together form the tail domain. The motor domain, which is organized into four subdomains (SH3-like motif, the upper and the lower 50kDa subdomains, and the converter region) connected by flexible linkers, interacts with filamentous actin to generate force through magnesium-dependent hydrolysis of ATP. The neck acts as a lever arm that amplifies the movement produced by conformational changes of the motor domain, and is the binding site for the light chains through two IQ motifs. The tail domain is fundamental for both dimerization of the heavy chains and formation of NM IIA functional filaments. Two heavy chains dimerize through the tail domain forming a long alpha-helical coiled-coil rod composed of typical heptad repeats. Dimers self-associate though the coiled-coil rods to form myosin filaments. The tail domain ends at the C-terminus with a 34-residue non-helical tailpiece. # Regulation of NM IIA structure and function There are three paralogs of non-muscle myosin II (NM II), NM IIA, IIB, and IIC, with each having the heavy chain encoded on a different chromosome. All three paralogs appear to bind the same or very similar light chains and share basic properties as to structure and activation, but all three play distinct roles during vertebrate development and adulthood (for general reviews on NM IIs, see ). All NM IIs have two important features: they are MgATPase enzymes that can hydrolyze ATP thereby converting chemical energy into mechanical movement. In addition, they can form bipolar filaments which can interact with and exert tension on actin filaments. These properties provide the basis for all NM II functions. The path to myosin filament formation, which is shared by NM II and smooth muscle myosin, starts with a folded inactive conformation of the NM II monomer which, upon phosphorylation of the 20 KDa light chain unfolds the molecule to produce a globular head region followed by an extended alpha-helical coiled-coil tail. The tail portion of the molecule can interact with other NM IIA hexamers to form bipolar filaments composed of 14-16 molecules. Phosphorylation of the 20 KDa light chains on Serine 19 and Threonine 18 by a number of different kinases, but most prominently by Rho-dependent kinase and/or by the calcium-calmodulin-dependent myosin light chain kinase, not only linearizes the folded structure but removes the inhibition imposed on the MgATPase activity due to the folded conformation. In addition to phosphorylation of the 20 KDa light chains, the NMHC IIs can also be phosphorylated, but the sites phosphorylated differ among the paralogs. In most cases phosphorylation of NMHC IIA can act to either dissociate the myosin filaments or to prevent filament formation. In addition to phosphorylation, NM IIA filament assembly and localization can be modulated by interaction with other proteins including S100A4 and Lethal giant larvae (Lgl1). The former is a calcium binding protein and is also known as metastatin, a well-characterized metastatic factor. S100A4 expression is associated with enhanced cell migration through maintenance of cell polarization and inhibition of cell turning. Similar to heavy chain phosphorylation, in vitro binding of S100A to the carboxy-terminal end of the NM IIA coiled-coil region prevents filament formation and S100A4 binding to previously formed filaments promotes filament disassembly. The tumor suppressor protein Lgl1 also inhibits the ability of NM IIA to assemble into filaments in vitro. In addition, it regulates the cellular localization of NM IIA and contributes to the maturation of focal adhesions. Other proteins that are known to interact with NM IIA include the actin binding protein tropomyosin 4.2 and a novel actin stress fiber associated protein, LIM and calponin-homology domains1 (LIMCH1). # Functions specific to NM IIA NM IIA plays a major role in early vertebrate development. Ablation of NM IIA in mice results in lethality by embryonic day (E) 6.5 due to abnormalities in the visceral endoderm which is disorganized due to a loss of E-cadherin mediated cell-cell adhesions. Lacking a normal polarized columnar layer of endoderm, the abnormal visceral endoderm of NM IIA knockout embryos fails to support the critical step of gastrulation. However, the development of a normal functioning visceral endoderm does not specifically depend on NM IIA since its function can be restored by genetically replacing the NMHC IIA with cDNA encoding NMHC II B (or NMHC IIC) that is under control of the NMHC IIA promoter. These “replacement” mice have a normal visceral endoderm and continue to proceed through gastrulation and undergo organogenesis. However, they die when they fail to develop a normal placenta. Absence of NM IIA results in a compact and underdeveloped labyrinthine layer in the placenta which lacks fetal blood vessel invasion. Moreover mutant p.R702C NM IIA mice show similar defects in placental formation and mice specifically ablated for NM IIA in the mouse trophoblast-lineage cells demonstrate placental defects similar to mice in which NMHC IIA is genetically replaced by NMHC IIB. There are significant differences in the relative abundance of the three NM II paralogs in various cells and tissues. However, NM IIA appears to be the predominant paralog in both tissues and cells in humans and mice. Mass spectroscopy analysis of the relative abundance of NMHC IIs in mouse tissues and human cell lines shows that NM IIA is predominant, although tissues like the heart vary from cell to cell; myocardial cells contain only NM IIB but NM IIA is more abundant in the non-myocyte cells. NM IIB is predominant in most parts of the brain and spinal cord but NM IIA is relatively more abundant in most other organs and cells lines. Both NM IIA and IIB are expressed early in development with NM IIC expression starting at E 11.5 in mice. Not only do most cells contain more than one paralog but there is evidence that the paralogs can co-assemble intracellularly into heterotypic filaments in a variety of settings in cultured cells. # Clinical significance MYH9-related disease. Mutations in MYH9 cause a Mendelian autosomal-dominant disorder known as MYH9-related disease (MYH9-RD). All affected individuals present congenital hematological alterations consisting in thrombocytopenia, platelet macrocytosis, and inclusions of the MYH9 protein in the cytoplasm of granulocytes. Most patients develop one or more non-congenital manifestations, including sensorineural deafness, kidney damage, presenile cataracts, and/or elevation of liver enzymes. The term MYH9-RD encompasses four syndromic pictures that were considered for many years as distinct disorders, namely May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome. After the identification of MYH9 as the gene responsible for all of these entities, it was recognized that they actually represent different clinical presentations of the same disease, now known as MYH9-RD or MYH9 disorder. MYH9-RD is a rare disease: prevalence is estimated around 3:1,000,000. The actual prevalence is expected to be higher, as mild forms are often discovered incidentally and patients are frequently misdiagnosed with other disorders. The disease has been reported worldwide and there is no evidence of variation in prevalence across ethnic populations. Thrombocytopenia can result in a variable degree of bleeding tendency. The majority of patients have no spontaneous bleeding or only mild cutaneous bleeding (easy bruising) and are at risk of significant hemorrhages only after surgery or other invasive procedures, deliveries, or trauma. Some patients have spontaneous mucosal bleeding, such as menorrhagia, epistaxis, and gum bleeding. Severe and life-threatening hemorrhages are not frequent. Platelets of MYH9-RD patients are characterized by a very large size: platelets larger than red blood cells (called "giant platelets") are always present at the examination of peripheral blood smears. Granulocyte inclusions of the NMHC IIA may be evident at the analysis of blood films after conventional staining as cytoplasmic basophilic (light blue) inclusions, called "Döhle-like bodies". More than 50% of MYH9-RD patients develop sensorineural hearing loss. Severity of the hearing impairment is greatly variable, as it ranges from a mild hearing defect that occurs in mid or advanced age to a progressive hearing loss that is evident in the first years of life and rapidly evolves to severe deafness. Kidney damage occurs in about 25% of patients. It presents with proteinuria and often progresses to kidney failure, which, in its most severe forms, may require dialysis and/or kidney transplantation. Around 20% of patients develop presenile cataracts. About 50% of MYH9-RD patients present chronic or intermittent elevation of liver transaminases or gamma-glutamyl transferases: this alteration appears to be benign, as no patients showed evolution to liver dysfunction. Diagnosis of MYH9-RD is confirmed by the identification of the NMHC IIA inclusions in granulocytes through an immunofluorescence assay on peripheral blood smears and/or by the detection of the causative mutation through mutational screening of the MYH9 gene. In most cases, MYH9-RD is caused by missense mutations affecting the head or tail domain of the NMHC IIA. Nonsense or frameshift alterations resulting in the deletion of a C-terminal fragment of the NMHC IIA (17 to 40 residues) are involved in approximately 20% of families. In-frame deletions or duplications have been identified in a few cases. The disease is transmitted as an autosomal-dominant trait, however, about 35% of index cases are sporadic. Sporadic forms mainly derive from de novo mutations; rare cases have been explained by germinal or somatic mosaicism. The incidence and the severity of the non-congenital manifestations of MYH9-RD correlate with the specific MYH9 mutation. The recent definition of genotype-phenotype correlations allows prediction of the clinical evolution of the disease in most cases. Genotype-phenotype correlations have been reported also for the severity of thrombocytopenia, platelet size, and the features of leukocyte inclusions. Within a phase 2 trial, eltrombopag, an agonist of the thrombopoietin receptor, significantly increased platelet count in 11 out of 12 patients affected with MYH9-RD. ACE-inhibitors or angiotensin II receptor blockers may be effective in reducing proteinuria when given at the early stage of kidney involvement. Cochlear implantation is effective in restoring hearing function in MYH9-RD patients with severe/profound deafness. Role of MYH9 variants in other human diseases. Evidence obtained in animals indicates that MYH9 acts as a tumor suppressor gene. Silencing of Myh9 in the epithelial cells in mice was associated with the development of squamous cell carcinoma (SCC) of the skin and the head and neck. In another mouse model, ablation of Myh9 in the tongue epithelium led to the development of tongue SCC. In mice predisposed to invasive lobular breast carcinoma (ILBC) because of E-cadherin ablation, the inactivation of Myh9 led to the development of tumors recapitulating the features of human ILBC. Some observations suggest that defective MYH9 expression is associated with oncogenesis and/or tumor progression in human SCC and ILBC, thus also supporting a role for MYH9 as a tumor suppressor in humans. Genetic variations in MYH9 may be involved in predisposition to chronic kidney disease (CKD). A haplotype of MYH9 (haplotype E1) was previously associated with the increased prevalence of glomerulosclerosis and non-diabetic end stage renal disease in African Americans and in Hispanic Americans. However, subsequent studies showed that this association is explained by strong linkage disequilibrium with two haplotypes (haplotypes G1 and G2) in the neighboring APOL1 gene. Nevertheless, some studies suggest an association of single-nucleotide polymorphisms in MYH9 with CKD that appears to be independent of the linkage with APOL1 G1 and G2. Inherited MYH9 mutations may be responsible for non-syndromic hearing loss. # Other model organisms Model organisms have been used in the study of MYH9 function. A conditional knockout mouse line, called Myh9tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals. # Other interactions MYH9 has been shown to interact with PRKCE.

MYH9 Myosin-9 also known as myosin, heavy chain 9, non-muscle or non-muscle myosin heavy chain IIa (NMMHC-IIA) is a protein which in humans is encoded by the MYH9 gene.[1][2] Non-muscle myosin IIA (NM IIA) is expressed in most cells and tissues where it participates in a variety of processes requiring contractile force, such as cytokinesis, cell migration, polarization and adhesion, maintenance of cell shape, and signal transduction. Myosin IIs are motor proteins that are part of a superfamily composed of more than 30 classes.[3][4][5] Class II myosins include muscle and non-muscle myosins that are organized as hexameric molecules consisting of two heavy chains (230 kDa), two regulatory light chains (20 KDa) controlling the myosin activity, and two essential light chains (17 kDa), which stabilize the heavy chain structure.[6][7][8][9][10] # Gene and protein structure MYH9 is a large gene spanning more than 106 kilo base pairs on chromosome 22q12.3. It is composed of 41 exons with the first ATG of the open reading frame localized in exon 2 and the stop codon in exon 41. It encodes non-muscle myosin heavy chain IIA (NMHC IIA), a protein of 1,960 amino acids. Consistent with its wide expression in cells and tissues, the promoter region of MYH9 is typical of housekeeping genes having no TATA box but high GC content, with multiple GC boxes. MYH9 is a well-conserved gene through evolution. The mouse ortholog (Myh9) is localized in a syntenic region on chromosome 15 and has the same genomic organization as that of the human gene. It encodes a protein of the same length, with 97.1% amino acid identity with the human MYH9 protein.[11] Like all class II myosins, the two NMHC IIAs dimerize producing an asymmetric molecular structure recognizable by two heads and a tail domain: the N-terminal half of each heavy chain generates the head domain, which consists of the globular motor domain and the neck domain, and the C-terminal halves of the two heavy chains together form the tail domain.[12] The motor domain, which is organized into four subdomains (SH3-like motif, the upper and the lower 50kDa subdomains, and the converter region) connected by flexible linkers,[13] interacts with filamentous actin to generate force through magnesium-dependent hydrolysis of ATP. The neck acts as a lever arm that amplifies the movement produced by conformational changes of the motor domain, and is the binding site for the light chains through two IQ motifs. The tail domain is fundamental for both dimerization of the heavy chains and formation of NM IIA functional filaments. Two heavy chains dimerize through the tail domain forming a long alpha-helical coiled-coil rod composed of typical heptad repeats. Dimers self-associate though the coiled-coil rods to form myosin filaments. The tail domain ends at the C-terminus with a 34-residue non-helical tailpiece.[10][12] # Regulation of NM IIA structure and function There are three paralogs of non-muscle myosin II (NM II), NM IIA, IIB, and IIC, with each having the heavy chain encoded on a different chromosome. All three paralogs appear to bind the same or very similar light chains and share basic properties as to structure and activation, but all three play distinct roles during vertebrate development and adulthood (for general reviews on NM IIs, see [7][9][10]). All NM IIs have two important features: they are MgATPase enzymes that can hydrolyze ATP thereby converting chemical energy into mechanical movement. In addition, they can form bipolar filaments which can interact with and exert tension on actin filaments. These properties provide the basis for all NM II functions. The path to myosin filament formation, which is shared by NM II and smooth muscle myosin, starts with a folded inactive conformation of the NM II monomer which, upon phosphorylation of the 20 KDa light chain unfolds the molecule to produce a globular head region followed by an extended alpha-helical coiled-coil tail.[14][15][16][17] The tail portion of the molecule can interact with other NM IIA hexamers to form bipolar filaments composed of 14-16 molecules. Phosphorylation of the 20 KDa light chains on Serine 19 and Threonine 18 by a number of different kinases, but most prominently by Rho-dependent kinase and/or by the calcium-calmodulin-dependent myosin light chain kinase, not only linearizes the folded structure but removes the inhibition imposed on the MgATPase activity due to the folded conformation. In addition to phosphorylation of the 20 KDa light chains, the NMHC IIs can also be phosphorylated, but the sites phosphorylated differ among the paralogs.[6] In most cases phosphorylation of NMHC IIA can act to either dissociate the myosin filaments or to prevent filament formation. In addition to phosphorylation, NM IIA filament assembly and localization can be modulated by interaction with other proteins including S100A4 and Lethal giant larvae (Lgl1). The former is a calcium binding protein and is also known as metastatin, a well-characterized metastatic factor. S100A4 expression is associated with enhanced cell migration through maintenance of cell polarization and inhibition of cell turning.[18][19] Similar to heavy chain phosphorylation, in vitro binding of S100A to the carboxy-terminal end of the NM IIA coiled-coil region prevents filament formation and S100A4 binding to previously formed filaments promotes filament disassembly. The tumor suppressor protein Lgl1 also inhibits the ability of NM IIA to assemble into filaments in vitro.[20][21] In addition, it regulates the cellular localization of NM IIA and contributes to the maturation of focal adhesions. Other proteins that are known to interact with NM IIA include the actin binding protein tropomyosin 4.2 [22] and a novel actin stress fiber associated protein, LIM and calponin-homology domains1 (LIMCH1).[23] # Functions specific to NM IIA NM IIA plays a major role in early vertebrate development. Ablation of NM IIA in mice results in lethality by embryonic day (E) 6.5 due to abnormalities in the visceral endoderm which is disorganized due to a loss of E-cadherin mediated cell-cell adhesions.[24] Lacking a normal polarized columnar layer of endoderm, the abnormal visceral endoderm of NM IIA knockout embryos fails to support the critical step of gastrulation. However, the development of a normal functioning visceral endoderm does not specifically depend on NM IIA since its function can be restored by genetically replacing the NMHC IIA with cDNA encoding NMHC II B (or NMHC IIC) that is under control of the NMHC IIA promoter.[25] These “replacement” mice have a normal visceral endoderm and continue to proceed through gastrulation and undergo organogenesis. However, they die when they fail to develop a normal placenta. Absence of NM IIA results in a compact and underdeveloped labyrinthine layer in the placenta which lacks fetal blood vessel invasion. Moreover mutant p.R702C NM IIA mice show similar defects in placental formation [26] and mice specifically ablated for NM IIA in the mouse trophoblast-lineage cells demonstrate placental defects similar to mice in which NMHC IIA is genetically replaced by NMHC IIB.[27] There are significant differences in the relative abundance of the three NM II paralogs in various cells and tissues. However, NM IIA appears to be the predominant paralog in both tissues and cells in humans and mice. Mass spectroscopy analysis of the relative abundance of NMHC IIs in mouse tissues and human cell lines [28] shows that NM IIA is predominant, although tissues like the heart vary from cell to cell; myocardial cells contain only NM IIB but NM IIA is more abundant in the non-myocyte cells. NM IIB is predominant in most parts of the brain and spinal cord but NM IIA is relatively more abundant in most other organs and cells lines. Both NM IIA and IIB are expressed early in development with NM IIC expression starting at E 11.5 in mice. Not only do most cells contain more than one paralog but there is evidence that the paralogs can co-assemble intracellularly into heterotypic filaments in a variety of settings in cultured cells.[29][30][31] # Clinical significance MYH9-related disease. Mutations in MYH9 cause a Mendelian autosomal-dominant disorder known as MYH9-related disease (MYH9-RD).[32][33][34][35] All affected individuals present congenital hematological alterations consisting in thrombocytopenia, platelet macrocytosis, and inclusions of the MYH9 protein in the cytoplasm of granulocytes. Most patients develop one or more non-congenital manifestations, including sensorineural deafness, kidney damage, presenile cataracts, and/or elevation of liver enzymes.[35][36][37] The term MYH9-RD encompasses four syndromic pictures that were considered for many years as distinct disorders, namely May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome. After the identification of MYH9 as the gene responsible for all of these entities, it was recognized that they actually represent different clinical presentations of the same disease, now known as MYH9-RD or MYH9 disorder.[34] MYH9-RD is a rare disease: prevalence is estimated around 3:1,000,000. The actual prevalence is expected to be higher, as mild forms are often discovered incidentally and patients are frequently misdiagnosed with other disorders. The disease has been reported worldwide and there is no evidence of variation in prevalence across ethnic populations.[38] Thrombocytopenia can result in a variable degree of bleeding tendency. The majority of patients have no spontaneous bleeding or only mild cutaneous bleeding (easy bruising) and are at risk of significant hemorrhages only after surgery or other invasive procedures, deliveries, or trauma. Some patients have spontaneous mucosal bleeding, such as menorrhagia, epistaxis, and gum bleeding.[35][36] Severe and life-threatening hemorrhages are not frequent. Platelets of MYH9-RD patients are characterized by a very large size: platelets larger than red blood cells (called "giant platelets") are always present at the examination of peripheral blood smears.[34][39] Granulocyte inclusions of the NMHC IIA may be evident at the analysis of blood films after conventional staining as cytoplasmic basophilic (light blue) inclusions, called "Döhle-like bodies".[34][35] More than 50% of MYH9-RD patients develop sensorineural hearing loss.[36] Severity of the hearing impairment is greatly variable, as it ranges from a mild hearing defect that occurs in mid or advanced age to a progressive hearing loss that is evident in the first years of life and rapidly evolves to severe deafness.[40] Kidney damage occurs in about 25% of patients. It presents with proteinuria and often progresses to kidney failure, which, in its most severe forms, may require dialysis and/or kidney transplantation.[36] Around 20% of patients develop presenile cataracts. About 50% of MYH9-RD patients present chronic or intermittent elevation of liver transaminases or gamma-glutamyl transferases: this alteration appears to be benign, as no patients showed evolution to liver dysfunction.[37] Diagnosis of MYH9-RD is confirmed by the identification of the NMHC IIA inclusions in granulocytes through an immunofluorescence assay on peripheral blood smears and/or by the detection of the causative mutation through mutational screening of the MYH9 gene.[41][42][43][44] In most cases, MYH9-RD is caused by missense mutations affecting the head or tail domain of the NMHC IIA. Nonsense or frameshift alterations resulting in the deletion of a C-terminal fragment of the NMHC IIA (17 to 40 residues) are involved in approximately 20% of families. In-frame deletions or duplications have been identified in a few cases.[36][41][45] The disease is transmitted as an autosomal-dominant trait, however, about 35% of index cases are sporadic.[42] Sporadic forms mainly derive from de novo mutations; rare cases have been explained by germinal or somatic mosaicism.[46][47][48] The incidence and the severity of the non-congenital manifestations of MYH9-RD correlate with the specific MYH9 mutation. The recent definition of genotype-phenotype correlations allows prediction of the clinical evolution of the disease in most cases.[36][49] Genotype-phenotype correlations have been reported also for the severity of thrombocytopenia, platelet size, and the features of leukocyte inclusions.[36][39][50] Within a phase 2 trial, eltrombopag, an agonist of the thrombopoietin receptor, significantly increased platelet count in 11 out of 12 patients affected with MYH9-RD.[51] ACE-inhibitors or angiotensin II receptor blockers may be effective in reducing proteinuria when given at the early stage of kidney involvement.[52][53] Cochlear implantation is effective in restoring hearing function in MYH9-RD patients with severe/profound deafness.[54] Role of MYH9 variants in other human diseases. Evidence obtained in animals indicates that MYH9 acts as a tumor suppressor gene. Silencing of Myh9 in the epithelial cells in mice was associated with the development of squamous cell carcinoma (SCC) of the skin and the head and neck.[55] In another mouse model, ablation of Myh9 in the tongue epithelium led to the development of tongue SCC.[56] In mice predisposed to invasive lobular breast carcinoma (ILBC) because of E-cadherin ablation, the inactivation of Myh9 led to the development of tumors recapitulating the features of human ILBC.[57] Some observations suggest that defective MYH9 expression is associated with oncogenesis and/or tumor progression in human SCC and ILBC, thus also supporting a role for MYH9 as a tumor suppressor in humans.[55][57] Genetic variations in MYH9 may be involved in predisposition to chronic kidney disease (CKD). A haplotype of MYH9 (haplotype E1) was previously associated with the increased prevalence of glomerulosclerosis[58] and non-diabetic end stage renal disease[59] in African Americans and in Hispanic Americans.[60] However, subsequent studies showed that this association is explained by strong linkage disequilibrium with two haplotypes (haplotypes G1 and G2) in the neighboring APOL1 gene.[61][62][63] Nevertheless, some studies suggest an association of single-nucleotide polymorphisms in MYH9 with CKD that appears to be independent of the linkage with APOL1 G1 and G2.[64][65][66] Inherited MYH9 mutations may be responsible for non-syndromic hearing loss.[67][68][69] # Other model organisms Model organisms have been used in the study of MYH9 function. A conditional knockout mouse line, called Myh9tm1a(EUCOMM)Wtsi[74][75] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[76][77][78] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[72][79] Twenty six tests were carried out on mutant mice and two significant abnormalities were observed.[72] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[72] # Other interactions MYH9 has been shown to interact with PRKCE.[80]

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21b7a70ab79a1601d0edac838b2be3eb70da086a

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MYL2

MYL2 Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the MYL2 gene. This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7). Ventricular myosin light chain-2 (MLC-2v) refers to the ventricular cardiac muscle form of myosin light chain 2 (Myl2). MLC-2v is a 19-KDa protein composed of 166 amino acids, that belongs to the EF-hand Ca2+ binding superfamily. MLC-2v interacts with the neck/tail region of the muscle thick filament protein myosin to regulate myosin motility and function. # Structure Cardiac, ventricular RLC is an 18.8 kDa protein composed of 166 amino acids. RLC and the second ventricular light chain, essential light chain (ELC, MYL3), are non-covalently bound to IQXXXRGXXXR motifs in the 9 nm S1-S2 lever arm of the myosin head, both alpha (MYH6) and beta (MYH7) isoforms. Both light chains are members of the EF-hand superfamily of proteins, which possess two helix-loop-helix motifs in two globular domains connected by an alpha-helical linker. # Function The N-terminal EF-hand domain of RLC binds calcium/magnesium at activating concentrations, however the dissociation rate is too slow to modulate cardiac contractility on a beat-by-beat basis. Perturbing the calcium binding region of RLC through site-directed mutagenesis (D47A) decreased tension and stiffness in isolated, skinned skeletal muscle fibers, suggesting that the conformational change induced by calcium binding to RLC is functionally important. Another mode of RLC modulation lies in its ability to be modified by phosphorylation and deamidation in the N-terminal region, resulting in significant charge alterations of the protein. RLC is phosphorylated by a cardiac-specific myosin light chain kinase (MYLK3), which was recently cloned. Studies have supported a role for myosin phosphatase targeting subunit 2 (MYPT2,PPP1R12B) in the dephosphorylation of RLC. Human RLC has an Asparagine at position 14 (Threonine in mouse) and a Serine at position 15 (same in mouse). Endogenous RLC exists as a mixture of unmodified (typically ~50%), singly-modified (either N14 deamidation or S15 phosphorylation) and doubly modified (N14 deamidation and S15 phosphorylation) protein. Both deamidation and phosphorylation contribute negative charge to the N-terminal region of RLC, undoubtedly altering its interaction with the C-terminal myosin alpha helical domain. Functional studies have supported a role for RLC phosphorylation in modulating cardiac myosin crossbridge kinetics. It is well established that RLC phosphorylation enhances myofilament sensitivity to calcium in isometrically-contracting, skinned cardiac fibers. It was also demonstrated that a lack of RLC phosphorylation decreases tension cost (isometric force/ATPase rate at a given pCa), suggesting that RLC phosphorylation augments cycling kinetics of myosin. It has been proposed that RLC phosphorylation promotes a "swing-out" of myosin heads, facilitating weak-to-strong crossbridge binding to actin per unit calcium. Additional insights regarding RLC phosphorylation in beating hearts have come from in vivo studies. Adult mice expressing a non-phosphorylatable cardiac RLC (TG-RLC(P-)) exhibited significant decreases in load-dependent and load-independent measures of contractility. In TG-RLC(P-), the time for the heart to reach peak elastance during ejection was elongated, ejection capacity was decreased and the inotropic response to dobutamine was blunted. It is also clear that ablation of RLC phosphorylation in vivo induces alterations in the phosphorylation of other sarcomeric proteins, namely cardiac myosin binding protein C and cardiac troponin I. Moreover, RLC phosphorylation, specifically, appears to be necessary for a normal inotropic response to dobutamine. In agreement with these findings, a second in vivo model, cardiac myosin light chain kinase (MYLK3) knockout (cMLCK neo/neo), showed depressed fractional shortening, progressing to left ventricular hypertrophy by 4–5 months of age. Taken together, these studies clearly demonstrate that RLC phosphorylation regulates cardiac dynamics in beating hearts, and is critical for eliciting a normal sympathetic response. # Expression patterns during cardiac development MLC-2v plays an essential role in early embryonic cardiac development and function. and represents one of the earliest markers of ventricular specification. During early development (E7.5-8.0), MLC-2v is expressed within the cardiac crescent. The expression pattern of MLC-2v becomes restricted to the ventricular segment of the linear heart tube at E8.0 and remains restricted within the ventricle into adulthood. # Phosphorylation sites and regulators Recent studies have highlighted a critical role for MLC2v phosphorylation in cardiac torsion, function and disease. In cardiac muscle, the critical phosphorylation sites have been identified as Ser14/Ser15 in the mouse heart and Ser15 in the human heart. The major kinase responsible for MLC-2v phosphorylation has been identified as cardiac myosin light chain kinase (MLCK), encoded for by Mylk3. Loss of cardiac MLCK in mice results in loss of cardiac MLC-2v phosphorylation and cardiac abnormalities. # Clinical significance Mutations in MYL2 have been associated with familial hypertrophic cardiomyopathy (FHC). Ten FHC mutations have been identified in RLC: E22K, A13T, N47K, P95A, F18L, R58Q, IVS6-1G>C, L103E, IVS5-2A>G, D166V. The first three-E22K, A13T and N47K-have been associated with an unusual mid-ventricular chamber obstruction type of hypertrophy. Three mutations-R58Q, D166V and IVS5-2-are associated with more malignant outcomes, manifesting with sudden cardiac death or at earlier ages. Functional studies demonstrate that FHC mutations in RLC affect its ability to both be phosphorylated and to bind calcium/magnesium. ## Effects on cardiac muscle contraction MLC-2v plays an important role in cross-bridge cycling kinetics and cardiac muscle contraction. MLC-2v phosphorylation at Ser14 and Ser15 increases myosin lever arm stiffness and promotes myosin head diffusion, which altogether slow down myosin kinetics and prolong the duty cycle as a means to fine-tune myofilament Ca2+ sensitivity to force. ## Effects on adult cardiac torsion, function and disease A gradient in the levels of both MLC2v phosphorylation and its kinase, cardiac MLCK, has been shown to exist across the human heart from endocardium (low phosphorylation) to epicardium (high phosphorylation). The existence of this gradient has been proposed to impact cardiac torsion due to the relative spatial orientation of endocardial versus epicardial myofibers. In support of this, recent studies have shown that MLC-2v phosphorylation is critical in regulating left ventricular torsion. Variations in myosin cycling kinetics and contractile properties as a result of differential MLC-2v phosphorylation (Ser14/15) influence both epicardial and endocardial myofiber tension development and recovery to control cardiac torsion and myofiber strain mechanics. A number of human studies have implicated loss of MLC-2v phosphorylation in the pathogenesis of human dilated cardiomyopathy and heart failure. MLC-2v dephosphorylation has also been reported in human patients carrying a rare form of familial hypertrophic cardiomyopathy (FHC) based on specific MLC-2v and MLCK mutations. # Animal studies MLC-2v plays a key role in the regulation of cardiac muscle contraction, through its interactions with myosin. Loss of MLC-2v in mice is associated with ultrastructural defects in sarcomere assembly and results in dilated cardiomyopathy and heart failure with reduced ejection fraction, leading to embryonic lethality at E12.5. More recently, a mutation in zebrafish tell tale heart (telm225) that encodes MLC-2, demonstrated that cardiac MLC-2 is required for thick filament stabilization and contractility in the embryonic zebrafish heart. The role of Myl2 mutations in pathogenesis has been determined through the generation of a number of mouse models. Transgenic mice overexpressing the human MLC-2v R58Q mutation, which is associated with FHC has been shown to lead to a reduction in MLC-2v phosphorylation in hearts. These mice exhibited features of FHC, including diastolic dysfunction that progressed with age. Similarly, cardiac overexpression of another FHC-associated MLC-2v mutation (D166V) results in loss of MLC-2v phosphorylation in mouse hearts. In addition to these findings, MLC-2v dephosphorylation in mice results in cardiac dilatation and dysfunction associated with features reminiscent of dilated cardiomyopathy, leading to heart failure and premature death. Altogether these studies highlight a role for MLC-2v phosphorylation in adult heart function. These studies also suggest that torsion defects might be an early manifestation of dilated cardiomyopathy consequent to loss of MLC-2v phosphorylation. MLC-2v also plays an important role in cardiac stress associated with hypertrophy. In a novel MLC2v Ser14Ala/Ser15Ala knockin mouse model, complete loss of MLC2v (Ser14/Ser15) phosphorylation led to a worsened and differential (eccentric as opposed to concentric) response to pressure overload-induced hypertrophy. In addition, mice lacking cardiac MLCK display heart failure and experience premature death in response to both pressure overload and swimming induced hypertrophy. Consistent with these findings, a cardiac-specific transgenic mouse model overexpressing cardiac MLCK attenuated the response to cardiac hypertrophy induced by pressure overload. Furthermore, in a cardiac-specific transgenic mouse model overexpressing skeletal myosin light chain kinase, the response to cardiac hypertrophy induced by treadmill exercise or isoproterenol was also attenuated. These studies further highlight the therapeutic potential of increasing MLC-2v phosphorylation in settings of cardiac pathological stress. # Notes

MYL2 Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the MYL2 gene.[1][2] This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7).[3] Ventricular myosin light chain-2 (MLC-2v) refers to the ventricular cardiac muscle form of myosin light chain 2 (Myl2). MLC-2v is a 19-KDa protein composed of 166 amino acids, that belongs to the EF-hand Ca2+ binding superfamily.[4] MLC-2v interacts with the neck/tail region of the muscle thick filament protein myosin to regulate myosin motility and function.[5] # Structure Cardiac, ventricular RLC is an 18.8 kDa protein composed of 166 amino acids.[6][7] RLC and the second ventricular light chain, essential light chain (ELC, MYL3), are non-covalently bound to IQXXXRGXXXR motifs in the 9 nm S1-S2 lever arm of the myosin head,[8] both alpha (MYH6) and beta (MYH7) isoforms. Both light chains are members of the EF-hand superfamily of proteins, which possess two helix-loop-helix motifs in two globular domains connected by an alpha-helical linker. # Function The N-terminal EF-hand domain of RLC binds calcium/magnesium at activating concentrations,[9] however the dissociation rate is too slow to modulate cardiac contractility on a beat-by-beat basis.[10] Perturbing the calcium binding region of RLC through site-directed mutagenesis (D47A) decreased tension and stiffness in isolated, skinned skeletal muscle fibers,[11] suggesting that the conformational change induced by calcium binding to RLC is functionally important.[12] Another mode of RLC modulation lies in its ability to be modified by phosphorylation and deamidation in the N-terminal region, resulting in significant charge alterations of the protein. RLC is phosphorylated by a cardiac-specific myosin light chain kinase (MYLK3), which was recently cloned.[13] Studies have supported a role for myosin phosphatase targeting subunit 2 (MYPT2,PPP1R12B) in the dephosphorylation of RLC.[14] Human RLC has an Asparagine at position 14 (Threonine in mouse) and a Serine at position 15 (same in mouse). Endogenous RLC exists as a mixture of unmodified (typically ~50%), singly-modified (either N14 deamidation or S15 phosphorylation) and doubly modified (N14 deamidation and S15 phosphorylation) protein.[3] Both deamidation and phosphorylation contribute negative charge to the N-terminal region of RLC, undoubtedly altering its interaction with the C-terminal myosin alpha helical domain. Functional studies have supported a role for RLC phosphorylation in modulating cardiac myosin crossbridge kinetics. It is well established that RLC phosphorylation enhances myofilament sensitivity to calcium in isometrically-contracting, skinned cardiac fibers.[15][16] It was also demonstrated that a lack of RLC phosphorylation decreases tension cost (isometric force/ATPase rate at a given pCa), suggesting that RLC phosphorylation augments cycling kinetics of myosin.[17] It has been proposed that RLC phosphorylation promotes a "swing-out" of myosin heads, facilitating weak-to-strong crossbridge binding to actin per unit calcium.[18] Additional insights regarding RLC phosphorylation in beating hearts have come from in vivo studies. Adult mice expressing a non-phosphorylatable cardiac RLC (TG-RLC(P-)) exhibited significant decreases in load-dependent[19] and load-independent measures of contractility.[17] In TG-RLC(P-), the time for the heart to reach peak elastance during ejection was elongated, ejection capacity was decreased and the inotropic response to dobutamine was blunted.[17] It is also clear that ablation of RLC phosphorylation in vivo induces alterations in the phosphorylation of other sarcomeric proteins, namely cardiac myosin binding protein C and cardiac troponin I. Moreover, RLC phosphorylation, specifically, appears to be necessary for a normal inotropic response to dobutamine.[17] In agreement with these findings, a second in vivo model, cardiac myosin light chain kinase (MYLK3) knockout (cMLCK neo/neo), showed depressed fractional shortening, progressing to left ventricular hypertrophy by 4–5 months of age.[20] Taken together, these studies clearly demonstrate that RLC phosphorylation regulates cardiac dynamics in beating hearts, and is critical for eliciting a normal sympathetic response. # Expression patterns during cardiac development MLC-2v plays an essential role in early embryonic cardiac development and function.[21] and represents one of the earliest markers of ventricular specification.[22] During early development (E7.5-8.0), MLC-2v is expressed within the cardiac crescent. The expression pattern of MLC-2v becomes restricted to the ventricular segment of the linear heart tube at E8.0 and remains restricted within the ventricle into adulthood.[22][23] # Phosphorylation sites and regulators Recent studies have highlighted a critical role for MLC2v phosphorylation in cardiac torsion, function and disease.[24] In cardiac muscle, the critical phosphorylation sites have been identified as Ser14/Ser15 in the mouse heart and Ser15 in the human heart.[25] The major kinase responsible for MLC-2v phosphorylation has been identified as cardiac myosin light chain kinase (MLCK), encoded for by Mylk3.[25][26] Loss of cardiac MLCK in mice results in loss of cardiac MLC-2v phosphorylation and cardiac abnormalities.[20][27] # Clinical significance Mutations in MYL2 have been associated with familial hypertrophic cardiomyopathy (FHC). Ten FHC mutations have been identified in RLC: E22K, A13T, N47K, P95A, F18L, R58Q, IVS6-1G>C, L103E, IVS5-2A>G, D166V. The first three-E22K, A13T and N47K-have been associated with an unusual mid-ventricular chamber obstruction type of hypertrophy.[28][29] Three mutations-R58Q, D166V and IVS5-2-are associated with more malignant outcomes, manifesting with sudden cardiac death or at earlier ages.[30][31][32][33] Functional studies demonstrate that FHC mutations in RLC affect its ability to both be phosphorylated and to bind calcium/magnesium.[34] ## Effects on cardiac muscle contraction MLC-2v plays an important role in cross-bridge cycling kinetics and cardiac muscle contraction.[35] MLC-2v phosphorylation at Ser14 and Ser15 increases myosin lever arm stiffness and promotes myosin head diffusion, which altogether slow down myosin kinetics and prolong the duty cycle as a means to fine-tune myofilament Ca2+ sensitivity to force.[35] ## Effects on adult cardiac torsion, function and disease A gradient in the levels of both MLC2v phosphorylation and its kinase, cardiac MLCK, has been shown to exist across the human heart from endocardium (low phosphorylation) to epicardium (high phosphorylation).[36] The existence of this gradient has been proposed to impact cardiac torsion due to the relative spatial orientation of endocardial versus epicardial myofibers.[36] In support of this, recent studies have shown that MLC-2v phosphorylation is critical in regulating left ventricular torsion.[27][35] Variations in myosin cycling kinetics and contractile properties as a result of differential MLC-2v phosphorylation (Ser14/15) influence both epicardial and endocardial myofiber tension development and recovery to control cardiac torsion and myofiber strain mechanics.[27][35] A number of human studies have implicated loss of MLC-2v phosphorylation in the pathogenesis of human dilated cardiomyopathy and heart failure.[25][37][38][39][40] MLC-2v dephosphorylation has also been reported in human patients carrying a rare form of familial hypertrophic cardiomyopathy (FHC) based on specific MLC-2v and MLCK mutations.[12][36][41] # Animal studies MLC-2v plays a key role in the regulation of cardiac muscle contraction, through its interactions with myosin.[24] Loss of MLC-2v in mice is associated with ultrastructural defects in sarcomere assembly and results in dilated cardiomyopathy and heart failure with reduced ejection fraction, leading to embryonic lethality at E12.5.[21] More recently, a mutation in zebrafish tell tale heart (telm225) that encodes MLC-2, demonstrated that cardiac MLC-2 is required for thick filament stabilization and contractility in the embryonic zebrafish heart.[42] The role of Myl2 mutations in pathogenesis has been determined through the generation of a number of mouse models.[35][43][44] Transgenic mice overexpressing the human MLC-2v R58Q mutation, which is associated with FHC has been shown to lead to a reduction in MLC-2v phosphorylation in hearts.[43] These mice exhibited features of FHC, including diastolic dysfunction that progressed with age.[43] Similarly, cardiac overexpression of another FHC-associated MLC-2v mutation (D166V) results in loss of MLC-2v phosphorylation in mouse hearts.[44] In addition to these findings, MLC-2v dephosphorylation in mice results in cardiac dilatation and dysfunction associated with features reminiscent of dilated cardiomyopathy, leading to heart failure and premature death.[14][27][35] Altogether these studies highlight a role for MLC-2v phosphorylation in adult heart function. These studies also suggest that torsion defects might be an early manifestation of dilated cardiomyopathy consequent to loss of MLC-2v phosphorylation.[35] MLC-2v also plays an important role in cardiac stress associated with hypertrophy.[27][35] In a novel MLC2v Ser14Ala/Ser15Ala knockin mouse model, complete loss of MLC2v (Ser14/Ser15) phosphorylation led to a worsened and differential (eccentric as opposed to concentric) response to pressure overload-induced hypertrophy.[35] In addition, mice lacking cardiac MLCK display heart failure and experience premature death in response to both pressure overload and swimming induced hypertrophy.[27] Consistent with these findings, a cardiac-specific transgenic mouse model overexpressing cardiac MLCK attenuated the response to cardiac hypertrophy induced by pressure overload.[27] Furthermore, in a cardiac-specific transgenic mouse model overexpressing skeletal myosin light chain kinase, the response to cardiac hypertrophy induced by treadmill exercise or isoproterenol was also attenuated.[45] These studies further highlight the therapeutic potential of increasing MLC-2v phosphorylation in settings of cardiac pathological stress. # Notes

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ad5b2a58cabd0575d4f39b16e6ca3dd1a7e61927

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MYL3

MYL3 Myosin essential light chain (ELC), ventricular/cardiac isoform is a protein that in humans is encoded by the MYL3 gene. This cardiac ventricular/slow skeletal ELC isoform is distinct from that expressed in fast skeletal muscle (MYL1) and cardiac atrial muscle (MYL4). Ventricular ELC is part of the myosin molecule and is important in modulating cardiac muscle contraction. # Structure Cardiac, ventricular ELC is 21.9 kDa and composed of 195 amino acids (See human MYL3 sequences features here). Cardiac ELC and the second light chain, regulatory light chain (RLC, MYL2), are non-covalently bound to IQXXXRGXXXR motifs in the 9 nm S1-S2 lever arm of the myosin head, both alpha (MYH6) and beta (MYH7) isoforms. Both light chains are members of the EF-hand superfamily of proteins, which possess helix-loop-helix motifs in two globular domains connected by an alpha-helical linker. Though EF hand motifs are specialized to bind divalent ions such as calcium, cardiac ELC does not bind calcium at physiological levels. The N-terminal region of cardiac ELC is functionlly unique in that it is positively charged, being rich in Lysine residues (amino acids 4-14), with subsequent unique structure governed by Proline-Alanine repeats (amino acids 15-36). # Function Studies have provided evidence for ELC as modulator of myosin crossbrige kinetics. Treating cardiac myofibrils with the Lysine-rich N-terminal peptide (amino acids 5-14) evoked a supramaximal increase in cardiac myofibrillar MgATPase activity at submaximal calcium concentrations, and further studies demonstrated that this region of ELC modulates the affinity of myosin for actin. # Clinical significance Mutations in MYL3 have been identified as a cause of familial hypertrophic cardiomyopathy, and associated with a mid-left ventricular chamber type hypertrophy. Five mutations in MYL3 have been identified to date: M149V, R154H, E56G, A57G and E143K. All of these cluster around two of the four EF-hand domains, suggesting that proper conformation in these regions is necessary for normal cardiac function.

MYL3 Myosin essential light chain (ELC), ventricular/cardiac isoform is a protein that in humans is encoded by the MYL3 gene.[1][2][3] This cardiac ventricular/slow skeletal ELC isoform is distinct from that expressed in fast skeletal muscle (MYL1) and cardiac atrial muscle (MYL4). Ventricular ELC is part of the myosin molecule and is important in modulating cardiac muscle contraction. # Structure Cardiac, ventricular ELC is 21.9 kDa and composed of 195 amino acids (See human MYL3 sequences features here). Cardiac ELC and the second light chain, regulatory light chain (RLC, MYL2), are non-covalently bound to IQXXXRGXXXR motifs in the 9 nm S1-S2 lever arm of the myosin head,[4] both alpha (MYH6) and beta (MYH7) isoforms. Both light chains are members of the EF-hand superfamily of proteins, which possess helix-loop-helix motifs in two globular domains connected by an alpha-helical linker. Though EF hand motifs are specialized to bind divalent ions such as calcium, cardiac ELC does not bind calcium at physiological levels.[5] The N-terminal region of cardiac ELC is functionlly unique in that it is positively charged, being rich in Lysine residues (amino acids 4-14), with subsequent unique structure governed by Proline-Alanine repeats (amino acids 15-36). # Function Studies have provided evidence for ELC as modulator of myosin crossbrige kinetics. Treating cardiac myofibrils with the Lysine-rich N-terminal peptide (amino acids 5-14) evoked a supramaximal increase in cardiac myofibrillar MgATPase activity at submaximal calcium concentrations,[6] and further studies demonstrated that this region of ELC modulates the affinity of myosin for actin.[7] # Clinical significance Mutations in MYL3 have been identified as a cause of familial hypertrophic cardiomyopathy, and associated with a mid-left ventricular chamber type hypertrophy.[8] Five mutations in MYL3 have been identified to date: M149V, R154H, E56G, A57G and E143K.[9][10][11][12] All of these cluster around two of the four EF-hand domains, suggesting that proper conformation in these regions is necessary for normal cardiac function.[8]

https://www.wikidoc.org/index.php/MYL3

9b064745a28603c714893511eedc0187e2798325

wikidoc

MYL4

MYL4 Atrial Light Chain-1 (ALC-1), also known as Essential Light Chain, Atrial is a protein that in humans is encoded by the MYL4 gene. ALC-1 is expressed in fetal cardiac ventricular and fetal skeletal muscle, as well as fetal and adult cardiac atrial tissue. ALC-1 expression is reactivated in human ventricular myocardium in various cardiac muscle diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy and congenital heart diseases. # Structure ALC-1 is a 21.6 kDa protein composed of 197 amino acids. ALC-1 is expressed in fetal cardiac ventricular and fetal skeletal muscle, as well as fetal and adult cardiac atrial tissue. ALC-1 binds the neck region of muscle myosin in adult atria. Two alternatively spliced transcript variants encoding the same protein have been found for this gene. Relative to ventricular essential light chain VLC-1, ALC-1 has an additional ~40 amino-acid N-terminal region that contains four to eleven residues that are critical for binding actin and modulating myosin kinetics. # Function ALC-1 is expressed very early in skeletal muscle and cardiac muscle development; two E-boxes and CArG box in the MYL4 promoter region regulate transcription. ALC-1 expression in cardiac ventricles decreases in early postnatal development, but is highly expressed in atria throughout all of adulthood. Normal atrial function is essential for embryogenesis, as inactivation of the MYL7 gene was embryonic lethal at ED10.5-11.5. Evidence of ALC-1 isoform expression on contractile mechanics of sarcomeres came from experiments studying fibers from patients expressing a higher level of ALC-1 relative to VLC-1 in cardiac left ventricular tissue. Fibers expressing high ALC-1 exhibited a higher maximal velocity and rate of shortening compared to fibers with low amounts of ALC-1, suggesting that ALC-1 increases cycling kinetics of myosin cross-bridges and regulates cardiac contractility. Further biochemical studies unveiled a weaker binding of the Alanine-Proline-rich N-terminus of ALC-1 to the C-terminus of actin relative to VLC-1, which may explain the mechanism underlying the differences in cycling kinetics. The importance of this region has however raised skepticism. Further evidence for the contractile-enhancing properties of ALC-1 came from studies employing transgenesis to replace VLC-1 with ALC-1 in the mouse ventricle. This study demonstrated an increase in unloaded shortening velocity, both in skinned fibers and in an in vitro motility assay, as well as enhanced contractility and relaxation in whole heart experiments. These studies were supported by further studies in transgenic rats overexpressing ALC-1 which showed enhanced rates of contraction and relaxation, as well as left ventricular developed pressure in Langendorff heart preparations. Importantly, overexpression of ALC-1 was shown to attenuate heart failure in pressure-overloaded animals, by enhancing left ventricular developed pressure, maximal velocity of pressure development and relaxation. # Clinical significance MYL4 expression in ventricular myocardium has shown to abnormally persist in neonates up through adulthood in patients with the congenital heart disease, tetralogy of Fallot. Altered ALC-1 expression is also altered in other congenital heart diseases, Double outlet right ventricle and infundibular pulmonary stenosis. Moreover, in patients with aortic stenosis or aortic insufficiency, ALC-1 expression in left ventricles was elevated, and following valve replacement decreased to lower levels; ALC-1 expression also correlated with left ventricular systolic pressure. Additionally, in patients with ischemic cardiomyopathy, dilated cardiomyopathy and hypertrophic cardiomyopathy, ALC-1 protein expression is shown to be reactivated, and ALC-1 expression correlates with calcium sensitivity of myofilament proteins in skinned fiber preparations, as well as ventricular dP/dtmax and ejection fraction. # Interactions ALC-1 interacts with: - ACTC1 - MYH7

MYL4 Atrial Light Chain-1 (ALC-1), also known as Essential Light Chain, Atrial is a protein that in humans is encoded by the MYL4 gene.[1][2] ALC-1 is expressed in fetal cardiac ventricular and fetal skeletal muscle, as well as fetal and adult cardiac atrial tissue. ALC-1 expression is reactivated in human ventricular myocardium in various cardiac muscle diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy and congenital heart diseases. # Structure ALC-1 is a 21.6 kDa protein composed of 197 amino acids.[3] ALC-1 is expressed in fetal cardiac ventricular and fetal skeletal muscle, as well as fetal and adult cardiac atrial tissue.[1] ALC-1 binds the neck region of muscle myosin in adult atria. Two alternatively spliced transcript variants encoding the same protein have been found for this gene.[4] Relative to ventricular essential light chain VLC-1, ALC-1 has an additional ~40 amino-acid N-terminal region that contains four to eleven residues that are critical for binding actin and modulating myosin kinetics.[5][6] # Function ALC-1 is expressed very early in skeletal muscle and cardiac muscle development; two E-boxes and CArG box in the MYL4 promoter region regulate transcription.[7] ALC-1 expression in cardiac ventricles decreases in early postnatal development, but is highly expressed in atria throughout all of adulthood.[8][9] Normal atrial function is essential for embryogenesis, as inactivation of the MYL7 gene was embryonic lethal at ED10.5-11.5.[10] Evidence of ALC-1 isoform expression on contractile mechanics of sarcomeres came from experiments studying fibers from patients expressing a higher level of ALC-1 relative to VLC-1 in cardiac left ventricular tissue. Fibers expressing high ALC-1 exhibited a higher maximal velocity and rate of shortening compared to fibers with low amounts of ALC-1, suggesting that ALC-1 increases cycling kinetics of myosin cross-bridges and regulates cardiac contractility.[11] Further biochemical studies unveiled a weaker binding of the Alanine-Proline-rich N-terminus of ALC-1[5] to the C-terminus of actin relative to VLC-1, which may explain the mechanism underlying the differences in cycling kinetics.[12][13] The importance of this region has however raised skepticism.[14] Further evidence for the contractile-enhancing properties of ALC-1 came from studies employing transgenesis to replace VLC-1 with ALC-1 in the mouse ventricle. This study demonstrated an increase in unloaded shortening velocity, both in skinned fibers and in an in vitro motility assay, as well as enhanced contractility and relaxation in whole heart experiments.[15] These studies were supported by further studies in transgenic rats overexpressing ALC-1 which showed enhanced rates of contraction and relaxation, as well as left ventricular developed pressure in Langendorff heart preparations.[16] Importantly, overexpression of ALC-1 was shown to attenuate heart failure in pressure-overloaded animals, by enhancing left ventricular developed pressure, maximal velocity of pressure development and relaxation.[17] # Clinical significance MYL4 expression in ventricular myocardium has shown to abnormally persist in neonates up through adulthood in patients with the congenital heart disease, tetralogy of Fallot.[8] Altered ALC-1 expression is also altered in other congenital heart diseases, Double outlet right ventricle and infundibular pulmonary stenosis.[11] Moreover, in patients with aortic stenosis or aortic insufficiency, ALC-1 expression in left ventricles was elevated, and following valve replacement decreased to lower levels; ALC-1 expression also correlated with left ventricular systolic pressure.[18] Additionally, in patients with ischemic cardiomyopathy, dilated cardiomyopathy and hypertrophic cardiomyopathy, ALC-1 protein expression is shown to be reactivated, and ALC-1 expression correlates with calcium sensitivity of myofilament proteins in skinned fiber preparations, as well as ventricular dP/dtmax and ejection fraction.[19][20][21][22][23] # Interactions ALC-1 interacts with: - ACTC1[5][6][13] - MYH7[24][25][26]

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8ecb28300bb44263b19c5f63b36dec1cfb2492f6

wikidoc

MYL7

MYL7 Atrial Light Chain-2 (ALC-2) also known as Myosin regulatory light chain 2, atrial isoform (MLC2a) is a protein that in humans is encoded by the MYL7 gene. ALC-2 expression is restricted to cardiac muscle atria in healthy individuals, where it functions to modulate cardiac development and contractility. In human diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy and others, ALC-2 expression is altered. # Structure Human ALC-2 protein has a molecular weight of 19.4 kDa and is composed of 175 amino acids. ALC-2 is an EF hand protein that binds to the neck region of alpha myosin heavy chain. ALC-2 and the ventricular isoform, VLC-2, share 59% homology, showing significant differences at their N-termini and at the regulatory phosphorylation site(s), Serine-15 and Serine/Asparagine-14. # Function ALC-2 expression has proven to be a useful marker of cardiac muscle chamber distinction, development and differentiation. ALC-2 shows a pattern distinct from atrial essential light chain (ALC-1) during cardiogenesis. ALC-2 expression in adult murine hearts is cardiac-specific throughout embryonic days 8-16, and from day 12 and on is restricted to atria, showing very low levels in aorta and undetectable in ventricles, skeletal muscle, uterus, and liver. This atrial patterning occurs prior to septation. Expression of ALC-2 has been shown to correlate with expression of alpha-myosin heavy chain in cardiac atria of non-human primates. ALC-2 and VLC-2 appear to function in the stabilization of thick filaments and regulation of contractility in the vertebrate heart. Functional insights into ALC-2 function have come from studies employing transgenesis. A study in which the ventricular isoform of regulatory light chain was overexpressed to replace the ALC-2 in cardiac atria was performed. This substitution resulted in atrial myocytes that contract and relax more forcefully and quickly, resulting in atrial cardiomyocytes that behave as ventricular cardiomyocytes. In disease models, ALC-2 expression in some instances can be downregulated and replaced by the ventricular isoform (VLC-2). In spontaneously hypertensive rats, VLC-2 mRNA expression is three times higher in atria; and this change precedes any detectable pressure overloading of the heart, suggesting that this change is a very early functional adaptation to cardiac hypertrophy. Moreover, in a porcine model of atrial fibrillation, VLC-2 mRNA expression showed the greatest change, being upregulated 9.4-fold and 7.3-fold in left and right atria, respectively. In a porcine model of left atrial remodeling following mitral regurgitation, VLC-2 was shown to be upregulated. Human ALC-2 is phosphorylated at its N-terminus at Serine-15 by a cardiac-specific myosin light chain kinase; ALC-2 has a serine at position 14, which is an Asparagine in the ventricular isoform that is shown to be deamidated (thus producing a negative charge similar to phosphorylation). Whether serine-14 of human ALC-2 is also phosphorylated remains to be determined. Endogenous phosphorylation level is around 30% of the total ALC-2. Alpha(1)-adrenergic stimulation by phenylephrine in atrial muscle strips showed an 80% increase in ALC-2 phosphorylation coordinate with enhanced contractile force, which was inhibited by both Rho kinase and myosin light chain kinase inhibition. In a canine model of atrial fibrillation, decreased atrial contractility was associated with decreased ALC-2 and myosin binding protein C phosphorylation. Moreover, the slow force response induced by stretch in human atrial muscle was shown to be modulated by enhanced phosphorylation of ALC-2 by myosin light chain kinase. # Clinical Significance Patients with hypertrophic cardiomyopathy shown an increased expression of ALC-2 in whole heart tissue. In patients with mitral valve disease, ischemic cardiomyopathy, dilated cardiomyopathy, coronary heart disease and pressure overload-induced cardiac hypertrophy, ALC-2 was shown to be replaced with VLC-2 in cardiac atria; in dilated cardiomyopathy, this change was concomitant with enhanced sensitivity of atrial fibers to calcium. In patients with congenital atrial septal defect carrying a missense mutation Ile820Asn in alpha myosin heavy chain, it was shown that binding of ALC-2 to alpha myosin heavy chain is disrupted. # Interactions ALC-2 is shown to interact with: - MYH6

MYL7 Atrial Light Chain-2 (ALC-2) also known as Myosin regulatory light chain 2, atrial isoform (MLC2a) is a protein that in humans is encoded by the MYL7 gene.[1][2] ALC-2 expression is restricted to cardiac muscle atria in healthy individuals, where it functions to modulate cardiac development and contractility. In human diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy and others, ALC-2 expression is altered. # Structure Human ALC-2 protein has a molecular weight of 19.4 kDa and is composed of 175 amino acids.[3] ALC-2 is an EF hand protein that binds to the neck region of alpha myosin heavy chain.[4] ALC-2 and the ventricular isoform, VLC-2, share 59% homology, showing significant differences at their N-termini and at the regulatory phosphorylation site(s), Serine-15 and Serine/Asparagine-14.[5] # Function ALC-2 expression has proven to be a useful marker of cardiac muscle chamber distinction, development and differentiation.[6][7][8][9][10] ALC-2 shows a pattern distinct from atrial essential light chain (ALC-1) during cardiogenesis. ALC-2 expression in adult murine hearts is cardiac-specific throughout embryonic days 8-16, and from day 12 and on is restricted to atria, showing very low levels in aorta and undetectable in ventricles, skeletal muscle, uterus, and liver. This atrial patterning occurs prior to septation.[11] Expression of ALC-2 has been shown to correlate with expression of alpha-myosin heavy chain in cardiac atria of non-human primates.[12] ALC-2 and VLC-2 appear to function in the stabilization of thick filaments and regulation of contractility in the vertebrate heart.[13] Functional insights into ALC-2 function have come from studies employing transgenesis. A study in which the ventricular isoform of regulatory light chain was overexpressed to replace the ALC-2 in cardiac atria was performed. This substitution resulted in atrial myocytes that contract and relax more forcefully and quickly, resulting in atrial cardiomyocytes that behave as ventricular cardiomyocytes.[14] In disease models, ALC-2 expression in some instances can be downregulated and replaced by the ventricular isoform (VLC-2). In spontaneously hypertensive rats, VLC-2 mRNA expression is three times higher in atria; and this change precedes any detectable pressure overloading of the heart, suggesting that this change is a very early functional adaptation to cardiac hypertrophy.[15] Moreover, in a porcine model of atrial fibrillation, VLC-2 mRNA expression showed the greatest change, being upregulated 9.4-fold and 7.3-fold in left and right atria, respectively.[16] In a porcine model of left atrial remodeling following mitral regurgitation, VLC-2 was shown to be upregulated.[17] Human ALC-2 is phosphorylated at its N-terminus at Serine-15 by a cardiac-specific myosin light chain kinase;[18][19] ALC-2 has a serine at position 14, which is an Asparagine in the ventricular isoform that is shown to be deamidated (thus producing a negative charge similar to phosphorylation). Whether serine-14 of human ALC-2 is also phosphorylated remains to be determined. Endogenous phosphorylation level is around 30% of the total ALC-2.[20] Alpha(1)-adrenergic stimulation by phenylephrine in atrial muscle strips showed an 80% increase in ALC-2 phosphorylation coordinate with enhanced contractile force, which was inhibited by both Rho kinase and myosin light chain kinase inhibition.[21] In a canine model of atrial fibrillation, decreased atrial contractility was associated with decreased ALC-2 and myosin binding protein C phosphorylation.[22] Moreover, the slow force response induced by stretch in human atrial muscle was shown to be modulated by enhanced phosphorylation of ALC-2 by myosin light chain kinase.[23] # Clinical Significance Patients with hypertrophic cardiomyopathy shown an increased expression of ALC-2 in whole heart tissue.[24] In patients with mitral valve disease, ischemic cardiomyopathy, dilated cardiomyopathy, coronary heart disease and pressure overload-induced cardiac hypertrophy, ALC-2 was shown to be replaced with VLC-2 in cardiac atria; in dilated cardiomyopathy, this change was concomitant with enhanced sensitivity of atrial fibers to calcium.[25][26] In patients with congenital atrial septal defect carrying a missense mutation Ile820Asn in alpha myosin heavy chain, it was shown that binding of ALC-2 to alpha myosin heavy chain is disrupted.[27] # Interactions ALC-2 is shown to interact with: - MYH6[4][27]

https://www.wikidoc.org/index.php/MYL7

9e579eaf1f9109eb9c156e1ec7c66e24718f09e5

wikidoc

MYOT

MYOT Myotilin is a protein that in humans is encoded by the MYOT gene. Myotilin (myofibrillar titin-like protein) also known as TTID (TiTin Immunoglobulin Domain) is a muscle protein that is found within the Z-disc of sarcomeres. # Structure Myotilin is a 55.3 kDa protein composed of 496 amino acids. Myotilin was originally identified as a novel alpha-actinin binding partner with two Ig-like domains, that localized to the Z-disc. The C2-type Ig-like domains reside at the C-terminal half, and are most homologous to Ig domains 2-3 of palladin and Ig domains 4-5 of myopalladin and more distantly related to Z-disc Ig domains 7 and 8 of titin. The C-terminal region hosts the binding sites for Z-band proteins, and 2 Ig domains are the site of homodimerization for myotilin. By contrast, the N-terminal part of myotilin is unique, consisting of a serine-rich region with no homology to known proteins. Several disease-associated mutations involve serine residues within the serine-rich domain. Myotilin expression in human tissues is mainly restricted to striated muscles and nerves. In muscles, myotilin is predominantly found within the Z-discs. Myotilin forms homodimers and binds alpha-actinin, actin, Filamin C, FATZ-1, FATZ-2 and ZASP. # Function Myotilin is a structural protein that, along with titin and alpha-actinin give structural integrity to sarcomeres at Z-discs in striated muscle. Myotilin induces the formation of actin bundles in vitro and in non-muscle cells. A ternary complex myotilin/actin/alpha-actinin can be observed in vitro and actin bundles formed under these conditions appear more tightly packed than those induced by alpha-actinin alone. It was demonstrated that myotilin stabilizes F-actin by slowing down the disassembly rate. Ectopic overexpression of truncated myotilin causes the disruption of nascent myofibrils and the co-accumulation of myotilin and titin in amorphous cytoplasmic precipitates. In mature sarcomeres, wild-type myotilin colocalizes with alpha-actinin and Z-disc titin, showing the striated pattern typical of sarcomeric proteins. Targeted disruption of the myotilin gene in mice does not cause significant alterations in muscle function. On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy. # Clinical significance Myotilin is mutated in various forms of muscular dystrophy: Limb-Girdle Muscular Dystrophy type 1A (LGMD1A), Myofibrillar Myopathy (MFM), Spheroid Body Myopathy and Distal Myopath. The mechanism underlying the pathology is still under investigation. It has been shown that actin binding properties of myotilin housing pathogenic mutations (Ser55Phe, Thr57Ile, Ser60Cys, and Ser95Ile) are normal, albeit with a slower rate of degradation. Surprisingly, YFP-fusion constructs of myotilin mutants (Ser55Phe, Ser55Ile, Thr57Ile, Ser60Cys, Ser60Phe, Ser95Ile, Arg405Lys) localized normally to Z-discs and exhibited normal dynamics in muscle cells.

MYOT Myotilin is a protein that in humans is encoded by the MYOT gene.[1][2][3] Myotilin (myofibrillar titin-like protein) also known as TTID (TiTin Immunoglobulin Domain) is a muscle protein that is found within the Z-disc of sarcomeres. # Structure Myotilin is a 55.3 kDa protein composed of 496 amino acids.[4] Myotilin was originally identified as a novel alpha-actinin binding partner with two Ig-like domains, that localized to the Z-disc.[5] The C2-type Ig-like domains reside at the C-terminal half, and are most homologous to Ig domains 2-3 of palladin and Ig domains 4-5 of myopalladin and more distantly related to Z-disc Ig domains 7 and 8 of titin. The C-terminal region hosts the binding sites for Z-band proteins, and 2 Ig domains are the site of homodimerization for myotilin.[6] By contrast, the N-terminal part of myotilin is unique, consisting of a serine-rich region with no homology to known proteins. Several disease-associated mutations involve serine residues within the serine-rich domain.[7] Myotilin expression in human tissues is mainly restricted to striated muscles and nerves. In muscles, myotilin is predominantly found within the Z-discs. Myotilin forms homodimers and binds alpha-actinin, actin,[8] Filamin C,[9] FATZ-1,[10] FATZ-2 [10] and ZASP.[11] # Function Myotilin is a structural protein that, along with titin and alpha-actinin give structural integrity to sarcomeres at Z-discs in striated muscle. Myotilin induces the formation of actin bundles in vitro and in non-muscle cells. A ternary complex myotilin/actin/alpha-actinin can be observed in vitro and actin bundles formed under these conditions appear more tightly packed than those induced by alpha-actinin alone. It was demonstrated that myotilin stabilizes F-actin by slowing down the disassembly rate. Ectopic overexpression of truncated myotilin causes the disruption of nascent myofibrils and the co-accumulation of myotilin and titin in amorphous cytoplasmic precipitates. In mature sarcomeres, wild-type myotilin colocalizes with alpha-actinin and Z-disc titin, showing the striated pattern typical of sarcomeric proteins. Targeted disruption of the myotilin gene in mice does not cause significant alterations in muscle function.[12] On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy.[13] # Clinical significance Myotilin is mutated in various forms of muscular dystrophy: Limb-Girdle Muscular Dystrophy type 1A (LGMD1A), Myofibrillar Myopathy (MFM), Spheroid Body Myopathy and Distal Myopath.[7] The mechanism underlying the pathology is still under investigation. It has been shown that actin binding properties of myotilin housing pathogenic mutations (Ser55Phe, Thr57Ile, Ser60Cys, and Ser95Ile) are normal,[14] albeit with a slower rate of degradation.[15] Surprisingly, YFP-fusion constructs of myotilin mutants (Ser55Phe, Ser55Ile, Thr57Ile, Ser60Cys, Ser60Phe, Ser95Ile, Arg405Lys) localized normally to Z-discs and exhibited normal dynamics in muscle cells.[16]

https://www.wikidoc.org/index.php/MYOT

b3ea4867c99ab1ea3622607f339ad8d7e0310c55

wikidoc

MYPN

MYPN Myopalladin is a protein that in humans is encoded by the MYPN gene. Myopalladin is a muscle protein responsible for tethering proteins at the Z-disc and for communicating between the sarcomere and the nucleus in cardiac and skeletal muscle # Structure Myopalladin is a 145.2 kDa protein composed of 1320 amino acids. Myopalladin has five Ig-like repeats within the protein, and a proline-rich domain. Myopalladin binds the Src homology domain of nebulette and nebulin and tethers it to alpha-actinin via its C-terminal domain binding to the EF hand domains of alpha-actinin. The N-terminal region of myopalladin binds to the nuclear protein CARP, known to regulate gene expression in muscle. It also has been shown to bind ANKRD23. # Function Myopalladin has dual subcellular localization, residing in both the nucleus and sarcomere/I-bands in muscle. Accordingly, myopalladin has functions in both sarcomere assembly and in control of gene expression. Specifics of these functions were gleaned from studies involving MYPN mutants associated with various cardiomyopathies. The Q529X myopalladin mutant demonstrated incompetence in recruiting key binding partners such as desmin, alpha-actinin and CARP to the Z-disc during myofibrilogenesis. In contrast, the Y20C mutant resulted in decreased expression of binding partners. # Clinical significance Mutations in MYPN have been linked to dilated cardiomyopathy, hypertrophic cardiomyopathy and restrictive cardiomyopathy.

MYPN Myopalladin is a protein that in humans is encoded by the MYPN gene. Myopalladin is a muscle protein responsible for tethering proteins at the Z-disc and for communicating between the sarcomere and the nucleus in cardiac and skeletal muscle[1][2][3] # Structure Myopalladin is a 145.2 kDa protein composed of 1320 amino acids.[4][5] Myopalladin has five Ig-like repeats within the protein, and a proline-rich domain. Myopalladin binds the Src homology domain of nebulette and nebulin and tethers it to alpha-actinin via its C-terminal domain binding to the EF hand domains of alpha-actinin. The N-terminal region of myopalladin binds to the nuclear protein CARP, known to regulate gene expression in muscle.[1] It also has been shown to bind ANKRD23.[6] # Function Myopalladin has dual subcellular localization, residing in both the nucleus and sarcomere/I-bands in muscle. Accordingly, myopalladin has functions in both sarcomere assembly and in control of gene expression.[1] Specifics of these functions were gleaned from studies involving MYPN mutants associated with various cardiomyopathies. The Q529X myopalladin mutant demonstrated incompetence in recruiting key binding partners such as desmin, alpha-actinin and CARP to the Z-disc during myofibrilogenesis. In contrast, the Y20C mutant resulted in decreased expression of binding partners.[7] # Clinical significance Mutations in MYPN have been linked to dilated cardiomyopathy, hypertrophic cardiomyopathy and restrictive cardiomyopathy.[7][8]

https://www.wikidoc.org/index.php/MYPN

2d710737be9db686849b5162cc5c864912abfe79

wikidoc

MYT1

MYT1 Myelin transcription factor 1 is a protein that in humans is encoded by the MYT1 gene. # Function The protein encoded by this gene is a member of a family of neural specific, zinc finger-containing DNA-binding proteins. The protein binds to the promoter regions of proteolipid proteins of the central nervous system and plays a role in the developing nervous system. # Interactive pathway map Click on genes, proteins and metabolites below to visit related articles. - ↑ The interactive pathway map can be edited at WikiPathways: "WP3584"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} # Interactions MYT1 has been shown to interact with PIN1.

MYT1 Myelin transcription factor 1 is a protein that in humans is encoded by the MYT1 gene.[1][2][3] # Function The protein encoded by this gene is a member of a family of neural specific, zinc finger-containing DNA-binding proteins. The protein binds to the promoter regions of proteolipid proteins of the central nervous system and plays a role in the developing nervous system.[3] # Interactive pathway map Click on genes, proteins and metabolites below to visit related articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "WP3584"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} # Interactions MYT1 has been shown to interact with PIN1.[4]

https://www.wikidoc.org/index.php/MYT1

a75264a42edc11f7d505330ba334458cdb8cbdc6

wikidoc

Male

Male # Overview Male (♂) refers to the sex of an organism, or part of an organism, which produces small mobile gametes, called spermatozoa. Each spermatozoon can fuse with a larger female gamete or ovum, in the process of fertilisation. A male cannot reproduce sexually without access to at least one ovum from a female, but some organisms can reproduce both sexually and asexually. Not all species share a common sex-determination system. In humans and most animals, sex is determined genetically but in other species it can be determined due to social, environmental, or other factors. The existence of two sexes seems to have been selected independently across different evolutionary lineages (see Convergent Evolution). Accordingly, sex is defined operationally across species by the type of gametes produced (ie: spermatozoa vs. ova) and differences between males and females in one lineage are not always predictive of differences in another. Male/Female dimorphism between organisms or reproductive organs of different sexes is not limited to animals; male gametes are produced by chytrids, diatoms and land plants, among others. In land plants, female and male designate not only the female and male gamete-producing organisms and structures but also the structures of the sporophytes that give rise to male and female plants. Female being the more dominant species, female gametes override any male gamete present. # Secondary sex characteristics In those species with two sexes, males may differ from females in ways other than production of spermatozoa. Males are generally smaller than females in seed plants (the pollen grain is the male plant) and many fishes and birds, but larger in many mammals, including humans. In birds, the male often exhibits a colourful plumage that attracts females. # Sex determination The sex of a particular organism may be determined by a number of factors. These may be genetic or environmental, or may naturally change during the course of an organism's life. Although most species with male and female sexes have individuals that are either male or female, hermaphroditic animals have both male and female reproductive organs. ## Genetic determination Most mammals, including humans, are genetically determined as such by the XY sex-determination system where males have an XY (as opposed to XX) sex chromosome. During reproduction, a male can give either an X sperm or a Y sperm, while a female can only give an X egg. A Y sperm and an X egg produce a boy, while an X sperm and an X egg produce a girl. The ZW sex-determination system, where males have a ZZ (as opposed to ZW) sex chromosome may be found in birds and some insects (mostly butterflies and moths) and other organisms. Members of Hymenoptera, such as ants and bees, are determined by haplodiploidy, where most males are haploid and females and some sterile males are diploid. ## Environmental determination In some species of reptiles, including alligators, sex is determined by the temperature at which the egg is incubated. Other species, such as some snails, practise sex change: adults start out male, then become female. In tropical clown fish, the dominant individual in a group becomes female while the other ones are male. In some arthropods, sex is determined by infection. Bacteria of the genus Wolbachia alter their sexuality; some species consist entirely of ZZ individuals, with sex determined by the presence of Wolbachia. # Anatomy All males, regardless of independent origin, kingdom, or other phylogenetic subdivision, share at least the anatomy to produce male gametes. Some have sophisticated organs and organ systems designed to produce, dispense, and deliver the gamete to a location suitable for ovum fertilisation. Even where structures and cell types have arisen independently, "sperm" is ordinarily used to refer to the male gamete. Among animals that undergo internal fertilization, "penis" is often used to refer to an organ inserted into the female for insemination. # Symbols A common symbol used to represent the male gender is the Mars symbol, ♂ (Unicode: U+2642 Alt codes: Alt+11)—a circle with an arrow pointing northeast. This is a stylized representation of the Roman god Mars' shield and spear.

Male Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Male (♂) refers to the sex of an organism, or part of an organism, which produces small mobile gametes, called spermatozoa. Each spermatozoon can fuse with a larger female gamete or ovum, in the process of fertilisation. A male cannot reproduce sexually without access to at least one ovum from a female, but some organisms can reproduce both sexually and asexually. Not all species share a common sex-determination system. In humans and most animals, sex is determined genetically but in other species it can be determined due to social, environmental, or other factors. The existence of two sexes seems to have been selected independently across different evolutionary lineages (see Convergent Evolution). Accordingly, sex is defined operationally across species by the type of gametes produced (ie: spermatozoa vs. ova) and differences between males and females in one lineage are not always predictive of differences in another. Male/Female dimorphism between organisms or reproductive organs of different sexes is not limited to animals; male gametes are produced by chytrids, diatoms and land plants, among others. In land plants, female and male designate not only the female and male gamete-producing organisms and structures but also the structures of the sporophytes that give rise to male and female plants. Female being the more dominant species, female gametes override any male gamete present. # Secondary sex characteristics In those species with two sexes, males may differ from females in ways other than production of spermatozoa. Males are generally smaller than females in seed plants (the pollen grain is the male plant) and many fishes and birds, but larger in many mammals, including humans. In birds, the male often exhibits a colourful plumage that attracts females. # Sex determination The sex of a particular organism may be determined by a number of factors. These may be genetic or environmental, or may naturally change during the course of an organism's life. Although most species with male and female sexes have individuals that are either male or female, hermaphroditic animals have both male and female reproductive organs. ## Genetic determination Most mammals, including humans, are genetically determined as such by the XY sex-determination system where males have an XY (as opposed to XX) sex chromosome. During reproduction, a male can give either an X sperm or a Y sperm, while a female can only give an X egg. A Y sperm and an X egg produce a boy, while an X sperm and an X egg produce a girl. The ZW sex-determination system, where males have a ZZ (as opposed to ZW) sex chromosome may be found in birds and some insects (mostly butterflies and moths) and other organisms. Members of Hymenoptera, such as ants and bees, are determined by haplodiploidy, where most males are haploid and females and some sterile males are diploid. ## Environmental determination In some species of reptiles, including alligators, sex is determined by the temperature at which the egg is incubated. Other species, such as some snails, practise sex change: adults start out male, then become female. In tropical clown fish, the dominant individual in a group becomes female while the other ones are male. In some arthropods, sex is determined by infection. Bacteria of the genus Wolbachia alter their sexuality; some species consist entirely of ZZ individuals, with sex determined by the presence of Wolbachia. # Anatomy All males, regardless of independent origin, kingdom, or other phylogenetic subdivision, share at least the anatomy to produce male gametes. Some have sophisticated organs and organ systems designed to produce, dispense, and deliver the gamete to a location suitable for ovum fertilisation. Even where structures and cell types have arisen independently, "sperm" is ordinarily used to refer to the male gamete. Among animals that undergo internal fertilization, "penis" is often used to refer to an organ inserted into the female for insemination. # Symbols A common symbol used to represent the male gender is the Mars symbol, ♂ (Unicode: U+2642 Alt codes: Alt+11)—a circle with an arrow pointing northeast. This is a stylized representation of the Roman god Mars' shield and spear.

https://www.wikidoc.org/index.php/Male

07a018722a76254aedb9130939399d7211e93eb6

wikidoc

Mass

Mass Mass is a fundamental concept in physics, roughly corresponding to the intuitive idea of "how much matter there is in an object". Mass is a central concept of classical mechanics and related subjects, and there are several definitions of mass within the framework of relativistic kinematics (see mass in special relativity and mass in General Relativity). In the theory of relativity, the quantity invariant mass, which in concept is close to the classical idea of mass, does not vary between single observers in different reference frames. In everyday usage, mass is more commonly referred to as weight, but in physics and engineering, weight means the strength of the gravitational pull on the object; that is, how heavy it is, measured in units of force. In everyday situations, the weight of an object is proportional to its mass, which usually makes it unproblematic to use the same word for both concepts. However, the distinction between mass and weight becomes important: - for measurements with a precision better than a few percent, due to slight differences in the strength of the Earth's gravitational field at different places - for places far from the surface of the Earth, such as in space or on other planets # Units of mass In the SI system of units, mass is measured in kilograms, kg. Many other units of mass are also employed, such as: - the gram: 1 g = 0.001 kg - the tonne: 1 tonne = 1000 kg - the atomic mass unit - the Planck mass - the solar mass - the eV/c2 Outside the SI system, a variety of different mass units are used, depending on context. Because of the relativistic connection between mass and energy (see mass in special relativity), it is possible to use any unit of energy as a unit of mass instead. For example, the eV energy unit is normally used as a unit of mass (roughly 1.783 × 10-36 kg) in particle physics. A mass can sometimes also be expressed in terms of length. Here one identifies the mass of a particle with its inverse Compton wavelength (1 cm-1 ≈ 3.52×10-41 kg). For more information on the different units of mass, see Orders of magnitude (mass). # Inertial and gravitational mass One may distinguish conceptually between three types of mass or properties called mass: - Inertial mass is a measure of an object's resistance to changing its state of motion when a force is applied. An object with small inertial mass changes its motion more readily, and an object with large inertial mass does so less readily. - Passive gravitational mass is a measure of the strength of an object's interaction with a gravitational field. Within the same gravitational field, an object with a smaller passive gravitational mass experiences a smaller force than an object with a larger passive gravitational mass. - Active gravitational mass is a measure of the strength of the gravitational field due to a particular object. For example, the gravitational field that one experiences on the Moon is weaker than that of the Earth because the Moon has less active gravitational mass. Although inertial mass, passive gravitational mass and active gravitational mass are conceptually distinct, no experiment has ever unambiguously demonstrated any difference between them. In classical mechanics, Newton's third law implies that active and passive gravitational mass must always be identical (or at least proportional), but the classical theory offers no compelling reason why the gravitational mass has to equal the inertial mass. That it does is merely an empirical fact. Albert Einstein developed his general theory of relativity starting from the assumption that this correspondence between inertial and (passive) gravitational mass is not accidental: that no experiment will ever detect a difference between them (the weak version of the equivalence principle). However, in the resulting theory gravitation is not a force and thus not subject to Newton's third law, so "the equality of inertial and active gravitational mass remains as puzzling as ever". ## Inertial mass Inertial mass is the mass of an object measured by its resistance to acceleration. To understand what the inertial mass of a body is, one begins with classical mechanics and Newton's Laws of Motion. Later on, we will see how our classical definition of mass must be altered if we take into consideration the theory of special relativity, which is more accurate than classical mechanics. However, the implications of special relativity will not change the meaning of "mass" in any essential way. According to Newton's second law, we say that a body has a mass m if, at any instant of time, it obeys the equation of motion where f is the force acting on the body and v is its velocity. For the moment, we will put aside the question of what "force acting on the body" actually means. Now, suppose that the mass of the body in question is a constant. This assumption, known as the conservation of mass, rests on the ideas that (i) mass is a measure of the amount of matter contained in a body, and (ii) matter can never be created or destroyed, only split up or recombined. These are very reasonable assumptions for everyday objects, though, as we will see, mass can indeed be created or destroyed when we take special relativity into account. Another point to note is that, even in classical mechanics, it is sometimes useful to treat the mass of an object as changing with time. For example, the mass of a rocket decreases as the rocket fires. However, this is an approximation, based on ignoring pieces of matter which enter or leave the system. In the case of the rocket, these pieces correspond to the ejected propellant; if we were to measure the total mass of the rocket and its propellant, we would find that it is conserved. When the mass of a body is constant, Newton's second law becomes where a denotes the acceleration of the body. This equation illustrates how mass relates to the inertia of a body. Consider two objects with different masses. If we apply an identical force to each, the object with a bigger mass will experience a smaller acceleration, and the object with a smaller mass will experience a bigger acceleration. We might say that the larger mass exerts a greater "resistance" to changing its state of motion in response to the force. However, this notion of applying "identical" forces to different objects brings us back to the fact that we have not really defined what a force is. We can sidestep this difficulty with the help of Newton's third law, which states that if one object exerts a force on a second object, it will experience an equal and opposite force. To be precise, suppose we have two objects A and B, with constant inertial masses mA and mB. We isolate the two objects from all other physical influences, so that the only forces present are the force exerted on A by B, which we denote fAB, and the force exerted on B by A, which we denote fBA. As we have seen, Newton's second law states that where aA and aB are the accelerations of A and B respectively. Suppose that these accelerations are non-zero, so that the forces between the two objects are non-zero. This occurs, for example, if the two objects are in the process of colliding with one another. Newton's third law then states that Substituting this into the previous equations, we obtain Note that our requirement that aA be non-zero ensures that the fraction is well-defined. This is, in principle, how we would measure the inertial mass of an object. We choose a "reference" object and define its mass mB as (say) 1 kilogram. Then we can measure the mass of any other object in the universe by colliding it with the reference object and measuring the accelerations. ## Gravitational mass Gravitational mass is the mass of an object measured using the effect of a gravitational field on the object. The concept of gravitational mass rests on Newton's law of gravitation. Let us suppose we have two objects A and B, separated by a distance |rAB|. The law of gravitation states that if A and B have gravitational masses MA and MB respectively, then each object exerts a gravitational force on the other, of magnitude where G is the universal gravitational constant. The above statement may be reformulated in the following way: if g is the acceleration of a reference mass at a given location in a gravitational field, then the gravitational force on an object with gravitational mass M is This is the basis by which masses are determined by weighing. In simple bathroom scales, for example, the force f is proportional to the displacement of the spring beneath the weighing pan (see Hooke's law), and the scales are calibrated to take g into account, allowing the mass M to be read off. Note that a balance (see the subheading within Weighing scale) as used in the laboratory or the health club measures gravitational mass; only the spring scale measures weight. ## Equivalence of inertial and gravitational masses The equivalence of inertial and gravitational masses is sometimes referred to as the Galilean equivalence principle or weak equivalence principle. The most important consequence of this equivalence principle applies to freely falling objects. Suppose we have an object with inertial and gravitational masses m and M respectively. If the only force acting on the object comes from a gravitational field g, combining Newton's second law and the gravitational law yields the acceleration This says that the ratio of gravitational to inertial mass of any object is equal to some constant K if and only if all objects fall at the same rate in a given gravitational field. This phenomenon is referred to as the universality of free-fall. (In addition, the constant K can be taken to be 1 by defining our units appropriately.) The first experiments demonstrating the universality of free-fall were conducted by Galileo. It is commonly stated that Galileo obtained his results by dropping objects from the Leaning Tower of Pisa, but this is most likely apocryphal; actually, he performed his experiments with balls rolling down inclined planes. Increasingly precise experiments have been performed, such as those performed by Loránd Eötvös, using the torsion balance pendulum, in 1889. As of 2008, no deviation from universality, and thus from Galilean equivalence, has ever been found, at least to the accuracy 1/1012. More precise experimental efforts are still being carried out. The universality of free-fall only applies to systems in which gravity is the only acting force. All other forces, especially friction and air resistance, must be absent or at least negligible. For example, if a hammer and a feather are dropped from the same height on Earth, the feather will take much longer to reach the ground; the feather is not really in free-fall because the force of air resistance upwards against the feather is comparable to the downward force of gravity. On the other hand, if the experiment is performed in a vacuum, in which there is no air resistance, the hammer and the feather should hit the ground at exactly the same time (assuming the acceleration of both objects towards each other, and of the ground towards both objects, for its own part, is negligible). This demonstration is easily done in a high-school laboratory, using two transparent tubes connected to a vacuum pump. A stronger version of the equivalence principle, known as the Einstein equivalence principle or the strong equivalence principle, lies at the heart of the general theory of relativity. Einstein's equivalence principle states that within sufficiently small regions of space-time, it is impossible to distinguish between a uniform acceleration and a uniform gravitational field. Thus, the theory postulates that inertial and gravitational masses are fundamentally the same thing.

Mass Template:Tfd Mass is a fundamental concept in physics, roughly corresponding to the intuitive idea of "how much matter there is in an object". Mass is a central concept of classical mechanics and related subjects, and there are several definitions of mass within the framework of relativistic kinematics (see mass in special relativity and mass in General Relativity). In the theory of relativity, the quantity invariant mass, which in concept is close to the classical idea of mass, does not vary between single observers in different reference frames. In everyday usage, mass is more commonly referred to as weight, but in physics and engineering, weight means the strength of the gravitational pull on the object; that is, how heavy it is, measured in units of force. In everyday situations, the weight of an object is proportional to its mass, which usually makes it unproblematic to use the same word for both concepts. However, the distinction between mass and weight becomes important: - for measurements with a precision better than a few percent, due to slight differences in the strength of the Earth's gravitational field at different places - for places far from the surface of the Earth, such as in space or on other planets # Units of mass In the SI system of units, mass is measured in kilograms, kg. Many other units of mass are also employed, such as: - the gram: 1 g = 0.001 kg - the tonne: 1 tonne = 1000 kg - the atomic mass unit - the Planck mass - the solar mass - the eV/c2 Outside the SI system, a variety of different mass units are used, depending on context. Because of the relativistic connection between mass and energy (see mass in special relativity), it is possible to use any unit of energy as a unit of mass instead. For example, the eV energy unit is normally used as a unit of mass (roughly 1.783 × 10-36 kg) in particle physics. A mass can sometimes also be expressed in terms of length. Here one identifies the mass of a particle with its inverse Compton wavelength (1 cm-1 ≈ 3.52×10-41 kg). For more information on the different units of mass, see Orders of magnitude (mass). # Inertial and gravitational mass One may distinguish conceptually between three types of mass or properties called mass:[1] - Inertial mass is a measure of an object's resistance to changing its state of motion when a force is applied. An object with small inertial mass changes its motion more readily, and an object with large inertial mass does so less readily. - Passive gravitational mass is a measure of the strength of an object's interaction with a gravitational field. Within the same gravitational field, an object with a smaller passive gravitational mass experiences a smaller force than an object with a larger passive gravitational mass. - Active gravitational mass is a measure of the strength of the gravitational field due to a particular object. For example, the gravitational field that one experiences on the Moon is weaker than that of the Earth because the Moon has less active gravitational mass. Although inertial mass, passive gravitational mass and active gravitational mass are conceptually distinct, no experiment has ever unambiguously demonstrated any difference between them. In classical mechanics, Newton's third law implies that active and passive gravitational mass must always be identical (or at least proportional), but the classical theory offers no compelling reason why the gravitational mass has to equal the inertial mass. That it does is merely an empirical fact. Albert Einstein developed his general theory of relativity starting from the assumption that this correspondence between inertial and (passive) gravitational mass is not accidental: that no experiment will ever detect a difference between them (the weak version of the equivalence principle). However, in the resulting theory gravitation is not a force and thus not subject to Newton's third law, so "the equality of inertial and active gravitational mass [...] remains as puzzling as ever".[2] ## Inertial mass Inertial mass is the mass of an object measured by its resistance to acceleration. To understand what the inertial mass of a body is, one begins with classical mechanics and Newton's Laws of Motion. Later on, we will see how our classical definition of mass must be altered if we take into consideration the theory of special relativity, which is more accurate than classical mechanics. However, the implications of special relativity will not change the meaning of "mass" in any essential way. According to Newton's second law, we say that a body has a mass m if, at any instant of time, it obeys the equation of motion where f is the force acting on the body and v is its velocity. For the moment, we will put aside the question of what "force acting on the body" actually means. Now, suppose that the mass of the body in question is a constant. This assumption, known as the conservation of mass, rests on the ideas that (i) mass is a measure of the amount of matter contained in a body, and (ii) matter can never be created or destroyed, only split up or recombined. These are very reasonable assumptions for everyday objects, though, as we will see, mass can indeed be created or destroyed when we take special relativity into account. Another point to note is that, even in classical mechanics, it is sometimes useful to treat the mass of an object as changing with time. For example, the mass of a rocket decreases as the rocket fires. However, this is an approximation, based on ignoring pieces of matter which enter or leave the system. In the case of the rocket, these pieces correspond to the ejected propellant; if we were to measure the total mass of the rocket and its propellant, we would find that it is conserved. When the mass of a body is constant, Newton's second law becomes where a denotes the acceleration of the body. This equation illustrates how mass relates to the inertia of a body. Consider two objects with different masses. If we apply an identical force to each, the object with a bigger mass will experience a smaller acceleration, and the object with a smaller mass will experience a bigger acceleration. We might say that the larger mass exerts a greater "resistance" to changing its state of motion in response to the force. However, this notion of applying "identical" forces to different objects brings us back to the fact that we have not really defined what a force is. We can sidestep this difficulty with the help of Newton's third law, which states that if one object exerts a force on a second object, it will experience an equal and opposite force. To be precise, suppose we have two objects A and B, with constant inertial masses mA and mB. We isolate the two objects from all other physical influences, so that the only forces present are the force exerted on A by B, which we denote fAB, and the force exerted on B by A, which we denote fBA. As we have seen, Newton's second law states that where aA and aB are the accelerations of A and B respectively. Suppose that these accelerations are non-zero, so that the forces between the two objects are non-zero. This occurs, for example, if the two objects are in the process of colliding with one another. Newton's third law then states that Substituting this into the previous equations, we obtain Note that our requirement that aA be non-zero ensures that the fraction is well-defined. This is, in principle, how we would measure the inertial mass of an object. We choose a "reference" object and define its mass mB as (say) 1 kilogram. Then we can measure the mass of any other object in the universe by colliding it with the reference object and measuring the accelerations. ## Gravitational mass Gravitational mass is the mass of an object measured using the effect of a gravitational field on the object. The concept of gravitational mass rests on Newton's law of gravitation. Let us suppose we have two objects A and B, separated by a distance |rAB|. The law of gravitation states that if A and B have gravitational masses MA and MB respectively, then each object exerts a gravitational force on the other, of magnitude where G is the universal gravitational constant. The above statement may be reformulated in the following way: if g is the acceleration of a reference mass at a given location in a gravitational field, then the gravitational force on an object with gravitational mass M is This is the basis by which masses are determined by weighing. In simple bathroom scales, for example, the force f is proportional to the displacement of the spring beneath the weighing pan (see Hooke's law), and the scales are calibrated to take g into account, allowing the mass M to be read off. Note that a balance (see the subheading within Weighing scale) as used in the laboratory or the health club measures gravitational mass; only the spring scale measures weight. ## Equivalence of inertial and gravitational masses The equivalence of inertial and gravitational masses is sometimes referred to as the Galilean equivalence principle or weak equivalence principle. The most important consequence of this equivalence principle applies to freely falling objects. Suppose we have an object with inertial and gravitational masses m and M respectively. If the only force acting on the object comes from a gravitational field g, combining Newton's second law and the gravitational law yields the acceleration This says that the ratio of gravitational to inertial mass of any object is equal to some constant K if and only if all objects fall at the same rate in a given gravitational field. This phenomenon is referred to as the universality of free-fall. (In addition, the constant K can be taken to be 1 by defining our units appropriately.) The first experiments demonstrating the universality of free-fall were conducted by Galileo. It is commonly stated that Galileo obtained his results by dropping objects from the Leaning Tower of Pisa, but this is most likely apocryphal; actually, he performed his experiments with balls rolling down inclined planes. Increasingly precise experiments have been performed, such as those performed by Loránd Eötvös, using the torsion balance pendulum, in 1889. As of 2008, no deviation from universality, and thus from Galilean equivalence, has ever been found, at least to the accuracy 1/1012. More precise experimental efforts are still being carried out. The universality of free-fall only applies to systems in which gravity is the only acting force. All other forces, especially friction and air resistance, must be absent or at least negligible. For example, if a hammer and a feather are dropped from the same height on Earth, the feather will take much longer to reach the ground; the feather is not really in free-fall because the force of air resistance upwards against the feather is comparable to the downward force of gravity. On the other hand, if the experiment is performed in a vacuum, in which there is no air resistance, the hammer and the feather should hit the ground at exactly the same time (assuming the acceleration of both objects towards each other, and of the ground towards both objects, for its own part, is negligible). This demonstration is easily done in a high-school laboratory, using two transparent tubes connected to a vacuum pump. A stronger version of the equivalence principle, known as the Einstein equivalence principle or the strong equivalence principle, lies at the heart of the general theory of relativity. Einstein's equivalence principle states that within sufficiently small regions of space-time, it is impossible to distinguish between a uniform acceleration and a uniform gravitational field. Thus, the theory postulates that inertial and gravitational masses are fundamentally the same thing.

https://www.wikidoc.org/index.php/Mass

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Mdm2

Mdm2 Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene. Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation. # Discovery and expression in tumor cells The murine double minute (mdm2) oncogene, which codes for the Mdm2 protein, was originally cloned, along with two other genes (mdm1 and mdm3) from the transformed mouse cell line 3T3-DM. Mdm2 overexpression, in cooperation with oncogenic Ras, promotes transformation of primary rodent fibroblasts, and mdm2 expression led to tumor formation in nude mice. The human homologue of this protein was later identified and is sometimes called Hdm2. Further supporting the role of mdm2 as an oncogene, several human tumor types have been shown to have increased levels of Mdm2, including soft tissue sarcomas and osteosarcomas as well as breast tumors. The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53. MDM2 depletion in the absence of p53 promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 (H3K27)and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. An additional Mdm2 family member, Mdm4 (also called MdmX), has been discovered and is also an important negative regulator of p53. MDM2 is also required for organ development and tissue homeostasis because unopposed p53 activation leads to p53-overactivation-dependent cell death, referred to as podoptosis. Podoptosis is caspase-independent and, therefore, different from apoptosis. The mitogenic role of MDM2 is also needed for wound healing upon tissue injury, while MDM2 inhibition impairs re-epithelialization upon epithelial damage. In addition, MDM2 has p53-independent transcription factor-like effects in nuclear factor-kappa beta (NFκB) activation. Therefore, MDM2 promotes tissue inflammation and MDM2 inhibition has potent anti-inflammatory effects in tissue injury. So, MDM2 blockade had mostly anti-inflammatory and anti-mitotic effects that can be of additive therapeutic efficacy in inflammatory and hyperproliferative disorders such as certain cancers or lymphoproliferative autoimmunity, such as systemic lupus erythematosus or crescentic glomerulonephritis. # Ubiquitination target: p53 The key target of Mdm2 is the p53 tumor suppressor. Mdm2 has been identified as a p53 interacting protein that represses p53 transcriptional activity. Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53. Mdm2 is a p53 responsive gene—that is, its transcription can be activated by p53. Thus when p53 is stabilized, the transcription of Mdm2 is also induced, resulting in higher Mdm2 protein levels. # E3 ligase activity The E3 ubiquitin ligase MDM2 is a negative regulator of the p53 tumor suppressor protein. MDM2 binds and ubiquitinates p53, facilitating it for degradation. p53 can induce transcription of MDM2, generating a negative feedback loop. Mdm2 also acts as an E3 ubiquitin ligase, targeting both itself and p53 for degradation by the proteasome (see also ubiquitin). Several lysine residues in p53 C-terminus have been identified as the sites of ubiquitination, and it has been shown that p53 protein levels are downregulated by Mdm2 in a proteasome-dependent manner. Mdm2 is capable of auto-polyubiquitination, and in complex with p300, a cooperating E3 ubiquitin ligase, is capable of polyubiquitinating p53. In this manner, Mdm2 and p53 are the members of a negative feedback control loop that keeps the level of p53 low in the absence of p53-stabilizing signals. This loop can be interfered with by kinases and genes like p14arf when p53 activation signals, including DNA damage, are high. # Structure and function The full-length transcript of the mdm2 gene encodes a protein of 491 amino acids with a predicted molecular weight of 56kDa. This protein contains several conserved structural domains including an N-terminal p53 interaction domain, the structure of which has been solved using x-ray crystallography. The Mdm2 protein also contains a central acidic domain (residues 230-300). The phosphorylation of residues within this domain appears to be important for regulation of Mdm2 function. In addition, this region contains nuclear export and import signals that are essential for proper nuclear-cytoplasmic trafficking of Mdm2. Another conserved domain within the Mdm2 protein is a zinc finger domain, the function of which is poorly understood. Mdm2 also contains a C-terminal RING domain (amino acid resdiues 430-480), which contains a Cis3-His2-Cis3 consensus that coordinates two molecules of zinc. These residues are required for zinc binding, which is essential for proper folding of the RING domain. The RING domain of Mdm2 confers E3 ubiquitin ligase activity and is sufficient for E3 ligase activity in Mdm2 RING autoubiquitination. The RING domain of Mdm2 is unique in that it incorporates a conserved Walker A or P-loop motif characteristic of nucleotide binding proteins, as well as a nucleolar localization sequence. The RING domain also binds specifically to RNA, although the function of this is poorly understood. # Regulation There are several known mechanisms for regulation of Mdm2. One of these mechanisms is phosphorylation of the Mdm2 protein. Mdm2 is phosphorylated at multiple sites in cells. Following DNA damage, phosphorylation of Mdm2 leads to changes in protein function and stabilization of p53. Additionally, phosphorylation at certain residues within the central acidic domain of Mdm2 may stimulate its ability to target p53 for degradation. HIPK2 is a protein that regulates Mdm2 in this way. The induction of the p14arf protein, the alternate reading frame product of the p16INK4a locus, is also a mechanism of negatively regulating the p53-Mdm2 interaction. p14arf directly interacts with Mdm2 and leads to up-regulation of p53 transcriptional response. ARF sequesters Mdm2 in the nucleolus, resulting in inhibition of nuclear export and activation of p53, since nuclear export is essential for proper p53 degradation. Inhibitors of the MDM2-p53 interaction include the cis-imidazoline analog nutlin. Levels and stability of Mdm2 are also modulated by ubiquitylation. Mdm2 auto ubiquitylates itself, which allows for its degradation by the proteasome. Mdm2 also interacts with a ubiquitin specific protease, USP7, which can reverse Mdm2-ubiquitylation and prevent it from being degraded by the proteasome. USP7 also protects from degradation the p53 protein, which is a major target of Mdm2. Thus Mdm2 and USP7 form an intricate circuit to finely regulate the stability and activity of p53, whose levels are critical for its function. # Interactions Mdm2 has been shown to interact with: - ABL1, - ARRB1, - ARRB2, - CCNG1, - CTBP1, - CTBP2, - DAXX, - DHFR, - EP300, - ERICH3, - FKBP3, - FOXO4, - GNL3, - HDAC1, - HIF1A, - HTATIP, - IGF1R, - MDM4, - NUMB, - P16, - P53, - P73, - PCAF, - PSMD10, - PSME3, - RPL5, - RPL11, - PML, - RPL26, - RRM2B, - RYBP, - TBP, and - UBC. # Mdm2 p53-independent role Mdm2 overexpression was shown to inhibit DNA double-strand break repair mediated through a novel, direct interaction between Mdm2 and Nbs1 and independent of p53. Regardless of p53 status, increased levels of Mdm2, but not Mdm2 lacking its Nbs1-binding domain, caused delays in DNA break repair, chromosomal abnormalities, and genome instability. These data demonstrated Mdm2-induced genome instability can be mediated through Mdm2:Nbs1 interactions and independent from its association with p53.

Mdm2 Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene.[1][2] Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation. # Discovery and expression in tumor cells The murine double minute (mdm2) oncogene, which codes for the Mdm2 protein, was originally cloned, along with two other genes (mdm1 and mdm3) from the transformed mouse cell line 3T3-DM. Mdm2 overexpression, in cooperation with oncogenic Ras, promotes transformation of primary rodent fibroblasts, and mdm2 expression led to tumor formation in nude mice. The human homologue of this protein was later identified and is sometimes called Hdm2. Further supporting the role of mdm2 as an oncogene, several human tumor types have been shown to have increased levels of Mdm2, including soft tissue sarcomas and osteosarcomas as well as breast tumors. The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53. MDM2 depletion in the absence of p53 promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 (H3K27)and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation.[3] An additional Mdm2 family member, Mdm4 (also called MdmX), has been discovered and is also an important negative regulator of p53. MDM2 is also required for organ development and tissue homeostasis because unopposed p53 activation leads to p53-overactivation-dependent cell death, referred to as podoptosis. Podoptosis is caspase-independent and, therefore, different from apoptosis. The mitogenic role of MDM2 is also needed for wound healing upon tissue injury, while MDM2 inhibition impairs re-epithelialization upon epithelial damage. In addition, MDM2 has p53-independent transcription factor-like effects in nuclear factor-kappa beta (NFκB) activation. Therefore, MDM2 promotes tissue inflammation and MDM2 inhibition has potent anti-inflammatory effects in tissue injury. So, MDM2 blockade had mostly anti-inflammatory and anti-mitotic effects that can be of additive therapeutic efficacy in inflammatory and hyperproliferative disorders such as certain cancers or lymphoproliferative autoimmunity, such as systemic lupus erythematosus or crescentic glomerulonephritis.[4] # Ubiquitination target: p53 The key target of Mdm2 is the p53 tumor suppressor. Mdm2 has been identified as a p53 interacting protein that represses p53 transcriptional activity. Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53. Mdm2 is a p53 responsive gene—that is, its transcription can be activated by p53. Thus when p53 is stabilized, the transcription of Mdm2 is also induced, resulting in higher Mdm2 protein levels. # E3 ligase activity The E3 ubiquitin ligase MDM2 is a negative regulator of the p53 tumor suppressor protein. MDM2 binds and ubiquitinates p53, facilitating it for degradation. p53 can induce transcription of MDM2, generating a negative feedback loop.[5] Mdm2 also acts as an E3 ubiquitin ligase, targeting both itself and p53 for degradation by the proteasome (see also ubiquitin). Several lysine residues in p53 C-terminus have been identified as the sites of ubiquitination, and it has been shown that p53 protein levels are downregulated by Mdm2 in a proteasome-dependent manner. Mdm2 is capable of auto-polyubiquitination, and in complex with p300, a cooperating E3 ubiquitin ligase, is capable of polyubiquitinating p53. In this manner, Mdm2 and p53 are the members of a negative feedback control loop that keeps the level of p53 low in the absence of p53-stabilizing signals. This loop can be interfered with by kinases and genes like p14arf when p53 activation signals, including DNA damage, are high. # Structure and function The full-length transcript of the mdm2 gene encodes a protein of 491 amino acids with a predicted molecular weight of 56kDa. This protein contains several conserved structural domains including an N-terminal p53 interaction domain, the structure of which has been solved using x-ray crystallography. The Mdm2 protein also contains a central acidic domain (residues 230-300). The phosphorylation of residues within this domain appears to be important for regulation of Mdm2 function. In addition, this region contains nuclear export and import signals that are essential for proper nuclear-cytoplasmic trafficking of Mdm2. Another conserved domain within the Mdm2 protein is a zinc finger domain, the function of which is poorly understood. Mdm2 also contains a C-terminal RING domain (amino acid resdiues 430-480), which contains a Cis3-His2-Cis3 consensus that coordinates two molecules of zinc. These residues are required for zinc binding, which is essential for proper folding of the RING domain. The RING domain of Mdm2 confers E3 ubiquitin ligase activity and is sufficient for E3 ligase activity in Mdm2 RING autoubiquitination. The RING domain of Mdm2 is unique in that it incorporates a conserved Walker A or P-loop motif characteristic of nucleotide binding proteins, as well as a nucleolar localization sequence. The RING domain also binds specifically to RNA, although the function of this is poorly understood. # Regulation There are several known mechanisms for regulation of Mdm2. One of these mechanisms is phosphorylation of the Mdm2 protein. Mdm2 is phosphorylated at multiple sites in cells. Following DNA damage, phosphorylation of Mdm2 leads to changes in protein function and stabilization of p53. Additionally, phosphorylation at certain residues within the central acidic domain of Mdm2 may stimulate its ability to target p53 for degradation. HIPK2 is a protein that regulates Mdm2 in this way. The induction of the p14arf protein, the alternate reading frame product of the p16INK4a locus, is also a mechanism of negatively regulating the p53-Mdm2 interaction. p14arf directly interacts with Mdm2 and leads to up-regulation of p53 transcriptional response. ARF sequesters Mdm2 in the nucleolus, resulting in inhibition of nuclear export and activation of p53, since nuclear export is essential for proper p53 degradation. Inhibitors of the MDM2-p53 interaction include the cis-imidazoline analog nutlin.[6] Levels and stability of Mdm2 are also modulated by ubiquitylation. Mdm2 auto ubiquitylates itself, which allows for its degradation by the proteasome. Mdm2 also interacts with a ubiquitin specific protease, USP7, which can reverse Mdm2-ubiquitylation and prevent it from being degraded by the proteasome. USP7 also protects from degradation the p53 protein, which is a major target of Mdm2. Thus Mdm2 and USP7 form an intricate circuit to finely regulate the stability and activity of p53, whose levels are critical for its function. # Interactions Mdm2 has been shown to interact with: - ABL1,[7] - ARRB1,[8][9] - ARRB2,[8][9][10] - CCNG1,[11] - CTBP1,[12] - CTBP2,[12] - DAXX,[13] - DHFR,[14] - EP300,[15] - ERICH3,[16] - FKBP3,[17] - FOXO4,[18] - GNL3,[19] - HDAC1,[20] - HIF1A,[21][22] - HTATIP,[23] - IGF1R,[24] - MDM4,[25][26][27][28] - NUMB,[29][30] - P16,[13][31][32][33][34] - P53,[35][36] - P73,[37][38] - PCAF,[39] - PSMD10,[40] - PSME3,[41] - RPL5,[19][31][42] - RPL11,[19][31] - PML,[43][44][45][46] - RPL26,[47] - RRM2B,[48] - RYBP,[49] - TBP,[50][51] and - UBC.[13][52][53] # Mdm2 p53-independent role Mdm2 overexpression was shown to inhibit DNA double-strand break repair mediated through a novel, direct interaction between Mdm2 and Nbs1 and independent of p53. Regardless of p53 status, increased levels of Mdm2, but not Mdm2 lacking its Nbs1-binding domain, caused delays in DNA break repair, chromosomal abnormalities, and genome instability. These data demonstrated Mdm2-induced genome instability can be mediated through Mdm2:Nbs1 interactions and independent from its association with p53.

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