REDIRECT: Protein Redirected to: Apolipoprotein E {August 12, 2007 5:36:19 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:28 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Apolipoprotein E. Invoking a Mandantory Inspection. {August 12, 2007 5:36:28 PM PDT}

 {{Protein
|Name=Apolipoprotein E
|Symbol=APOE
|AltSymbols=AD2
|HGNCid=613
|Chromosome=19
|Arm=q
|Band=13.31
|LocusSupplementaryData=
|ECnumber=
|OMIM=107741
|EntrezGene=348
|RefSeq=NM_000041
|UniProt=P02649
}}
Apolipoprotein E (APOE), a main apoprotein of the chylomicron, binds to a specific receptor on liver cells and peripheral cells.

Function

APOE<ref>{{cite journal |author=Singh PP, Singh M, Mastana SS |title=Genetic variation of apolipoproteins in North Indians |journal=Hum. Biol. |volume=74 |issue=5 |pages=673-82 |year=2002 |pmid=12495081 |doi=}}</ref> is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation, and cognition. Neonates with brain injuries and/or defects who also have abnormalities in the APOE gene may have an increased risk for cerebral palsy, according to researchers at the Northwestern University Feinberg School of Medicine. Defects in APOE result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL remnants.

APOE is 299 amino acids long and transports lipoproteins, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen. In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved low density lipoprotein receptor gene family.

Gene

The APOE gene, ApoE, is mapped to chromosome 19 in a cluster with Apolipoprotein C1 and Apolipoprotein C2. ApoE consists of four exons and three introns, totaling 3597 base pairs.

The gene is polymorphic, with three major alleles, ApoE2, ApoE3, ApoE4, which translate into three isoforms of the protein: normal - ApoE-Îµ3; dysfunctional - ApoE-Îµ2 and ApoE-Îµ4. These isoforms differ from each other only by single amino acid substitutions at positions 112 and 158, but have profound physiological consequences.

E2 is associated with the genetic disorder type III hyperlipoproteinemia and with both increased and decreased risk for atherosclerosis.

E4 has been implicated in atherosclerosis and AD, impaired cognitive function, and reduced neurite outgrowth.

ApoE is a target gene of liver X receptor, a nuclear receptor member that play role in metabolism regulation of cholesterol, fatty acid, and glucose homeostasis.

Alzheimer's Disease (AD)

APOE-Îµ4 has been shown to cause an increased susceptibility to Alzheimer's disease.<!--

--><ref name="pmid8346443">{{cite journal |author=Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA |title=Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families |journal=Science |volume=261 |issue=5123 |pages=921-3 |year=1993 |pmid=8346443 |doi=}}</ref><!--

--> The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance while working in the Roses lab at Duke University. Linkage studies were followed by association analysis confirming the role of the APOE-Îµ4 allele.

Although 40-65% of AD patients have at least one copy of the 4 allele ApoE4 is not a determinant of the disease - at least a third of patients with AD are ApoE4 negative and some ApoE4 homozygotes never develop the disease.

Among ApoE4 carriers, another gene, GAB2, is thought to further influence the risk of getting AD.<!--

--><ref name="pmid17553421">{{cite journal |author=Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA |title=GAB2 Alleles Modify Alzheimer's Risk in APOE varepsilon4 Carriers |journal= |volume=54 |issue=5 |pages=713-720 |year=2007 |pmid=17553421 |doi=10.1016/j.neuron.2007.05.022}} [http://www.neuron.org/content/article/fulltext?uid=PIIS0896627307003790&highlight=GAB2 Free full text] [http://download.neuron.org/pdfs/0896-6273/PIIS0896627307003790.pdf Free PDF] [http://www.tgen.org/research/index.cfm?pageid=1065 Genetic data in the public domain]</ref><!--

-->

There is also evidence that the 2 allele may serve a protective role in AD.<!--

--><ref name="pmid7920638">{{cite journal |author=Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE |title=Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease |journal=Nat. Genet. |volume=7 |issue=2 |pages=180-4 |year=1994 |pmid=7920638 |doi=10.1038/ng0694-180}}</ref>

Thus, the genotype most at risk for Alzheimer's disease and at earlier age is ApoE 4,4. The ApoE 3,4 genotype is at increased risk, though not to the degree that those homozygous for ApoE 4 are. The genotype ApoE 3,3 is considered at normal risk for Alzheimer's disease. The genotype ApoE 2,3 is considered at less risk for Alzheimer's disease. Interestingly, people with both a copy of the 2 allele and the 4 allele, ApoE 2,4, are at normal risk similar to the ApoE 3,3 genotype.

References

External links

{{MeshName|Apolipoproteins+E}}

Category:Apolipoproteins

Category:Alzheimer's disease

ru:Ð�Ð¿Ð¾Ð»Ð¸Ð¿Ð¾Ð¿Ñ€Ð¾Ñ‚ÐµÐ¸Ð½ E

tr:Apolipoprotein E

zh:è½½è„‚è›‹ç™½ E

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_APOE_image.jpg

| image_source = PDB rendering based on 1b68.

| PDB = {{PDB2|1b68}}, {{PDB2|1bz4}}, {{PDB2|1ea8}}, {{PDB2|1gs9}}, {{PDB2|1h7i}}, {{PDB2|1le2}}, {{PDB2|1le4}}, {{PDB2|1lpe}}, {{PDB2|1nfn}}, {{PDB2|1nfo}}, {{PDB2|1or2}}, {{PDB2|1or3}}

| Name = apolipoprotein E

| HGNCid = 613

| Symbol = APOE

| AltSymbols =; AD2; MGC1571; apoprotein

| OMIM = 107741

| ECnumber =

| Homologene = 30951

| MGIid = 88057

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000302 |text = response to reactive oxygen species}} {{GNF_GO|id=GO:0001540 |text = beta-amyloid binding}} {{GNF_GO|id=GO:0005319 |text = lipid transporter activity}} {{GNF_GO|id=GO:0005543 |text = phospholipid binding}} {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0006707 |text = cholesterol catabolic process}} {{GNF_GO|id=GO:0006869 |text = lipid transport}} {{GNF_GO|id=GO:0006874 |text = cellular calcium ion homeostasis}} {{GNF_GO|id=GO:0006917 |text = induction of apoptosis}} {{GNF_GO|id=GO:0007010 |text = cytoskeleton organization and biogenesis}} {{GNF_GO|id=GO:0007271 |text = synaptic transmission, cholinergic}} {{GNF_GO|id=GO:0007611 |text = learning and/or memory}} {{GNF_GO|id=GO:0008015 |text = circulation}} {{GNF_GO|id=GO:0008034 |text = lipoprotein binding}} {{GNF_GO|id=GO:0008201 |text = heparin binding}} {{GNF_GO|id=GO:0016209 |text = antioxidant activity}} {{GNF_GO|id=GO:0030516 |text = regulation of axon extension}} {{GNF_GO|id=GO:0042157 |text = lipoprotein metabolic process}} {{GNF_GO|id=GO:0042311 |text = vasodilation}} {{GNF_GO|id=GO:0042627 |text = chylomicron}} {{GNF_GO|id=GO:0042632 |text = cholesterol homeostasis}} {{GNF_GO|id=GO:0046907 |text = intracellular transport}} {{GNF_GO|id=GO:0048156 |text = tau protein binding}} {{GNF_GO|id=GO:0048168 |text = regulation of neuronal synaptic plasticity}} {{GNF_GO|id=GO:0050749 |text = apolipoprotein E receptor binding}} {{GNF_GO|id=GO:0051262 |text = protein tetramerization}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 348

| Hs_Ensembl = ENSG00000130203

| Hs_RefseqProtein = NP_000032

| Hs_RefseqmRNA = NM_000041

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 19

| Hs_GenLoc_start = 50100879

| Hs_GenLoc_end = 50104489

| Hs_Uniprot = P02649

| Mm_EntrezGene = 11816

| Mm_Ensembl = ENSMUSG00000002985

| Mm_RefseqmRNA = NM_009696

| Mm_RefseqProtein = NP_033826

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 7

| Mm_GenLoc_start = 18854795

| Mm_GenLoc_end = 18857574

| Mm_Uniprot =

}}

Summary

Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis in the liver. Apolipoprotein E, a main apoprotein of the chylomicron, binds to a specific receptor on liver cells and peripheral cells. ApoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. The APOE gene is mapped to chromosome 19 in a cluster with APOC1 and APOC2. Defects in apolipoprotein E result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants.

APP

REDIRECT: Protein Redirected to: Amyloid_precursor_protein {August 12, 2007 5:36:28 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:31 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Amyloid_precursor_protein. Invoking a Mandantory Inspection. {August 12, 2007 5:36:31 PM PDT}

 Image:2fjz_app.png ion. The side chains of the two histidine and one tyrosine residues that play a role in metal coordination are shown in the Cu(I) bound, Cu(II) bound, and unbound conformations, which differ by only small changes in orientation.]]
Image:1rw6_e2_app.png and one of the most highly conserved regions of the protein from Drosophila to humans. This domain, which resembles the structure of spectrin, is thought to bind heparan sulfate proteoglycans.<ref name="WangHa">Wang Y, Ha Y. (2006). The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain. Mol Cell 15(3):343-53. PMID 15304215</ref> ]]
Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation<ref name="Priller">Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. (2006). Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26(27):7212-21. PMID 16822978</ref> and neural plasticity.<ref name="Turner">Turner PR, O'Connor K, Tate WP, Abraham WC. (2003). Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 70(1):1-32. PMID 12927332</ref> APP is best known and most commonly studied as the precursor molecule whose proteolysis generates amyloid beta, a 39-42 amino acid peptide whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

Genetics

In humans, the gene for APP is located on chromosome 21 and contains at least 18 exons in 240 kilobases.<ref name="Yoshikai"> Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y (1990). Genomic organization of the human amyloid beta-protein precursor gene Gene 87:257-263. PMID 2110105</ref><ref name="Lamb"> Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, Kearns WG, Pearson PL, Price DL, Gearhart JD. (1993). Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice Nat Genet 5:22-30. PMID 8220418 </ref> Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 365 to 770 amino acids, with certain isoforms preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease.<ref name="Matsui">Matsui T, Ingelsson M, Fukumoto H, Ramasamy K, Kowa H, Frosch MP, Irizarry MC, Hyman BT. (2007). Expression of APP pathway mRNAs and proteins in Alzheimer's disease. Brain Res Epub. PMID 17586478 </ref> Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals.<ref name="Zheng">Zheng H, Koo EH. (2006). The amyloid precursor protein: beyond amyloid. Mol Neurodegener 3;1:5. PMID 16930452</ref> The amyloid beta region of the protein, located in the membrane-spanning domain, is not well conserved across species and has no obvious connection with APP's native-state biological functions.<ref name="Zheng" />

Mutations in critical regions of APP, including the region that generates amyloid beta, are known to cause familial susceptibility to Alzheimer's disease.<ref name="Goate">Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349(6311):704-6. PMID 1671712 </ref><ref name="Murrell">Murrell J, Farlow M, Ghetti B, Benson MD. (1991). A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254(5028):97-9. PMID 1925564 </ref><ref name="Chartier">Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, et al. (1991). Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353(6347):844-6. PMID 1944558</ref> For example, several mutations outside the AÎ² region associated with familial Alzheimer's have been found to dramatically increase production of AÎ².<ref name="Citron">Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ. (1992). Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360(6405):672-4. PMID 1465129</ref>

Structure

A number of distinct, largely independently folding structural domains have been identified in the APP sequence. The extracellular region, much larger than the intracellular region, is divided into the E1 and E2 domains; E1 contains several subdomains including a growth factor-like domain (GFLD), a metal-binding motif, and a serine protease inhibitor domain that is absent from the isoform differentially expressed in the brain.<ref name="Sisodia"> Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL. (1993). Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. J Neurosci 13:3136-3142. PMID 8331390 </ref> The E2 domain contains a coiled coil dimerization motif and may bind proteoglycans in the extracellular matrix.<ref name="WangHa" /> The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, including the copper-binding domain in multiple configurations and ion binding states<ref name="Kong">Kong GK, Galatis D, Barnham KJ, Polekhina G, Adams JJ, Masters CL, Cappai R, Parker MW, McKinstry WJ. (2005). Crystallization and preliminary crystallographic studies of the copper-binding domain of the amyloid precursor protein of Alzheimer's disease. Acta Crystallograph 61(Pt 1):93-5. PMID 16508101. See also 2007 PDB IDs 2FJZ, 2FK2, 2FKL.</ref> and the E2 dimerization domain.<ref name="WangHa" />

Post-translational processing

APP undergoes extensive post-translational modification including glycosylation, phosphorylation, and tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments.<ref name="De Strooper">De Strooper B, Annaert W. (2000). Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci 113 ( Pt 11):1857-70. PMID 10806097 </ref> It is commonly cleaved by proteases in the secretase family; alpha secretase and beta secretase both remove nearly the entire extracellular domain to release membrane-anchored carboxy-terminal fragments that may be associated with apoptosis.<ref name="Zheng" /> Cleavage by gamma secretase within the membrane-spanning domain generates the amyloid-beta fragment; gamma secretase is a large multi-subunit complex whose components have not yet been fully characterized, but notably include presenilin, whose gene has been identified as a major genetic risk factor for Alzheimer's.<ref name="Chen">Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P. (2006). TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature 440:1208-1212. PMID 16641999 </ref>

The amyloidogenic processing of APP has been linked to its presence in lipid rafts. When APP molecules occupy a lipid raft region of membrane, they are more accessible to and differentially cleaved by beta secretase, whereas APP molecules outside a raft are differentially cleaved by the non-amyloidogenic alpha secretase.<ref name="Ehehalt">Ehehalt R, Keller P, Haass C, Thiele C, Simons K. (2003). Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol 160(1):113-23. PMID 12515826 </ref> Gamma secretase activity has also been associated with lipid rafts.<ref name="Vetrivel">Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, Wong PC, Xu H, Thinakaran G. (2004). Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J Biol Chem 279(43):44945-54. PMID 15322084</ref> The role of cholesterol in lipid raft maintenance has been cited as a likely explanation for observations that high cholesterol and apolipoprotein E genotype are major risk factors for Alzheimer's disease.<ref name="Riddell">Riddell DR, Christie G, Hussain I, Dingwall C. (2001). Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr Biol 11(16):1288-93. PMID 11525745</ref>

Biological function

Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive. The most well-substantiated role for APP is in synaptic formation and repair;<ref name="Priller" /> its expression is upregulated during neuronal differentiation and after neural injury. Roles in cell signaling, long-term potentiation, and cell adhesion have been proposed and supported by as-yet limited research.<ref name="Zheng" /> In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.<ref name="Selkoe"> Selkoe D, Kopan R. (2003). Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 26:565-597. PMID 12730322 </ref>APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss.<ref name="Phinney">Phinney AL, Calhoun ME, Wolfer DP, Lipp HP, Zheng H, Jucker M. (1999). No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta-amyloid precursor protein-null mice. Neuroscience 90(4):1207-16. PMID 10338291 </ref> On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.<ref name="Matsuyama">Matsuyama S, Teraoka R, Mori H, Tomiyama T. (2007). Inverse correlation between amyloid precursor protein and synaptic plasticity in transgenic mice. Neuroreport 18(10):1083-7. PMID 17558301 </ref>

References

External links

{{MeshName|Amyloid+Protein+Precursor}}

Category:Alzheimer's disease

Category:Integral membrane proteins

Category:Neurochemistry

fr:ProtÃ©ine prÃ©curtrice de l'amyloÃ¯de

es:ProteÃna Precursora AmiloÃdea

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_APP_image.jpg

| image_source = PDB rendering based on 1aap.

| PDB = {{PDB2|1aap}}, {{PDB2|1amb}}, {{PDB2|1amc}}, {{PDB2|1aml}}, {{PDB2|1ba4}}, {{PDB2|1ba6}}, {{PDB2|1brc}}, {{PDB2|1ca0}}, {{PDB2|1iyt}}, {{PDB2|1mwp}}, {{PDB2|1owt}}, {{PDB2|1rw6}}, {{PDB2|1taw}}, {{PDB2|1tkn}}, {{PDB2|1z0q}}, {{PDB2|1zjd}}, {{PDB2|2beg}}, {{PDB2|2fjz}}, {{PDB2|2fk1}}, {{PDB2|2fk2}}, {{PDB2|2fk3}}, {{PDB2|2fkl}}, {{PDB2|2fma}}, {{PDB2|2g47}}

| Name = amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)

| HGNCid = 620

| Symbol = APP

| AltSymbols =; AAA; ABETA; ABPP; AD1; APPI; CTFgamma; CVAP; PN2

| OMIM = 104760

| ECnumber =

| Homologene = 56379

| MGIid = 88059

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000085 |text = G2 phase of mitotic cell cycle}} {{GNF_GO|id=GO:0001967 |text = suckling behavior}} {{GNF_GO|id=GO:0003677 |text = DNA binding}} {{GNF_GO|id=GO:0004867 |text = serine-type endopeptidase inhibitor activity}} {{GNF_GO|id=GO:0005488 |text = binding}} {{GNF_GO|id=GO:0005506 |text = iron ion binding}} {{GNF_GO|id=GO:0005507 |text = copper ion binding}} {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005624 |text = membrane fraction}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005794 |text = Golgi apparatus}} {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0005905 |text = coated pit}} {{GNF_GO|id=GO:0006378 |text = mRNA polyadenylation}} {{GNF_GO|id=GO:0006878 |text = cellular copper ion homeostasis}} {{GNF_GO|id=GO:0006897 |text = endocytosis}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0007155 |text = cell adhesion}} {{GNF_GO|id=GO:0007219 |text = Notch signaling pathway}} {{GNF_GO|id=GO:0007409 |text = axonogenesis}} {{GNF_GO|id=GO:0007617 |text = mating behavior}} {{GNF_GO|id=GO:0008088 |text = axon cargo transport}} {{GNF_GO|id=GO:0008201 |text = heparin binding}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0008344 |text = adult locomotory behavior}} {{GNF_GO|id=GO:0008542 |text = visual learning}} {{GNF_GO|id=GO:0009986 |text = cell surface}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} {{GNF_GO|id=GO:0016199 |text = axon midline choice point recognition}} {{GNF_GO|id=GO:0016322 |text = neuron remodeling}} {{GNF_GO|id=GO:0016358 |text = dendrite development}} {{GNF_GO|id=GO:0030198 |text = extracellular matrix organization and biogenesis}} {{GNF_GO|id=GO:0030424 |text = axon}} {{GNF_GO|id=GO:0030900 |text = forebrain development}} {{GNF_GO|id=GO:0031410 |text = cytoplasmic vesicle}} {{GNF_GO|id=GO:0031594 |text = neuromuscular junction}} {{GNF_GO|id=GO:0035253 |text = ciliary rootlet}} {{GNF_GO|id=GO:0040014 |text = regulation of body size}} {{GNF_GO|id=GO:0042802 |text = identical protein binding}} {{GNF_GO|id=GO:0045177 |text = apical part of cell}} {{GNF_GO|id=GO:0045931 |text = positive regulation of progression through mitotic cell cycle}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}} {{GNF_GO|id=GO:0048471 |text = perinuclear region of cytoplasm}} {{GNF_GO|id=GO:0048669 |text = collateral sprouting in the absence of injury}} {{GNF_GO|id=GO:0050803 |text = regulation of synapse structure and activity}} {{GNF_GO|id=GO:0050885 |text = regulation of balance}} {{GNF_GO|id=GO:0050905 |text = neuromuscular process}} {{GNF_GO|id=GO:0051124 |text = synaptic growth at neuromuscular junction}} {{GNF_GO|id=GO:0051233 |text = spindle midzone}} {{GNF_GO|id=GO:0051563 |text = smooth endoplasmic reticulum calcium ion homeostasis}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 351

| Hs_Ensembl = ENSG00000142192

| Hs_RefseqProtein = NP_000475

| Hs_RefseqmRNA = NM_000484

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 21

| Hs_GenLoc_start = 26174733

| Hs_GenLoc_end = 26465003

| Hs_Uniprot = P05067

| Mm_EntrezGene = 11820

| Mm_Ensembl = ENSMUSG00000022892

| Mm_RefseqmRNA = NM_007471

| Mm_RefseqProtein = NP_031497

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 16

| Mm_GenLoc_start = 84837873

| Mm_GenLoc_end = 85057149

| Mm_Uniprot =

}}

Summary

This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different isoforms have been found for this gene.

REDIRECT: Protein Redirected to: Androgen_receptor {August 12, 2007 5:36:31 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:34 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Androgen_receptor. Invoking a Mandantory Inspection. {August 12, 2007 5:36:34 PM PDT}

 {{Protein
|Name=Androgen Receptor
|image=Steroid receptor.png
|caption=The ligand binding domain of the human androgen receptor in a complex with testosterone.
|Symbol=AR
|AltSymbols=
|HGNCid=644
|Chromosome=X
|Arm=q
|Band=
|LocusSupplementaryData=11.2-12
|ECnumber=
|OMIM=313700
|EntrezGene=367
|RefSeq=NM_000125
|UniProt=P10275
|PDB=2AM9
}}
The androgen receptor (AR) is a type of  nuclear receptor which is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone.<ref name="pmid9949684">{{cite journal | author = Roy AK, Lavrovsky Y, Song CS, Chen S, Jung MH, Velu NK, Bi BY, Chatterjee B | title = Regulation of androgen action | journal = Vitam. Horm. | volume = 55 | issue = | pages = 309-52 | year = 1999 | pmid = 9949684 | doi = | issn = }}</ref>  The main function of the androgen receptor is as a DNA binding transcription factor which regulates gene expression.<ref name="pmid3549275">{{cite journal | author = Mooradian AD, Morley JE, Korenman SG | title = Biological actions of androgens | journal = Endocr. Rev. | volume = 8 | issue = 1 | pages = 1-28 | year = 1987 | pmid = 3549275 | doi = | issn = }}</ref>  However the androgen receptor also has additional functions independent of DNA binding<ref name="pmid12351684">{{cite journal | author = Heinlein CA, Chang C | title = The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions | journal = Mol. Endocrinol. | volume = 16 | issue = 10 | pages = 2181-7 | year = 2002 | pmid = 12351684 | doi = 10.1210/me.2002-0070 | issn = }}</ref>
The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.

Structure

=Isoforms=

Image:androgen_receptor_sequence.png

Two isoforms of the androgen receptor (A and B) have been identified:<ref name="pmid8108393">{{cite journal | author = Wilson CM, McPhaul MJ | title = A and B forms of the androgen receptor are present in human genital skin fibroblasts | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 91 | issue = 4 | pages = 1234-8 | year = 1994 | pmid = 8108393 | doi = 10.1073/pnas.91.4.1234 | issn = }}</ref>

AR-A - 87 kDa - N-terminus truncated (lacks the first 187 amino acids)
AR-B - 110 kDa - full length

=Domains=

Like other nuclear receptors, the androgen receptor is modular in structure and is comprised of the following functional domains labeled A through F:

A/B) - N-terminal regulatory domain contains:<ref name="pmid7706276">{{cite journal | author = Jenster G, van der Korput HA, Trapman J, Brinkmann AO | title = Identification of two transcription activation units in the N-terminal domain of the human androgen receptor | journal = J. Biol. Chem. | volume = 270 | issue = 13 | pages = 7341-6 | year = 1995 | pmid = 7706276 | doi = 10.1074/jbc.270.13.7341 | issn = }}</ref>
activation function 1 (AF-1) between residues 101 and 370 required for full ligand activated transcriptional activity
activation function 5 (AF-5) between residues 360-485 is responsible for the constitutively activity (activity without bound ligand)
dimerization surface involving residues 1-36 (containing the FXXLF motif where F = phenylalanine, L = leucine, and X = any amino acid residue) and 370-494 which both interact with the LBD in an unusual (for a nuclear receptor) head-to-tail interaction<ref name="pmid8530400">{{cite journal | author = Langley E, Zhou ZX, Wilson EM | title = Evidence for an anti-parallel orientation of the ligand-activated human androgen receptor dimer | journal = J. Biol. Chem. | volume = 270 | issue = 50 | pages = 29983-90 | year = 1995 | pmid = 8530400 | doi = 10.1074/jbc.270.50.29983| issn = }}</ref><ref name="pmid9717843">{{cite journal | author = Berrevoets CA, Doesburg P, Steketee K, Trapman J, Brinkmann AO | title = Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2) | journal = Mol. Endocrinol. | volume = 12 | issue = 8 | pages = 1172-83 | year = 1998 | pmid = 9717843 | doi = 10.1210/me.12.8.1172 | issn = }}</ref><ref name="pmid15178743">{{cite journal | author = Dubbink HJ, Hersmus R, Verma CS, van der Korput HA, Berrevoets CA, van Tol J, Ziel-van der Made AC, Brinkmann AO, Pike AC, Trapman J | title = Distinct recognition modes of FXXLF and LXXLL motifs by the androgen receptor | journal = Mol. Endocrinol. | volume = 18 | issue = 9 | pages = 2132-50 | year = 2004 | pmid = 15178743 | doi = 10.1210/me.2003-0375 | issn = }}</ref>
C) - DNA binding domain (DBD)
D) - Hinge region - flexible region that connects the DBD with the LBD; influences subcellular trafficking
E) - Ligand binding domain (LBD) containing
activation function 2 (AF-2), responsible for agonist induced activity (activity in the presence of bound agonist)
AF-2 binds both coactivator proteins (containing the LXXLL motif) and/or the AF-1 region of another molecule of androgen receptor (containing the FXXLF motif) to form a head-to-tail dimer<ref name="pmid15178743"/>
F) - C-terminal domain

Gene

The {{gene|AR}} gene for the androgen receptor is located on the X chromosome at Xq11-12.

Function

=Genomic=

In some cell types testosterone interacts directly with androgen receptors while in others testosterone is converted by 5-alpha-reductase to dihydrotestosterone, an even more potent agonist for androgen receptor activation. Testosterone appears to be the primary androgen receptor activating hormone in the Wolffian duct while dihydrotestosterone is the main androgenic hormone in the urogenital sinus, urogenital tubercle, and hair follicles.

The primary mechanism of action for androgen receptors is direct regulation of gene transcription. The binding of an androgen to the androgen receptor results in a conformational change in the receptor which in turn causes dissociation of heat shock proteins, dimerization, and transport from the cytosol to the cell nucleus where the androgen receptor dimer binds to a specific sequence of DNA known as a hormone response element. Androgen receptors interact with other proteins in the nucleus resulting in up or down regulation of specific gene transcription. Up-regulation or activation of transcription results in increased synthesis of messenger RNA which in turn is transcribed by ribosomes to produce specific proteins. One of the known target genes of androgen receptor activation is insulin-like growth factor I (IGF-1). Thus, changes in levels of specific proteins in cells is one way that androgen receptors control cell behavior.

Androgens cause slow epiphysis, or maturation of the bones, but more of the potent epiphysis effect comes from the estrogen produced by aromatization of androgens. Steroid users of teen age may find that their growth had been stunted by androgen and/or estrogen excess. People with too little sex hormones can be short during puberty but end up taller as adults as in androgen insensitivity syndrome or estrogen insensitivity syndrome.

=Non-genomic=

More recently, androgen receptors have been shown to have a second mode of action. As has been also found for other steroid hormone receptors such as estrogen receptors, androgen receptors can have actions that are independent of their interactions with DNA.<ref name="pmid12351684">{{cite journal | author = Heinlein CA, Chang C | title = The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions | journal = Mol. Endocrinol. | volume = 16 | issue = 10 | pages = 2181-7 | year = 2002 | pmid = 12351684 | doi = 10.1210/me.2002-0070 | issn = }}</ref><ref name="Fix_2004">{{cite journal |author=Fix C, Jordan C, Cano P, Walker WH|title=Testosterone activates mitogen-activated protein kinase and the cAMP response element binding protein transcription factor in Sertoli cells|journal= Proc Natl Acad Sci U S A |volume= 101 |issue= 30 |pages= 10919-24 |year= 2004| doi = 10.1073/pnas.0404278101 |pmid= 15263086}}</ref> Androgen receptors interact with certain signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of changes in gene transcription, such as changes in ion transport. Regulation of signal transduction pathways by cytoplasmic androgen receptors can indirectly lead to changes in gene transcription, for example, by leading to phosphorylation of other transcription factors.

One function of androgen receptor that is independent of direct binding to its target DNA sequence, is facilitated by recruitment via other DNA binding proteins. One example is Serum Response Factor, a protein which activates several genes that cause muscle growth.<ref name="pmid15623502">{{cite journal | author = Vlahopoulos S, Zimmer WE, Jenster G, Belaguli NS, Balk SP, Brinkmann AO, Lanz RB, Zoumpourlis VC, Schwartz RJ | title = Recruitment of the androgen receptor via serum response factor facilitates expression of a myogenic gene | journal = J. Biol. Chem. | volume = 280 | issue = 9 | pages = 7786-92 | year = 2005 | pmid = 15623502 | doi = 10.1074/jbc.M413992200 | issn = }}</ref>

AR deficiencies

The androgen insensitivity syndrome, formerly known as testicular feminization, is caused by a mutation of the Androgen Receptor gene located on the X chromosome (locus:Xq11-Xq12).

The androgen receptor seems to affect neuron physiology and is defective in

Kennedy disease.

References

External links

{{MeshName|Androgen+Receptors}}
[http://www.androgendb.mcgill.ca/ Androgen receptor gene database]
[http://www.endotext.org/male/male3/male3.pdf Androgen physiology: receptor and metabolic disorders]
[http://ethesis.helsinki.fi/julkaisut/laa/biola/vk/thompson/molecula.pdf Molecular Mechanisms of Androgen Receptor Interactions]

Category:Intracellular receptors

fr:rÃ©cepteur des androgÃ¨nes

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_AR_image.jpg

| image_source = PDB rendering based on 1e3g.

| PDB = {{PDB2|1e3g}}, {{PDB2|1gs4}}, {{PDB2|1i37}}, {{PDB2|1i38}}, {{PDB2|1r4i}}, {{PDB2|1t5z}}, {{PDB2|1t63}}, {{PDB2|1t65}}, {{PDB2|1t73}}, {{PDB2|1t74}}, {{PDB2|1t76}}, {{PDB2|1t79}}, {{PDB2|1t7f}}, {{PDB2|1t7m}}, {{PDB2|1t7r}}, {{PDB2|1t7t}}, {{PDB2|1xj7}}, {{PDB2|1xnn}}, {{PDB2|1xow}}, {{PDB2|1xq3}}, {{PDB2|1z95}}, {{PDB2|2am9}}, {{PDB2|2ama}}, {{PDB2|2amb}}, {{PDB2|2ao6}}, {{PDB2|2ax6}}, {{PDB2|2ax7}}, {{PDB2|2ax8}}, {{PDB2|2ax9}}, {{PDB2|2axa}}, {{PDB2|2ihq}}, {{PDB2|2nw4}}, {{PDB2|2oz7}}

| Name = androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease)

| HGNCid = 644

| Symbol = AR

| AltSymbols =; AIS; DHTR; HUMARA; KD; NR3C4; SBMA; SMAX1; TFM

| OMIM = 313700

| ECnumber =

| Homologene = 28

| MGIid = 88064

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0001701 |text = in utero embryonic development}} {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0004882 |text = androgen receptor activity}} {{GNF_GO|id=GO:0005496 |text = steroid binding}} {{GNF_GO|id=GO:0005497 |text = androgen binding}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006810 |text = transport}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0007548 |text = sex differentiation}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0008289 |text = lipid binding}} {{GNF_GO|id=GO:0008584 |text = male gonad development}} {{GNF_GO|id=GO:0016049 |text = cell growth}} {{GNF_GO|id=GO:0019102 |text = male somatic sex determination}} {{GNF_GO|id=GO:0030521 |text = androgen receptor signaling pathway}} {{GNF_GO|id=GO:0030850 |text = prostate gland development}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}} {{GNF_GO|id=GO:0046983 |text = protein dimerization activity}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 367

| Hs_Ensembl = ENSG00000169083

| Hs_RefseqProtein = NP_000035

| Hs_RefseqmRNA = NM_000044

| Hs_GenLoc_db =

| Hs_GenLoc_chr = X

| Hs_GenLoc_start = 66681190

| Hs_GenLoc_end = 66867186

| Hs_Uniprot = P10275

| Mm_EntrezGene = 11835

| Mm_Ensembl = ENSMUSG00000046532

| Mm_RefseqmRNA = NM_013476

| Mm_RefseqProtein = NP_038504

| Mm_GenLoc_db =

| Mm_GenLoc_chr = X

| Mm_GenLoc_start = 94352469

| Mm_GenLoc_end = 94519866

| Mm_Uniprot =

}}

Summary

The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract causes spinal bulbar muscular atrophy (Kennedy disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Two alternatively spliced variants encoding distinct isoforms have been described.

BCL2

REDIRECT: Protein Redirected to: Bcl-2 {August 12, 2007 5:36:34 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:37 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Bcl-2. Invoking a Mandantory Inspection. {August 12, 2007 5:36:37 PM PDT}

 {{Protein
| Name = B-cell CLL/lymphoma 2
| caption = Crystal structure of BCL-2, isoform 1.
| image = BCL2_Crystal_Structure.rsh.png
| width = 200
| HGNCid = 990
| Symbol = BCL2
| AltSymbols =
| EntrezGene = 596
| OMIM = 151430
| RefSeq = NM_000633
| UniProt = P10415
| PDB = 1G5M
| ECnumber =
| Chromosome = 18
| Arm = q
| Band = 21.3
| LocusSupplementaryData =
}}
Bcl-2 is the prototype for a family of mammalian genes and the proteins they produce. They govern mitochondrial outer membrane permeabilisation (MOMP) and can be either pro-apoptotic (Bax, BAD, Bak and Bok among others) or anti-apoptotic (including Bcl-2 proper, Bcl-xL, and Bcl-w, among an assortment of others). There are a total of 25 genes in the Bcl-2 family known to date. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described as a reciprocal gene translocation in chromosomes 14 and 18 in follicular lymphomas.

Function of Bcl-2

There are a number of theories concerning how the Bcl-2 gene family exert their pro- or anti-apoptotic effect. An important one states that this is achieved by activation or inactivation of an inner mitochondrial permeability transition pore, which is involved in the regulation of matrix Ca2+, pH, and voltage. It is also thought that some Bcl-2 family proteins can induce (pro-apoptotic members) or inhibit (anti-apoptotic members) the release of cytochrome c in to the cytosol which, once there, activates caspase-9 and caspase-3, leading to apoptosis. Zamzami et al. suggest that the release of cytochrome c is in fact mediated by effects of the PT pore on the inner mitochondrial membrane, linking the theories.<ref>Zamzami N, Brenner C, Marzo I, Susin SA, Kroemer G. Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene 1998;16:2265-82. PMID 9619836.</ref>

Image:Bcl2fam.jpg

The members of the Bcl-2 family share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4) (see the figure on your left). The BH domains are known to be crucial for function, as deletion of these domains via molecular cloning affects survival/apoptosis rates. The anti-apoptotic Bcl-2 proteins, such as Bcl-2 and Bcl-xL, conserve all four BH domains. The BH domains also serve to subdivide the pro-apoptotic Bcl-2 proteins into those with several BH domains (e.g. Bax and Bak) or those proteins that have only the BH3 domain (e.g. Bid, Bim and Bad). The Bcl-2 family has a general structure that consists of a hydrophobic helix surrounded by amphipathic helices. Many members of the family have transmembrane domains. The site of action for the Bcl-2 family is mostly on the outer mitochondrial membrane (OMM). Within the mitochondria are apoptogenic factors (cytochrome c, Smac/DIABLO, Omi) that if released activate the executioners of apoptosis, the caspases. Depending on their function, once activated, Bcl-2 proteins either promote the release of these factors, or keep them sequestered in the mitochondria. The exact mechanisms surrounding Bcl-2 regulated mitochondrial outer membrane permeabilization (MOMP) have yet to be elucidated, but it is believed that the multidomain, pro-apoptotic Bcl-2 proteins can activate MOMP directly, a process that is inhibited by the binding of anti-apoptotic Bcl-2 proteins. In contrast, the BH3-only, pro-apoptotic Bcl-2 proteins activate MOMP indirectly by binding the anti-apoptotic Bcl-2 proteins, freeing the multidomain, pro-apoptotic Bcl-2 proteins to activate MOMP.

The protein Bcl-2 is an anti-apoptotic protein that resides in the OMM and the membrane of the endoplasmic reticulum. Over expression of Bcl-2 is known to block cytochrome c release, possibly through the inhibition of Bax and Bak. The protein also conforms to the general structure of Bcl-2 proteins, with a transmembrane domain in its C-terminus.

Role in disease

The Bcl-2 gene has been implicated in a number of cancers, including melanoma, breast, prostate, and lung carcinomas, as well as schizophrenia and autoimmunity. It is also thought to be involved in resistance to conventional cancer treatment. This supports a role for decreased apoptosis in the pathogenesis of cancer.

Schizophrenia is a neurodegenerative chronic illness that affects about 60 million individuals world wide and is characterized by hallucinations, disorderly thought, delusions and changes in sensitivity and emotional state. The mechanism of apoptosis is connected to schizophrenia because it is known to occur in the early development of the nervous system and also eliminates injured or diseased neurons throughout life. (Schizophrenia Research. 2006; 81, 47â€“63). An increase in apoptosis caused by stresses such as excessive calcium flux, oxidative stress and mitochondrial dysfunction, has been found in schizophrenia. This apoptotic activity is localized in the synapses and neuritis, whose structural components contain substrates for caspases. Researchers have found that increasing apoptotic stimuli, increased caspase-3 activity, thus degenerating the neuritis and synaptic spines. "The stresses, mentioned above, increase the ratio of pro/anti-apoptotic factors, therefore increasing the likelihood of this caspase activity event which leads to schizophrenia." (Schizophrenia Research. 2006; 81, 47â€“63).

Apoptosis also plays a very active role in regulating the immune system. When it is functional, it can cause immune unresponsiveness to self-antigens via both central and peripheral tolerance. "In the case of defective apoptosis, it may contribute to etiological aspects of autoimmune diseases." (Clinical and Developmental Immunology. 2006. 13(2-4); 273-282). The autoimmune disease, type 1 diabetes can be caused by defective apoptosis, which leads to aberrant T cell AICD and defective peripheral tolerance. Due to the fact that dendritic cells (DCs) are of the most important antigen presenting cells of the immune system, their activity must be tightly regulated by such mechanisms as apoptosis. "Researchers have found that mice containing DCs that are Bim -/-, thus unable to induce effective apoptosis, obtain autoimmune diseases more so than those that have normal DCs."(Clinical and Developmental Immunology. 2006. 13(2-4); 273-282). "Other studies have shown that the lifespan of DCs may be controlled by factors such as a timer dependent on anti-apoptotic Bcl-2." (Clinical and Developmental Immunology. 2006. 13(2-4); 273-282). These investigations illuminate the importance of regulating antigen presentation as mis-regulation can lead to autoimmunity.

Cancer is one of the worlds leading causes of death and occurs when the homeostatic balance between cell growth and death is disturbed. Research in cancer biology has discovered that a variety of aberrations in gene expression of anti-apoptotic, pro-apoptotic and BH3-only proteins can contribute to the many forms of the disease. An interesting example can be seen in lymphomas. The over-expression of the anti-apoptotic Bcl-2 protein in lymphocytes alone did not act in an oncogenic manner. "Its combined expression with the cell cycle mitogen promoting myc gene led to an aggressive malignancy of the B-cell lineage leading to the creation of lymphomas." (Blood. 2007. 1; 16).

In follicular B-cell lymphoma, a chromosomal translocation occurs between the fourteenth and the eighteenth chromosomes - t(14;18) - which places the Bcl-2 gene next to the immunoglobulin heavy chain locus. This fusion gene is deregulated, leading to the transcription of excessively high levels of anti-apoptotic bcl-2 protein.<ref>Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988;335:440-2. PMID: 3262202.</ref> This decreases the propensity of these cells for undergoing apoptosis.

Apoptosis plays a very important role in regulating a variety of diseases that have enormous social impacts. Bcl-2 is essential to the process of apoptosis because it suppresses the initiation of the cell-death process.

Further research into the family of Bcl-2 proteins will provide us with a more complete picture on how these proteins interact with each other to promote and inhibit apoptosis. An understanding of the mechanisms involved will help us find potential treatments such as inhibitors to target over-expressed proteins that may lead to disabling diseases such as cancer, neurodegenerative diseases and autoimmunity.

Targeted therapies

An antisense oligonucleotide drug Genasense (G3139) has been developed to target Bcl-2. An antisense DNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing respectively RNA or protein). An antisense drug is a short sequence of RNA which hybridises with and inactivates mRNA, preventing the protein from being formed.

It was shown that the proliferation of human lymphoma s (with t(14;18) translocation) could be inhibited by antisense RNA targeted at the start codon region of Bcl-2 mRNA. In vitro studies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA.<ref>Dias N, Stein CA. Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides. Eur J Pharm Biopharm 2002;54:263-9. PMID 12445555.</ref>

These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial is currently underway (Mavoromatis and Cheson 2004).

Genasense did not receive FDA approval after disappointing results in a melanoma trial.

Abbott has recently described a novel inhibitor of Bcl-2 and Bcl-xL, known as ABT-737.<ref>Oltersdorf T, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 435:677-681. PMID: 15902208</ref>. ABT-737 is one among many so-called BH3 mimetic small molecule inhibitors (SMI) targeting Bcl-2 and Bcl-2-related proteins such as Bcl-xL and Mcl-1, which may prove valuable in the therapy of lymphoma and other blood cancers.<ref>John C. Reed, and Maurizio Pellecchia, "Apoptosis-based therapies for hematologic malignancies", Blood. 106(2):408-418 (2005). PMID: 15797997</ref>.

References

External links

[http://www.celldeath.de/encyclo/misc/bcl2.htm The Bcl-2 Family at celldeath.de]
[http://www.caspases.org/showpopterms.php?search=Bcl-2 Bcl-2 publications sorted by impact at caspases.org]
{{MeshName|bcl-2+Genes}}
{{MeshName|c-bcl-2+Proteins}}

Category:Genes

Category:Integral membrane proteins

Category:Peripheral membrane proteins

Category:Oncology

Category:Programmed cell death

de:Bcl-2

es:Bcl-2

fr:Bcl-2

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_BCL2_image.jpg

| image_source = PDB rendering based on 2o2f.

| PDB = {{PDB2|2o2f}}

| Name = B-cell CLL/lymphoma 2

| HGNCid = 990

| Symbol = BCL2

| AltSymbols =; Bcl-2

| OMIM = 151430

| ECnumber =

| Homologene = 527

| MGIid = 88138

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}} {{GNF_GO|id=GO:0001836 |text = release of cytochrome c from mitochondria}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005739 |text = mitochondrion}} {{GNF_GO|id=GO:0005741 |text = mitochondrial outer membrane}} {{GNF_GO|id=GO:0005783 |text = endoplasmic reticulum}} {{GNF_GO|id=GO:0005829 |text = cytosol}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006959 |text = humoral immune response}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} {{GNF_GO|id=GO:0042802 |text = identical protein binding}} {{GNF_GO|id=GO:0051453 |text = regulation of cellular pH}} {{GNF_GO|id=GO:0051902 |text = negative regulation of mitochondrial depolarization}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 596

| Hs_Ensembl = ENSG00000171791

| Hs_RefseqProtein = NP_000624

| Hs_RefseqmRNA = NM_000633

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 18

| Hs_GenLoc_start = 58941559

| Hs_GenLoc_end = 59137593

| Hs_Uniprot = P10415

| Mm_EntrezGene = 12043

| Mm_Ensembl = ENSMUSG00000057329

| Mm_RefseqmRNA = NM_009741

| Mm_RefseqProtein = NP_033871

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 1

| Mm_GenLoc_start = 108365740

| Mm_GenLoc_end = 108541821

| Mm_Uniprot =

}}

Summary

This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, such as in the case of translocation of BCL2 to Ig heavy chain locus, is thought to be the cause of follicular lymphoma. Two transcript variants, produced by alternate splicing, differ in their C-terminal ends.

BRCA1

REDIRECT: Protein Redirected to: BRCA1 {August 12, 2007 5:36:37 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:40 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: BRCA1. Invoking a Mandantory Inspection. {August 12, 2007 5:36:40 PM PDT}

 {{Protbox
|Name=Breast cancer type 1 susceptibility protein
|Photo=BRCA Genes-location of BRCA1 and BRCA2 on chromosomes 13 and 17.gif
|Caption=Location of the genes BRCA1 and BRCA2 on chromosomes 13 and 17
|HGNCid = 1100
|Symbol = BRCA1
|AltSymbols =
|Codes={{EntrezGene|672}}, {{RefSeq|NM_007295}}, {{UniProt|P38398}}, {{OMIM|113705}}
|EntrezGene =
|OMIM =
|RefSeq =
|UniProt =
|PDB =
|ECnumber =
|Chromosome = 17
|Arm = q
|Band = 21
|LocusSupplementaryData =-q24
|Gene=
|Gene_type=
|Protein_length= 1863
|Molecular_weight=207732
|Structure=
|Review=
|Type=
|Functions= DNA repair, Tumor suppressor, Transcription regulator
|Domains=ZFC3 domain, 2 BRCT domains
|Motifs= 2NLS motifs, CC motif
|Alternative_products=
|Catalytic_activity=
|Cofactors=
|Enzyme_regulation=
|Diseases= breast-ovarian cancer (BOC) {{OMIM|113705}}
|Pharmaceuticals=
|Taxa= Homo sapiens
|Cells= many; ovaries, testis, mammary glands, lymphocyte, prostate, cervix
|Location= Primary: Nucleus; Secondary: Cytoplasm, Centrosome
|Mods=
|Names= RING finger protein 53, Breast cancer 1 Early Onset, PSCP, RNF53
|Pathways=
|Interactions=
|Pages=
|Actions=
|Agonists=
|Antagonists=
}}
BRCA1 (breast cancer 1, early onset) is a human gene that belongs to a class of genes known as tumor suppressors, which regulate the cell cycle and prevent uncontrolled proliferation.  The BRCA1 protein product of the gene is part of the DNA damage detection and repair system.  Variation in the gene has been implicated in some cancers.  The BRCA1 gene is located on the long (q) arm of chromosome 17 at position 21, from base pair 38,449,843 to base pair 38,530,933.

Function and mechanism

The BRCA1 protein is directly involved in the repair of damaged DNA. In the nucleus of many types of normal cells, the BRCA1 protein is thought to interact with RAD51 to mend breaks in DNA, though the details and significance of this interaction is the subject of debate.<ref>{{cite journal | author=S.J. Boulton | title=Cellular functions of the BRCA tumour-suppressor proteins | journal=Biochemical Society Transactions | year=2006 | pages=633-645 | volume=34 | issue=5 | id=PMID 17052168 }}</ref> These breaks can be caused by natural radiation or other exposures, but also occur when chromosomes exchange genetic material in preparation for cell division. The BRCA2 protein, which has a function similar to that of BRCA1, also interacts with the RAD51 protein. By repairing DNA, these three proteins play a role in maintaining the stability of the human genome.

Research suggests that both the BRCA1 and BRCA2 proteins regulate the activity of other genes and play a critical role in embryo development. The BRCA1 protein probably interacts with many other proteins, including tumor suppressors and regulators of the cell division cycle.

Related conditions

Certain variations of the BRCA1 gene lead to an increased risk for breast cancer. Researchers have identified more than 600 mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer. These mutations can be changes in one or a small number of DNA base pairs (the building blocks of DNA). In some cases, large segments of DNA are rearranged. A mutated BRCA1 gene usually makes a protein that does not function properly because it is abnormally short. Researchers believe that the defective BRCA1 protein is unable to help fix mutations that occur in other genes. These defects accumulate and may allow cells to grow and divide uncontrollably to form a tumor.

In addition to breast cancer, mutations in the BRCA1 gene also increase the risk on ovarian, Fallopian tube, prostate and colon cancers. Moreover, precancerous lesions (dysplasia) within the Fallopian tube have been linked to BRCA1 gene mutations.

References

External links

Online Mendelian Inheritance in Man: {{OMIM|113705}}
{{EntrezGene|672}}
[http://www.genecards.org/cgi-bin/carddisp?BRCA1 GeneCard]
[http://www.exactantigen.com/review/BRCA1.html BRCA1 antibody review]

Category:Tumor markers

Category:Tumor suppressor genes

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_BRCA1_image.jpg

| image_source = PDB rendering based on 1jm7.

| PDB = {{PDB2|1jm7}}, {{PDB2|1jnx}}, {{PDB2|1n5o}}, {{PDB2|1oqa}}, {{PDB2|1t15}}, {{PDB2|1t29}}, {{PDB2|1t2u}}, {{PDB2|1t2v}}, {{PDB2|1y98}}

| Name = breast cancer 1, early onset

| HGNCid = 1100

| Symbol = BRCA1

| AltSymbols =; BRCAI; BRCC1; IRIS; PSCP; RNF53

| OMIM = 113705

| ECnumber =

| Homologene = 5276

| MGIid = 104537

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000075 |text = cell cycle checkpoint}} {{GNF_GO|id=GO:0000151 |text = ubiquitin ligase complex}} {{GNF_GO|id=GO:0000793 |text = condensed chromosome}} {{GNF_GO|id=GO:0003674 |text = molecular_function}} {{GNF_GO|id=GO:0003677 |text = DNA binding}} {{GNF_GO|id=GO:0003684 |text = damaged DNA binding}} {{GNF_GO|id=GO:0003713 |text = transcription coactivator activity}} {{GNF_GO|id=GO:0004842 |text = ubiquitin-protein ligase activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005575 |text = cellular_component}} {{GNF_GO|id=GO:0005622 |text = intracellular}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0006260 |text = DNA replication}} {{GNF_GO|id=GO:0006281 |text = DNA repair}} {{GNF_GO|id=GO:0006357 |text = regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0006359 |text = regulation of transcription from RNA polymerase III promoter}} {{GNF_GO|id=GO:0006633 |text = fatty acid biosynthetic process}} {{GNF_GO|id=GO:0006978 |text = DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007059 |text = chromosome segregation}} {{GNF_GO|id=GO:0007098 |text = centrosome cycle}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0008274 |text = gamma-tubulin ring complex}} {{GNF_GO|id=GO:0008630 |text = DNA damage response, signal transduction resulting in induction of apoptosis}} {{GNF_GO|id=GO:0009048 |text = dosage compensation, by inactivation of X chromosome}} {{GNF_GO|id=GO:0015631 |text = tubulin binding}} {{GNF_GO|id=GO:0016481 |text = negative regulation of transcription}} {{GNF_GO|id=GO:0016567 |text = protein ubiquitination}} {{GNF_GO|id=GO:0019899 |text = enzyme binding}} {{GNF_GO|id=GO:0030521 |text = androgen receptor signaling pathway}} {{GNF_GO|id=GO:0031398 |text = positive regulation of protein ubiquitination}} {{GNF_GO|id=GO:0031436 |text = BRCA1-BARD1 complex}} {{GNF_GO|id=GO:0042127 |text = regulation of cell proliferation}} {{GNF_GO|id=GO:0042981 |text = regulation of apoptosis}} {{GNF_GO|id=GO:0045717 |text = negative regulation of fatty acid biosynthetic process}} {{GNF_GO|id=GO:0045739 |text = positive regulation of DNA repair}} {{GNF_GO|id=GO:0045786 |text = negative regulation of progression through cell cycle}} {{GNF_GO|id=GO:0045893 |text = positive regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0046600 |text = negative regulation of centriole replication}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}} {{GNF_GO|id=GO:0050681 |text = androgen receptor binding}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 672

| Hs_Ensembl = ENSG00000012048

| Hs_RefseqProtein = NP_009226

| Hs_RefseqmRNA = NM_007295

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 17

| Hs_GenLoc_start = 38449840

| Hs_GenLoc_end = 38530994

| Hs_Uniprot = P38398

| Mm_EntrezGene = 12189

| Mm_Ensembl = ENSMUSG00000017146

| Mm_RefseqmRNA = NM_009764

| Mm_RefseqProtein = NP_033894

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 11

| Mm_GenLoc_start = 101305657

| Mm_GenLoc_end = 101367902

| Mm_Uniprot =

}}

Summary

This gene encodes a nuclear phosphoprotein that plays a role in maintaining genomic stability and acts as a tumor suppressor. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as BASC for BRCA1-associated genome surveillance complex. This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complex. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants have been described for this gene but only some have had their full-length natures identified.

CASP3

REDIRECT: Protein Redirected to: Caspase 3 {August 12, 2007 5:36:40 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:42 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Caspase 3. Invoking a Mandantory Inspection. {August 12, 2007 5:36:42 PM PDT}

 {{protein
|Name=caspase 3, apoptosis-related cysteine peptidase
|caption=Caspase-3 (blue) with bound inhibitor (yellow).
|image=Caspase3_1rhk.png
|width=
|HGNCid=1504
|Symbol=CASP3
|AltSymbols=
|EntrezGene=836
|OMIM=600636
|RefSeq=NM_004346
|UniProt=P42574
|PDB=1RHK
|ECnumber=
|Chromosome=4
|Arm=q
|Band=34
|LocusSupplementaryData=
}}
Caspase 3 is a caspase protein. It interacts with caspase 8.
Image:TNF signaling.jpg-R1. Dashed grey lines represent multiple steps]]
{{biochem-stub}}
{{Cysteine proteases}}

Appended Protein Page ******

<!-- BOT: MANUAL_INSPECTION_REQUIRED = NO - change this option to YES to have the protein box bot require an operator inspection before updating occurs.  -->
<!-- BOT: PROTEIN BOX UPDATE = YES - This protein box is automatically updated by protein box bot. Change the update option to NO to have the bot skip updating this protein box -->
{{GNF_Protein_box
| image = PBB_Protein_CASP3_image.jpg
| image_source = PDB rendering based on 1cp3.
| PDB = {{PDB2|1cp3}}, {{PDB2|1gfw}}, {{PDB2|1i3o}}, {{PDB2|1nme}}, {{PDB2|1nmq}}, {{PDB2|1nms}}, {{PDB2|1pau}}, {{PDB2|1qx3}}, {{PDB2|1re1}}, {{PDB2|1rhj}}, {{PDB2|1rhk}}, {{PDB2|1rhm}}, {{PDB2|1rhq}}, {{PDB2|1rhr}}, {{PDB2|1rhu}}, {{PDB2|2c1e}}, {{PDB2|2c2k}}, {{PDB2|2c2m}}, {{PDB2|2c2o}}, {{PDB2|2cdr}}, {{PDB2|2cjx}}, {{PDB2|2cjy}}, {{PDB2|2cnk}}, {{PDB2|2cnl}}, {{PDB2|2cnn}}, {{PDB2|2cno}}, {{PDB2|2dko}}, {{PDB2|2h5i}}, {{PDB2|2h5j}}, {{PDB2|2h65}}, {{PDB2|2j30}}, {{PDB2|2j31}}, {{PDB2|2j32}}, {{PDB2|2j33}}
| Name = caspase 3, apoptosis-related cysteine peptidase
| HGNCid = 1504
| Symbol = CASP3
| AltSymbols =; CPP32; CPP32B; SCA-1
| OMIM = 600636
| ECnumber =
| Homologene = 37912
| MGIid = 107739
| GeneAtlas_image =
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = ~~~~~
| Function = {{GNF_GO|id=GO:0001782 |text = B cell homeostasis}} {{GNF_GO|id=GO:0001836 |text = release of cytochrome c from mitochondria}} {{GNF_GO|id=GO:0004861 |text = cyclin-dependent protein kinase inhibitor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0006309 |text = DNA fragmentation during apoptosis}} {{GNF_GO|id=GO:0006508 |text = proteolysis}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0006917 |text = induction of apoptosis}} {{GNF_GO|id=GO:0007507 |text = heart development}} {{GNF_GO|id=GO:0007605 |text = sensory perception of sound}} {{GNF_GO|id=GO:0008234 |text = cysteine-type peptidase activity}} {{GNF_GO|id=GO:0008625 |text = induction of apoptosis via death domain receptors}} {{GNF_GO|id=GO:0008631 |text = induction of apoptosis by oxidative stress}} {{GNF_GO|id=GO:0009411 |text = response to UV}} {{GNF_GO|id=GO:0009611 |text = response to wounding}} {{GNF_GO|id=GO:0030216 |text = keratinocyte differentiation}} {{GNF_GO|id=GO:0030693 |text = caspase activity}} {{GNF_GO|id=GO:0030889 |text = negative regulation of B cell proliferation}} {{GNF_GO|id=GO:0043029 |text = T cell homeostasis}} {{GNF_GO|id=GO:0045165 |text = cell fate commitment}} {{GNF_GO|id=GO:0045736 |text = negative regulation of cyclin-dependent protein kinase activity}} {{GNF_GO|id=GO:0046007 |text = negative regulation of activated T cell proliferation}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 836
| Hs_Ensembl = ENSG00000164305
| Hs_RefseqProtein = NP_004337
| Hs_RefseqmRNA = NM_004346
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 4
| Hs_GenLoc_start = 185785845
| Hs_GenLoc_end = 185807623
| Hs_Uniprot = P42574
| Mm_EntrezGene = 12367
| Mm_Ensembl = ENSMUSG00000031628
| Mm_RefseqmRNA = XM_991820
| Mm_RefseqProtein = XP_996914
| Mm_GenLoc_db =
| Mm_GenLoc_chr = 8
| Mm_GenLoc_start = 48116235
| Mm_GenLoc_end = 48137523
| Mm_Uniprot =
}}
}}
<!-- BOT: SUMMARY BEGIN UPDATE = YES - This summary is automatically updated by protein box bot.  Change the update option to NO to have the bot skip updating this summary -->

Summary

This gene encodes a protein which is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein cleaves and activates caspases 6, 7 and 9, and the protein itself is processed by caspases 8, 9 and 10. It is the predominant caspase involved in the cleavage of amyloid-beta 4A precursor protein, which is associated with neuronal death in Alzheimer's disease. Alternative splicing of this gene results in two transcript variants that encode the same protein.

CDKN1A

REDIRECT: Protein Redirected to: p21 {August 12, 2007 5:36:42 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:45 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: p21. Invoking a Mandantory Inspection. {August 12, 2007 5:36:45 PM PDT}

 {{ProteinShort | Name =p21WAF/p21CIP | caption = | image = | width = | HGNCid = 1784 | Symbol = CDKN1A | AltSymbols = | EntrezGene = 1026 | OMIM = 116899 | RefSeq = NM_000389 | UniProt = P38936 | PDB = | ECnumber = | Chromosome = | Arm = | Band = | LocusSupplementaryData = }}
{{lowercase|title=p21}}
p21, also known as cyclin-dependent kinase inhibitor 1A or CDKN1A, is a human gene on chromosome 6 (location 6p21.2), that encodes a cyclin-dependent kinase inhibitor that directly inhibits the activity of cyclin-CDK2 and cyclin-CDK4 complexes.  p21 functions as a regulator of cell cycle progression at G1 phase<ref name="Gartel2005">A. L. Gartel and S. K. Radhakrishnan (2005) "Lost in transcription: p21 repression, mechanisms, and consequences" in Cancer Research Volume 65, pages 3980-3985. {{Entrez Pubmed|15899785}}</ref>. The expression of p21 is controlled by the tumor suppressor protein p53.
The function of this gene relates in part to stress response <ref name="Rodriguez2006">R. Rodriguez and M. Meuth. (2006) "Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress" in Molecular Biology of the Cell Volume 17, pages 402-412. {{Entrez Pubmed|16280359}}</ref>.
p21 is also mediating the resistance of hematopoietic cells to an infection with HIV <ref name="Zhang et al., 2007">Zhang J, Scadden DT, Crumpacker CS.: Primitive hematopoietic cells resist HIV-1 infection via p21. J Clin Invest. 2007 Feb 1;117(2):473-481. PMID 17273559 </ref> by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus.

External links

{{McGrawHillAnimation|genetics|Tumor%20Suppressor%20Gene}}
{{MeshName|Cyclin-Dependent+Kinase+Inhibitor+p21}}

References

Appended Protein Page ******

{{GNF_Protein_box

| image =

| image_source =

| PDB =

| Name = cyclin-dependent kinase inhibitor 1A (p21, Cip1)

| HGNCid = 1784

| Symbol = CDKN1A

| AltSymbols =; CAP20; CDKN1; CIP1; MDA-6; P21; SDI1; WAF1; p21CIP1

| OMIM = 116899

| ECnumber =

| Homologene = 333

| MGIid = 104556

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000307 |text = cyclin-dependent protein kinase holoenzyme complex}} {{GNF_GO|id=GO:0004672 |text = protein kinase activity}} {{GNF_GO|id=GO:0004861 |text = cyclin-dependent protein kinase inhibitor activity}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0006974 |text = response to DNA damage stimulus}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007050 |text = cell cycle arrest}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0008629 |text = induction of apoptosis by intracellular signals}} {{GNF_GO|id=GO:0009411 |text = response to UV}} {{GNF_GO|id=GO:0016301 |text = kinase activity}} {{GNF_GO|id=GO:0030332 |text = cyclin binding}} {{GNF_GO|id=GO:0030890 |text = positive regulation of B cell proliferation}} {{GNF_GO|id=GO:0043066 |text = negative regulation of apoptosis}} {{GNF_GO|id=GO:0043071 |text = positive regulation of non-apoptotic programmed cell death}} {{GNF_GO|id=GO:0045736 |text = negative regulation of cyclin-dependent protein kinase activity}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 1026

| Hs_Ensembl = ENSG00000124762

| Hs_RefseqProtein = NP_000380

| Hs_RefseqmRNA = NM_000389

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 6

| Hs_GenLoc_start = 36754413

| Hs_GenLoc_end = 36763094

| Hs_Uniprot = P38936

| Mm_EntrezGene = 12575

| Mm_Ensembl = ENSMUSG00000023067

| Mm_RefseqmRNA = NM_007669

| Mm_RefseqProtein = NP_031695

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 17

| Mm_GenLoc_start = 28821439

| Mm_GenLoc_end = 28828386

| Mm_Uniprot =

}}

Summary

This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis following caspase activation. Two alternatively spliced variants, which encode an identical protein, have been reported.

CDKN2A

REDIRECT: Protein Redirected to: P16INK4a {August 12, 2007 5:36:45 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:48 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: P16INK4a. Invoking a Mandantory Inspection. {August 12, 2007 5:36:48 PM PDT}

 {{Mergeto|P16 (gene)|date=January 2007}}
{{protein
| Name = cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
| caption =
| image =
| width =
| HGNCid = 1787
| Symbol = CDKN2A
| AltSymbols = CDKN2, MLM
| EntrezGene = 1029
| OMIM = 600160
| RefSeq = NM_000077
| UniProt = P42771
| PDB =
| ECnumber =
| Chromosome = 9
| Arm = p
| Band = 21
| LocusSupplementaryData =
}}
{{lowercase|p16INK4a}}
p16INK4a is a principle product of the CDKN2A locus. Its alternate reading frame product is p14ARF. p16INK4a regulates the cell cycle by binding and deactivating various cyclin-CDK complexes.
A study published in 2007 in the New England Journal of medicine established that there is a strong association between polymorphisms on chromosome 9p21.3 (SNP, rs1333049) and coronary artery disease. This region codes for the INK4 proteins p16INK4a and p15INK4b. The corresponding genes are CDKN2A and CDKN2B. The proteins may inhibit cell growth induced by Transforming Growth Factor-beta.

External links

[http://www.upi.com/NewsTrack/view.php?StoryID=20060906-023232-7367r "Scientists study mammalian aging"] at United Press International
{{cite journal |author=Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE |title=p16INK4a induces an age-dependent decline in islet regenerative potential |journal=Nature |volume=443 |issue=7110 |pages=453-7 |year=2006 |pmid=16957737 |url=http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature05092.html}}
NEJM 2007 [http://content.nejm.org/cgi/content/abstract/357/5/443 Genomewide Association Analysis of Coronary Artery Disease]

Category:Genes

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_CDKN2A_image.jpg

| image_source = PDB rendering based on 1a5e.

| PDB = {{PDB2|1a5e}}, {{PDB2|1bi7}}, {{PDB2|1dc2}}, {{PDB2|2a5e}}

| Name = cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)

| HGNCid = 1787

| Symbol = CDKN2A

| AltSymbols =; ARF; CDK4I; CDKN2; CMM2; INK4; INK4a; MLM; MTS1; TP16; p14; p14ARF; p16; p16INK4; p16INK4a; p19

| OMIM = 600160

| ECnumber =

| Homologene = 55430

| MGIid =

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000075 |text = cell cycle checkpoint}} {{GNF_GO|id=GO:0000079 |text = regulation of cyclin-dependent protein kinase activity}} {{GNF_GO|id=GO:0003677 |text = DNA binding}} {{GNF_GO|id=GO:0004861 |text = cyclin-dependent protein kinase inhibitor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005575 |text = cellular_component}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005654 |text = nucleoplasm}} {{GNF_GO|id=GO:0005730 |text = nucleolus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006364 |text = rRNA processing}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007050 |text = cell cycle arrest}} {{GNF_GO|id=GO:0007569 |text = cell aging}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0008544 |text = epidermis development}} {{GNF_GO|id=GO:0016301 |text = kinase activity}} {{GNF_GO|id=GO:0045736 |text = negative regulation of cyclin-dependent protein kinase activity}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 1029

| Hs_Ensembl = ENSG00000147889

| Hs_RefseqProtein = NP_000068

| Hs_RefseqmRNA = NM_000077

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 9

| Hs_GenLoc_start = 21957751

| Hs_GenLoc_end = 21984490

| Hs_Uniprot = P42771

| Mm_EntrezGene =

| Mm_Ensembl =

| Mm_RefseqmRNA =

| Mm_RefseqProtein =

| Mm_GenLoc_db =

| Mm_GenLoc_chr =

| Mm_GenLoc_start =

| Mm_GenLoc_end =

| Mm_Uniprot =

}}

Summary

This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, MDM1, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene.

CTNNB1

REDIRECT: Protein Redirected to: Beta-catenin {August 12, 2007 5:36:48 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:50 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Beta-catenin. Invoking a Mandantory Inspection. {August 12, 2007 5:36:50 PM PDT}

 {{protein | Name = Beta catenin 1 | caption = | image =  | width = | HGNCid = 2514 | Symbol = CTNNB1 | AltSymbols = | EntrezGene = 1499 | OMIM = 116806 | RefSeq = NM_001904 | UniProt = P35222 | PDB = | ECnumber = | Chromosome = 3 | Arm = p | Band = 21 | LocusSupplementaryData = }}
Beta-catenin is a subunit of the cadherin protein complex.  In Drosophila, the homologous protein is called armadillo.
'''
Beta-catenin in the canonical Wnt signaling pathway.'''
Beta-catenin has been implicated as an integral component in the Wnt signaling pathway.

Function

When beta-catenin was sequenced it was found to be a member of the armadillo family of proteins. These proteins have multiple copies of the so-called armadillo repeat domain which is specialized for protein-protein binding. An increase in beta-catenin production has been noted in those people who have Basal Cell Carcinoma and leads to the increase in proliferation of related tumors.<ref>G. Saldanha, V. Ghura, L. Potter and A. Fletcher. "Nuclear beta-catenin in basal cell carcinoma correlates with increased proliferation" in The British Journal of Dermatology (2004) Volume 151, pages 157-164. {{Entrez Pubmed|15270885}}</ref> When beta-catenin is not associated with cadherins and alpha-catenin, it can interact with other proteins such as ICAT and APC.

Role in Liver Biology

Recent evidence suggests that beta-catenin plays an important role in various aspects of liver biology including liver development (both embryonic and postnatal), liver regeneration following partial hepatectomy. HGF-induced hepatpomegaly, liver zonation, and pathogenesis of liver cancer.<ref>{{cite journal |author=Thompson MD, Monga SP |title=WNT/beta-catenin signaling in liver health and disease |journal=Hepatology |volume=45 |issue=5 |pages=1298-305 |year=2007 |pmid=17464972 |doi=10.1002/hep.21651}}</ref>

Interactions of beta-catenin with other proteins

Image:Betareg.PNG

As mentioned above, beta-catenin contains armadillo repeats and is able to bind to other proteins. Inside cells, beta-catenin can be found in complexes with cadherins, transcription factors (TF in Figure 2) and other proteins such as axin, a component of the Wnt signalling pathway. The ability of beta-catenin to bind to other proteins is regulated by tyrosine kinases<ref>J. Lilien and J. Balsamo "The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin" in Current opinion in cell biology (2005) Volume 17, pages 459-465. {{Entrez Pubmed|16099633}}</ref> and serine kinases such as GSK-3.<ref>M. D. Castellone, H. Teramoto, B. O. Williams, K. M. Druey, J. S. Gutkind. "Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis" in ''Science (2005) Volume 310, pages 1504-1510. {{Entrez Pubmed|16293724}}</ref>

When beta-catenin is not assembled in complexes with cadherins, it can form a complex with axin. While bound to axin, beta-catenin can be phosphorylated by GSK-3, which creates a signal for the rapid ubiquitin-dependent degradation of beta-catenin by proteosomes. Various signals such as the Wnt signalling pathway can inhibit GSK-3-mediated phosphorylation of beta-catenin,<ref>X. Liu, J. S. Rubin and A. R. Kimmel. "Rapid, Wnt-induced changes in GSK3beta associations that regulate beta-catenin stabilization are mediated by Galpha proteins" in Current Biology (2005) Volume 15, pages 1989-1997. {{Entrez Pubmed|16303557}}</ref> allowing beta-catenin to go to the cell nucleus, interact with transcription factors, and regulate gene transcription.

Beta-catenin can be phosphorylated by other kinases such as protein kinase A (PKA). Phosphorylation of beta-catenin by PKA has been associated with reduced degradation of beta-catenin, increased levels of beta-catenin in the nucleus and interaction of beta-catenin with TCF family transcription factors to regulate gene expression.<ref>S. Hino, C. Tanji, K. I. Nakayama and A. Kikuchi "Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination" in Molecular and Cellular Biology (2005) Volume 20, pages 9063-9072. {{Entrez Pubmed|16199882}}</ref>

The Role of Beta-Catenin in The Wnt Signaling Pathway

When Wnt is not present, GSK3 (a kinase) constitutively phosphorylates the beta-catenin protein. Beta-catenin is associated with Axin (scaffolding protein) complexed with GSK3 and APC (adenomatosis polyposis coli). The APC in this pathway is completely separate and unrelated to the Anaphase Promoting Complex involved in cell cycle regulation. The creation of said complex acts to substantially increase the phosphorylation of beta-catenin by facilitating the the action of GSK3. When beta-catenin is phosphorylated it is degraded and thus will not build up in the cell to a significant level. When Wnt binds to Frizzled (Fz), its receptor, dishevelled (Dsh) is recruited to the membrane. GSK3 is inhibited by the activation of Dsh by Fz. Because of this, beta-catenin is permited to build up in the cytosol and can be subsequently translocated into the nucleus to perform a variety of functions. It can act in conjunction with TCF to activate specific genes as well as cause the export of TCF from the nucleus.

External links

{{MeshName|Beta+Catenin}}
[http://ccr.cancer.gov/Staff/gallery.asp?profileid=5411 "A diverse set of proteins modulate the canonical Wnt/beta-catenin signaling pathway." at cancer.gov]
[http://mammary.nih.gov/lgp/lab/slides/LGP-research-past.html#a1 "The role of beta-catenin in signal transduction, cell fate determination and trans-differentiation" at nih.gov]

References

Category:Signal transduction

Category:Proteins

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_CTNNB1_image.jpg

| image_source = PDB rendering based on 1dow.

| PDB = {{PDB2|1dow}}, {{PDB2|1g3j}}, {{PDB2|1i7w}}, {{PDB2|1i7x}}, {{PDB2|1jdh}}, {{PDB2|1jpp}}, {{PDB2|1jpw}}, {{PDB2|1luj}}, {{PDB2|1m1e}}, {{PDB2|1qz7}}, {{PDB2|1t08}}, {{PDB2|1th1}}, {{PDB2|1v18}}, {{PDB2|2bct}}, {{PDB2|2gl7}}, {{PDB2|3bct}}

| Name = catenin (cadherin-associated protein), beta 1, 88kDa

| HGNCid = 2514

| Symbol = CTNNB1

| AltSymbols =; CTNNB; FLJ25606

| OMIM = 116806

| ECnumber =

| Homologene = 1434

| MGIid = 88276

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000122 |text = negative regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0000904 |text = cellular morphogenesis during differentiation}} {{GNF_GO|id=GO:0001501 |text = skeletal development}} {{GNF_GO|id=GO:0001569 |text = patterning of blood vessels}} {{GNF_GO|id=GO:0001706 |text = endoderm formation}} {{GNF_GO|id=GO:0001708 |text = cell fate specification}} {{GNF_GO|id=GO:0001709 |text = cell fate determination}} {{GNF_GO|id=GO:0001711 |text = endodermal cell fate commitment}} {{GNF_GO|id=GO:0003682 |text = chromatin binding}} {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003713 |text = transcription coactivator activity}} {{GNF_GO|id=GO:0004871 |text = signal transducer activity}} {{GNF_GO|id=GO:0005198 |text = structural molecule activity}} {{GNF_GO|id=GO:0005488 |text = binding}} {{GNF_GO|id=GO:0005624 |text = membrane fraction}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005667 |text = transcription factor complex}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005856 |text = cytoskeleton}} {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0005913 |text = cell-cell adherens junction}} {{GNF_GO|id=GO:0007268 |text = synaptic transmission}} {{GNF_GO|id=GO:0007398 |text = ectoderm development}} {{GNF_GO|id=GO:0007507 |text = heart development}} {{GNF_GO|id=GO:0009950 |text = dorsal/ventral axis specification}} {{GNF_GO|id=GO:0009954 |text = proximal/distal pattern formation}} {{GNF_GO|id=GO:0010003 |text = gastrulation (sensu Mammalia)}} {{GNF_GO|id=GO:0016055 |text = Wnt receptor signaling pathway}} {{GNF_GO|id=GO:0016323 |text = basolateral plasma membrane}} {{GNF_GO|id=GO:0016328 |text = lateral plasma membrane}} {{GNF_GO|id=GO:0016331 |text = morphogenesis of embryonic epithelium}} {{GNF_GO|id=GO:0016337 |text = cell-cell adhesion}} {{GNF_GO|id=GO:0030027 |text = lamellipodium}} {{GNF_GO|id=GO:0030097 |text = hemopoiesis}} {{GNF_GO|id=GO:0030316 |text = osteoclast differentiation}} {{GNF_GO|id=GO:0030324 |text = lung development}} {{GNF_GO|id=GO:0030521 |text = androgen receptor signaling pathway}} {{GNF_GO|id=GO:0030858 |text = positive regulation of epithelial cell differentiation}} {{GNF_GO|id=GO:0030900 |text = forebrain development}} {{GNF_GO|id=GO:0031016 |text = pancreas development}} {{GNF_GO|id=GO:0031528 |text = microvillus membrane}} {{GNF_GO|id=GO:0035116 |text = embryonic hindlimb morphogenesis}} {{GNF_GO|id=GO:0035117 |text = embryonic arm morphogenesis}} {{GNF_GO|id=GO:0042127 |text = regulation of cell proliferation}} {{GNF_GO|id=GO:0042475 |text = odontogenesis (sensu Vertebrata)}} {{GNF_GO|id=GO:0042733 |text = embryonic digit morphogenesis}} {{GNF_GO|id=GO:0045177 |text = apical part of cell}} {{GNF_GO|id=GO:0045294 |text = alpha-catenin binding}} {{GNF_GO|id=GO:0045296 |text = cadherin binding}} {{GNF_GO|id=GO:0045453 |text = bone resorption}} {{GNF_GO|id=GO:0045596 |text = negative regulation of cell differentiation}} {{GNF_GO|id=GO:0045669 |text = positive regulation of osteoblast differentiation}} {{GNF_GO|id=GO:0045671 |text = negative regulation of osteoclast differentiation}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0048469 |text = cell maturation}} {{GNF_GO|id=GO:0048489 |text = synaptic vesicle transport}} {{GNF_GO|id=GO:0050681 |text = androgen receptor binding}} {{GNF_GO|id=GO:0050808 |text = synapse organization and biogenesis}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 1499

| Hs_Ensembl = ENSG00000168036

| Hs_RefseqProtein = XP_001133660

| Hs_RefseqmRNA = XM_001133660

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 3

| Hs_GenLoc_start = 41216004

| Hs_GenLoc_end = 41256938

| Hs_Uniprot = P35222

| Mm_EntrezGene = 12387

| Mm_Ensembl = ENSMUSG00000006932

| Mm_RefseqmRNA = NM_007614

| Mm_RefseqProtein = NP_031640

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 9

| Mm_GenLoc_start = 120782173

| Mm_GenLoc_end = 120809205

| Mm_Uniprot =

}}

Summary

Beta-catenin is an adherens junction protein. Adherens junctions (AJs; also called the zonula adherens) are critical for the establishment and maintenance of epithelial layers, such as those lining organ surfaces. AJs mediate adhesion between cells, communicate a signal that neighboring cells are present, and anchor the actin cytoskeleton. In serving these roles, AJs regulate normal cell growth and behavior. At several stages of embryogenesis, wound healing, and tumor cell metastasis, cells form and leave epithelia. This process, which involves the disruption and reestablishment of epithelial cell-cell contacts, may be regulated by the disassembly and assembly of AJs. AJs may also function in the transmission of the 'contact inhibition' signal, which instructs cells to stop dividing once an epithelial sheet is complete.[supplied by OMIM]

EGFR

REDIRECT: Protein Redirected to: Epidermal growth factor receptor {August 12, 2007 5:36:50 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:53 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Epidermal growth factor receptor. Invoking a Mandantory Inspection. {August 12, 2007 5:36:53 PM PDT}

 {{Protein
|Name=Epidermal growth factor receptor
|image=EGFR_structure.png
|caption=The extracellular domain of EGFR in a complex with EGF {{PDB|1NQL}}
|Symbol=EGFR
|AltSymbols=ERBB1
|HGNCid=3236
|Chromosome=7
|Arm=p
|Band=12
|LocusSupplementaryData=
|ECnumber=2.7.1.112
|OMIM=131550
|EntrezGene=1956
|RefSeq=NM_005228
|UniProt=P00533
}}
{{otheruses4|a cell suface receptor|estimated measure of kidney function (eGFR)|Glomerular filtration rate}}
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands. The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). Mutations affecting EGFR expression or activity could result in cancer.

Function

EGFR (epidermal growth factor receptor) exists on the cell surface and is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor Î± (TGFÎ±) (note, a full list of the ligands able to activate EGFR and other members of the ErbB family is given in the ErbB article). ErbB2 has no known direct activating ligand, and may be in an activated state constitutively.

Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer - although there is some evidence that preformed inactive dimers may also exist before ligand binding. In addition to forming homodimers after ligand binding, EGFR may pair with another member of the ErbB receptor family, such as ErbB2/Her2/neu, to create an activated heterodimer. There is also evidence to suggest that clusters of activated EGFRs form, although it remains unclear whether this clustering is important for activation itself or occurs subsequent to activation of individual dimers.

Image:EGF Receptor.jpg

EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of five tyrosine (Y) residues in the C-terminal domain of EGFR occurs. These are Y992, Y1045, Y1068, Y1148 and Y1173 as shown in the diagram to the left. This autophosphorylation elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation{{ref_N|1|a}}. Such proteins modulate phenotypes such as cell migration, adhesion, and proliferation. The kinase domain of EGFR can also cross-phosphorylate tyrosine residues of other receptors it is aggregated with, and can itself be activated in that manner.

Clinical applications

Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including lung cancer and glioblastoma multiforme. In this latter case a more or less specific mutation of EGFR, called EGFRvIII is often met with [http://www.healthvalue.net/egfreceptor.html].

Mutations involving EGFR could lead to its constant activation which could result in uncontrolled cell division – a predisposition for cancer{{ref_N|2|a}} . Consequently, mutations of EGFR have been identified in several types of cancer, and it is the target of an expanding class of anticancer therapies.

The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including gefitinib{{ref_N|3|a}} and erlotinib for lung cancer, and cetuximab for colon cancer.

Many therapeutic approaches are aimed at the EGFR [http://www.healthvalue.net/EGFR-engl.html]. Cetuximab and panitumumab are examples of monoclonal antibody inhibitors. However the former is of the IgG1 type, the latter of the IgG2 type; consequences on antibody dependent cellular cytotoxicity can be quite different [http://www.healthvalue.net/IgG1_IgG2.html]. Other monoclonals in clinical development are zalutumumab, nimotuzumab, matuzumab. Gefitinib, erlotinib and lapatinib (the latter still in clinical trials) are examples of small molecule kinase inhibitors. The monoclonal antibodies block the extracellular ligand binding domain. With the binding site blocked, signal molecules can no longer attach there and activate the tyrosine kinase. Another method is using small molecules to inhibit the EGFR tyrosine kinase, which is on the cytoplasmic side of the receptor. Without kinase activity, EGFR is unable to activate itself, which is a prerequisite for binding of downstream adaptor proteins. Ostensibly by halting the signaling cascade in cells that rely on this pathway for growth, tumor proliferation and migration is diminished.

In July 2007 it was discovered that the blood clotting protein Fibrinogen inhibits EGFR, thereby blocking regrowth of injured neuronal cells in the spine. [http://www.eurekalert.org/pub_releases/2007-07/uoc--bcp070307.php]

References

{{note_N|1|a}} A comprehensive pathway map of epidermal growth factor receptor signaling. Molecular Systems Biology doi:10.1038/msb4100014, 2005 May [http://www.nature.com/msb/journal/v1/n1/full/msb4100014.html]
{{note_N|2|a}} Image:Free text.png Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004 May 20; 350(21): 2129-39. PMID 15118073 [http://content.nejm.org/cgi/content/full/350/21/2129 Free text]
{{note_N|3|a}} EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004 Jun 4; 304(5676): 1497-500. PMID 15118125

External links

{{cite journal |author=Herbst R |title=Review of epidermal growth factor receptor biology |journal=Int J Radiat Oncol Biol Phys |volume=59 |issue=2 Suppl |pages=21-6 |year=2004 |id=PMID 15142631}}
{{MeshName|Epidermal+Growth+Factor+Receptor}}
[http://www.eurekalert.org/pub_releases/2007-07/uoc--bcp070307.php Fibrinogen, a blood-clotting protein, found to inhibit EGFR] Explains lack of healing in spinal injuries.

Category:Tyrosine kinase receptors

Category:Oncogenes

de:EGF-Rezeptor

fr:RÃ©cepteur Ã l'EGF

ja:ä¸Šçš®æˆ�é•·å› å�å�—å®¹ä½“

fi:Epidermaalisen kasvutekijÃ¤n reseptori

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_EGFR_image.jpg

| image_source = PDB rendering based on 1ivo.

| PDB = {{PDB2|1ivo}}, {{PDB2|1m14}}, {{PDB2|1m17}}, {{PDB2|1mox}}, {{PDB2|1nql}}, {{PDB2|1xkk}}, {{PDB2|1yy9}}, {{PDB2|1z9i}}, {{PDB2|2gs2}}, {{PDB2|2gs6}}, {{PDB2|2gs7}}, {{PDB2|2itn}}, {{PDB2|2ito}}, {{PDB2|2itp}}, {{PDB2|2itq}}, {{PDB2|2itt}}, {{PDB2|2itu}}, {{PDB2|2itv}}, {{PDB2|2itw}}, {{PDB2|2itx}}, {{PDB2|2ity}}, {{PDB2|2itz}}, {{PDB2|2j5e}}, {{PDB2|2j5f}}, {{PDB2|2j6m}}

| Name = epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)

| HGNCid = 3236

| Symbol = EGFR

| AltSymbols =; ERBB; ERBB1; mENA

| OMIM = 131550

| ECnumber =

| Homologene = 74545

| MGIid = 95294

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0001503 |text = ossification}} {{GNF_GO|id=GO:0003690 |text = double-stranded DNA binding}} {{GNF_GO|id=GO:0004710 |text = MAP/ERK kinase kinase activity}} {{GNF_GO|id=GO:0004888 |text = transmembrane receptor activity}} {{GNF_GO|id=GO:0005006 |text = epidermal growth factor receptor activity}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0005622 |text = intracellular}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005768 |text = endosome}} {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0006950 |text = response to stress}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007166 |text = cell surface receptor linked signal transduction}} {{GNF_GO|id=GO:0007173 |text = epidermal growth factor receptor signaling pathway}} {{GNF_GO|id=GO:0007202 |text = phospholipase C activation}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} {{GNF_GO|id=GO:0016323 |text = basolateral plasma membrane}} {{GNF_GO|id=GO:0016337 |text = cell-cell adhesion}} {{GNF_GO|id=GO:0016740 |text = transferase activity}} {{GNF_GO|id=GO:0030122 |text = AP-2 adaptor complex}} {{GNF_GO|id=GO:0030139 |text = endocytic vesicle}} {{GNF_GO|id=GO:0030235 |text = nitric-oxide synthase regulator activity}} {{GNF_GO|id=GO:0030335 |text = positive regulation of cell migration}} {{GNF_GO|id=GO:0042327 |text = positive regulation of phosphorylation}} {{GNF_GO|id=GO:0042802 |text = identical protein binding}} {{GNF_GO|id=GO:0043006 |text = calcium-dependent phospholipase A2 activation}} {{GNF_GO|id=GO:0043406 |text = positive regulation of MAPK activity}} {{GNF_GO|id=GO:0045429 |text = positive regulation of nitric oxide biosynthetic process}} {{GNF_GO|id=GO:0045786 |text = negative regulation of progression through cell cycle}} {{GNF_GO|id=GO:0046777 |text = protein amino acid autophosphorylation}} {{GNF_GO|id=GO:0046982 |text = protein heterodimerization activity}} {{GNF_GO|id=GO:0050679 |text = positive regulation of epithelial cell proliferation}} {{GNF_GO|id=GO:0050730 |text = regulation of peptidyl-tyrosine phosphorylation}} {{GNF_GO|id=GO:0050999 |text = regulation of nitric-oxide synthase activity}} {{GNF_GO|id=GO:0051015 |text = actin filament binding}} {{GNF_GO|id=GO:0051205 |text = protein insertion into membrane}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 1956

| Hs_Ensembl = ENSG00000146648

| Hs_RefseqProtein = NP_005219

| Hs_RefseqmRNA = NM_005228

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 7

| Hs_GenLoc_start = 55054219

| Hs_GenLoc_end = 55242524

| Hs_Uniprot = P00533

| Mm_EntrezGene = 13649

| Mm_Ensembl = ENSMUSG00000020122

| Mm_RefseqmRNA = NM_007912

| Mm_RefseqProtein = NP_031938

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 11

| Mm_GenLoc_start = 16652206

| Mm_GenLoc_end = 16813912

| Mm_Uniprot =

}}

ERBB2

REDIRECT: Protein Redirected to: HER2 {August 12, 2007 5:36:53 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:55 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: HER2. Invoking a Mandantory Inspection. {August 12, 2007 5:36:55 PM PDT}

 #REDIRECT HER2/neu

Appended Protein Page ******

<!-- BOT: MANUAL_INSPECTION_REQUIRED = NO - change this option to YES to have the protein box bot require an operator inspection before updating occurs.  -->
<!-- BOT: PROTEIN BOX UPDATE = YES - This protein box is automatically updated by protein box bot. Change the update option to NO to have the bot skip updating this protein box -->
{{GNF_Protein_box
| image = PBB_Protein_ERBB2_image.jpg
| image_source = PDB rendering based on 1n8z.
| PDB = {{PDB2|1n8z}}, {{PDB2|1s78}}, {{PDB2|2a91}}
| Name = v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)
| HGNCid = 3430
| Symbol = ERBB2
| AltSymbols =; HER-2; HER-2/neu; HER2; NEU; NGL; TKR1; c-erb B2
| OMIM = 164870
| ECnumber =
| Homologene = 3273
| MGIid = 95410
| GeneAtlas_image =
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = ~~~~~
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004713 |text = protein-tyrosine kinase activity}} {{GNF_GO|id=GO:0004715 |text = non-membrane spanning protein tyrosine kinase activity}} {{GNF_GO|id=GO:0004716 |text = receptor signaling protein tyrosine kinase activity}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0005006 |text = epidermal growth factor receptor activity}} {{GNF_GO|id=GO:0005506 |text = iron ion binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0006118 |text = electron transport}} {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0007169 |text = transmembrane receptor protein tyrosine kinase signaling pathway}} {{GNF_GO|id=GO:0007422 |text = peripheral nervous system development}} {{GNF_GO|id=GO:0007507 |text = heart development}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0009055 |text = electron carrier activity}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} {{GNF_GO|id=GO:0016324 |text = apical plasma membrane}} {{GNF_GO|id=GO:0016740 |text = transferase activity}} {{GNF_GO|id=GO:0030879 |text = mammary gland development}} {{GNF_GO|id=GO:0042552 |text = myelination}} {{GNF_GO|id=GO:0042802 |text = identical protein binding}} {{GNF_GO|id=GO:0043125 |text = ErbB-3 class receptor binding}} {{GNF_GO|id=GO:0043406 |text = positive regulation of MAPK activity}} {{GNF_GO|id=GO:0045765 |text = regulation of angiogenesis}} {{GNF_GO|id=GO:0046982 |text = protein heterodimerization activity}} {{GNF_GO|id=GO:0048015 |text = phosphoinositide-mediated signaling}} {{GNF_GO|id=GO:0050679 |text = positive regulation of epithelial cell proliferation}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 2064
| Hs_Ensembl = ENSG00000141736
| Hs_RefseqProtein = NP_004439
| Hs_RefseqmRNA = NM_004448
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 17
| Hs_GenLoc_start = 35104766
| Hs_GenLoc_end = 35138441
| Hs_Uniprot = P04626
| Mm_EntrezGene = 13866
| Mm_Ensembl = ENSMUSG00000062312
| Mm_RefseqmRNA = NM_001003817
| Mm_RefseqProtein = NP_001003817
| Mm_GenLoc_db =
| Mm_GenLoc_chr = 11
| Mm_GenLoc_start = 98228574
| Mm_GenLoc_end = 98253806
| Mm_Uniprot =
}}
}}
<!-- BOT: SUMMARY BEGIN UPDATE = YES - This summary is automatically updated by protein box bot.  Change the update option to NO to have the bot skip updating this summary -->

Summary

This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized.

ESR1

REDIRECT: Protein Redirected to: Estrogen receptor {August 12, 2007 5:36:55 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:36:58 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Estrogen receptor. Invoking a Mandantory Inspection. {August 12, 2007 5:36:58 PM PDT}

 {{protein
| Name = estrogen receptor alpha
| caption =
| image =
| width =
| HGNCid = 3467
| Symbol = ERÎ±
| AltSymbols = (ESR1, ESR)
| EntrezGene = 2099
| OMIM = 133430
| RefSeq = NM_000125
| UniProt = P03372
| PDB = 1ERE
| ECnumber =
| Chromosome = 6
| Arm = q
| Band = 24
| LocusSupplementaryData = -q27
}}
{{protein
| Name = estrogen receptor beta
| caption = A dimer of the ligand-binding region of ERÎ²
| image = ERbeta.jpg
| width = 200
| HGNCid = 3468
| Symbol = ERÎ²
| AltSymbols = (ESR2)
| EntrezGene = 2100
| OMIM = 601663
| RefSeq = NM_001040275
| UniProt = Q92731
| PDB = 1QKM
| ECnumber =
| Chromosome = 14
| Arm = q
| Band = 21
| LocusSupplementaryData = -q22
}}
The estrogen receptor (ER) is a member of the nuclear hormone family of intracellular receptors which is activated by the hormone 17Î²-estradiol.<ref name="pmid17132854">{{cite journal | author = Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA | title = International Union of Pharmacology. LXIV. Estrogen receptors | journal = Pharmacol. Rev. | volume = 58 | issue = 4 | pages = 773-81 | year = 2006 | pmid = 17132854 | doi = 10.1124/pr.58.4.8}}</ref>  The main function of the estrogen receptor is as a DNA binding transcription factor which regulates gene expression.  However the estrogen receptor also has additional functions independent of DNA binding.<ref name="pmid15705661">{{cite journal | author = Levin ER | title = Integration of the extranuclear and nuclear actions of estrogen | journal = Mol. Endocrinol. | volume = 19 | issue = 8 | pages = 1951-9 | year = 2005 | pmid = 15705661 | doi = 10.1210/me.2004-0390}}</ref>

Proteomics

There are two different forms of the estrogen receptor usually referred to as Î± and Î² each encoded by a separate gene ({{gene|ESR1}} and {{gene|ESR2}} respectively). Hormone activated estrogen receptors form dimers, and since the two forms are coexpressed in many cell types, the receptors may form ERÎ± (Î±Î±) or ERÎ² (Î²Î²) homodimers or ERÎ±Î² (Î±Î²) heterodimers.<ref name="pmid15314175">{{cite journal | author = Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M | title = Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways | journal = Mol. Cell. Biol. | volume = 24 | issue = 17 | pages = 7681-94 | year = 2004 | pmid = 15314175 | doi = 10.1128/MCB.24.17.7681-7694.2004}}</ref>

Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of seven domains (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER):

Image:Er_domains.svg

Genetics

The two forms of the estrogen receptor are encoded by different genes, {{gene|ESR1}} and {{gene|ESR2}} on the sixth and fourteenth chromosome (6q25.1 and 14q), respectively.

Distribution

Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:

The ERÎ± is found in endometrium, breast cancer cells, ovarian stroma cells and in the hypothalamus.<ref name="pmid15990721">{{cite journal | author = Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H | title = Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice | journal = Neuro Endocrinol. Lett. | volume = 26 | issue = 3 | pages = 197-203 | year = 2005 | pmid = 15990721 | doi = | url = http://www.nel.edu/pdf_/26_3/260305A01_15990721_Yaghmaie_.pdf}}</ref>
The expression of the ERÎ² protein has been documented in kidney, brain, bone, heart,<ref name="pmid11861041">{{cite journal | author = Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA | title = Estrogenic hormone action in the heart: regulatory network and function | journal = Cardiovasc. Res. | volume = 53 | issue = 3 | pages = 709-19 | year = 2002 | pmid = 11861041 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/s0008636301005260}}</ref> lungs, intestinal mucosa, prostate, and endothelial cells.

Binding and Functional Selectivity

Image:Estrogen receptor bound to estradiol and tamoxifen.png

Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor:

17-beta-estradiol binds equally well to both receptors
estrone and raloxifene bind preferentially to the alpha receptor
estriol and genistein to the beta receptor

Subtype selective estrogen receptor modulators preferentially bind to either the Î±- or Î²-subtype of the receptor. Additionally, the different estrogen receptor combinations may respond differently to various ligands which may translate into tissue selective agonistic and antagonistic effects.<ref name="pmid15950373">{{cite journal | author = Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N | title = Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release | journal = Mol. Cell. Endocrinol. | volume = 239 | issue = 1-2 | pages = 27-36 | year = 2005 | pmid = 15950373 | doi = 10.1016/j.mce.2005.04.008}}</ref>

The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as transcriptional coactivator or corepressors. Furthermore the ratio of coactivator to corepressor protein varies in different tissues.<ref name="Shang_2002">{{cite journal |author=Shang Y, Brown M|title=Molecular determinants for the tissue specificity of SERMs|journal= Science |volume= 295 |issue= 5564 |pages= 2465-8 |year= 2002 | doi = 10.1126/science.1068537 |pmid= 11923541}}</ref> As a consequence, the same ligand may be an agonist in some tissue (where agonists predominate) while antagonistic in other tissues (where corepressors dominate). Tamoxifen, for example, is an antagonist in breast and is therefore used as a breast cancer treatment<ref name="pmid16511588">{{cite journal | author = Deroo BJ, Korach KS | title = Estrogen receptors and human disease | journal = J. Clin. Invest. | volume = 116 | issue = 3 | pages = 561-70 | year = 2006 | pmid = 16511588 | doi = 10.1172/JCI27987}}</ref> but an ER agonist in bone (thereby preventing osteoporosis) and an agonist in the endometrium (increasing the risk of uterine cancer) .

Signal transduction

Since estrogen is a steroidal hormone it can pass through the phospholipid membranes of the cell, and receptors therefore do not need to be membrane bound in order to bind with estrogen.

=Genomic=

In the absence of hormone, estrogen receptors are largely located in the cytosol. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequently binding of the receptor dimer to specific sequences of DNA known as hormone response elements. The DNA/receptor complex then recruits other proteins which are responsible for the transcription of downstream DNA into mRNA and finally protein which results in a change in cell function. Estrogen receptors also occur within the cell nucleus and both estrogen receptor subtypes have a DNA-binding domain and can function as transcription factors to regulate the production of proteins.

The receptor also interacts with activator protein 1 and Sp-1 to promote transcription, via several coactivators such as PELP-1.<ref name="pmid15705661">{{cite journal | author = Levin ER | title = Integration of the extranuclear and nuclear actions of estrogen | journal = Mol. Endocrinol. | volume = 19 | issue = 8 | pages = 1951-9 | year = 2005 | pmid = 15705661 | doi = 10.1210/me.2004-0390}}</ref>

=Nongenomic=

Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen.<ref name="pmid15642158">{{cite journal | author = Zivadinovic D, Gametchu B, Watson CS | title = Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses | journal = Breast Cancer Res. | volume = 7 | issue = 1 | pages = R101-12 | year = 2005 | pmid = 15642158 | doi = 10.1186/bcr958}}</ref><ref name="BjÃ¶rnstrÃ¶m_2004">{{cite journal |author=BjÃ¶rnstrÃ¶m L, SjÃ¶berg M|title=Estrogen receptor-dependent activation of AP-1 via non-genomic signalling|journal= Nucl Recept |volume= 2 |issue= 1 |pages= 3 |year= 2004 | doi =10.1186/1478-1336-2-3 |pmid= 15196329}}</ref>

Additionally some ER may associate with cell membranes by attachment to caveolin-1 and form complexes with G proteins, striatin, receptor tyrosine kinases (e.g. EGFR and IGF-1), and non-receptor tyrosine kinases (e.g. Src)<ref name=pmid15642158/><ref name=pmid15705661/>. Through striatin, some of this membrane bound ER may lead to increased levels of Ca2+ and nitric oxide (NO).<ref name="pmid15569929">{{cite journal | author = Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH | title = Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 49 | pages = 17126-31 | year = 2004 | pmid = 15569929 | doi = 10.1073/pnas.0407492101}}</ref> Through the receptor tyrosine kinases signals are sent to the nucleus through the mitogen-activated protein kinase (MAPK/ERK) pathway and phosphoinositide 3-kinase (Pl3K/AKT) pathway.<ref name="pmid7491495">{{cite journal | author = Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P | title = Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase | journal = Science | volume = 270 | issue = 5241 | pages = 1491-4 | year = 1995 | pmid = 7491495 | doi = 10.1126/science.270.5241.1491}}</ref> Glycogen synthase kinase-3 (GSK)-3Î² inhibits transcription by nuclear ER by inhibiting phosphorylation of serine 118 of nuclear ERÎ±. Phosphorylation of GSK-3Î² removes its inhibitory effect, and this can be achieved by the PI3K/AKT pathway and the MAPK/ERK pathway, via rsk.

Disease

= Aging =

Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamus as they grow old. Female mice that were given a calorically restricted diet during the majority of their lives, maintained higher levels of ERÎ± in the pre-optic hypothalamus than their non-calorically restricted counterparts.<ref name="pmid15990721">{{cite journal | author = Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H | title = Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice | journal = Neuro Endocrinol. Lett. | volume = 26 | issue = 3 | pages = 197-203 | year = 2005 | pmid = 15990721 | doi = | url = http://www.nel.edu/pdf_/26_3/260305A01_15990721_Yaghmaie_.pdf}}</ref>

= Cancer =

Estrogen receptors are overexpressed in around 70% of breast cancer cases, referred to as "ER positive". Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:

Firstly, binding of estrogen to the ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication leading to mutations.
Secondly, estrogen metabolism produces genotoxic waste.

The result of both processes is disruption of cell cycle, apoptosis and DNA repair and therefore tumour formation. ERÎ± is certainly associated with more differentiated tumours, while evidence that ERÎ² is involved is controversial. Different versions of the ESR1 gene have been identified (with single-nucleotide polymorphisms) and are associated with different risks of developing breast cancer.<ref name="pmid16511588">

Endocrine therpapy for breast cancer involves selective estrogen receptor modulators (SERMS) which behave as ER antagonists in breast tissue or aromatase inhibitors. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors<ref>M Clemons, S Danson, A Howell, 2002. "Tamoxifen (Nolvadox): A Review," Cancer Treat. Rev. 28, 165-180.</ref>. Another SERM, raloxifene, has been used as a preventative chemotherapy for women judged to have a high risk of developing breast cancer.<ref name="pmid15755972">{{cite journal | author = Fabian CJ, Kimler BF | title = Selective estrogen-receptor modulators for primary prevention of breast cancer | journal = J. Clin. Oncol. | volume = 23 | issue = 8 | pages = 1644-55 | year = 2005 | pmid = 15755972 | doi = 10.1200/JCO.2005.11.005 | issn = }}</ref> Another chemotheraputic anti-estrogen, ICI 182,780 (Faslodex) which acts as a complete antagonist also promotes degradation of the estrogen receptor.

Estrogen and the ERs have also been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer and endometrial cancer. Advanced colon cancer is associated with a loss of ERÎ², the predominant ER in colon tissue, and colon cancer is treated with ERÎ² specific agonists.<ref name="pmid14500559">{{cite journal | author = Harris HA, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, Kharode YP, Marzolf J, Komm BS, Winneker RC, Frail DE, Henderson RA, Zhu Y, Keith JC | title = Evaluation of an estrogen receptor-beta agonist in animal models of human disease | journal = Endocrinology | volume = 144 | issue = 10 | pages = 4241-9 | year = 2003 | pmid = 14500559 | doi = 10.1210/en.2003-0550 | issn = }}</ref>

= Obesity =

A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from transgenic mice that were genetically engineered to lack a functional aromatase gene. These mice have very low levels of estrogen and are obese.<ref name="pmid12933663">{{cite journal | author = Hewitt KN, Boon WC, Murata Y, Jones ME, Simpson ER | title = The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis | journal = Endocrinology | volume = 144 | issue = 9 | pages = 3895-903 | year = 2003 | pmid = 12933663 | doi = | issn = }}</ref> Obesity was also observed in estrogen deficient female mice lacking the follicle-stimulating hormone receptor.<ref name="pmid11089565">{{cite journal | author = Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR | title = Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice | journal = Endocrinology | volume = 141 | issue = 11 | pages = 4295-308 | year = 2000 | pmid = 11089565 | doi = 10.1210/en.141.11.4295 | issn = }}</ref> The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.<ref name="pmid11095962">{{cite journal | author = Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly-Y M, Bohlooly M, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson JA | title = Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice | journal = Biochem. Biophys. Res. Commun. | volume = 278 | issue = 3 | pages = 640-5 | year = 2000 | pmid = 11095962 | doi = 10.1006/bbrc.2000.3827 | issn = }}</ref>

Research history

Estrogen receptors were first identified by Elwood V. Jensen at the University of Chicago in the 1950s,<ref name="pmid12796359">{{cite journal | author = Jensen EV, Jordan VC | title = The estrogen receptor: a model for molecular medicine | journal = Clin. Cancer Res. | volume = 9 | issue = 6 | pages = 1980-9 | year = 2003 | pmid = 12796359 | doi = | issn = | url = http://clincancerres.aacrjournals.org/cgi/content/abstract/9/6/1980}}</ref> for which Jensen was awarded the Lasker Award<ref>David Bracey, 2004 "[http://www.uc.edu/news/NR.asp?id=1993 UC Scientist Wins 'American Nobel' Research Award]." University of Cincinnati press release.</ref>. The gene for a second estrogen receptor (ERÎ²) was identified in 1996.<ref name="pmid8650195">{{cite journal | author = Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA | title = Cloning of a novel receptor expressed in rat prostate and ovary | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 12 | pages = 5925-30 | year = 1996 | pmid = 8650195 | doi = 10.1073/pnas.93.12.5925| issn = }}</ref>

References

External links

{{MeshName|Estrogen+Receptors}}
[http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb45_1.html Molecule of the month] February 2006 at the Protein Data Bank.

Category:Intracellular receptors

de:Ã–strogenrezeptor

fr:RÃ©cepteur des Å“strogÃ¨nes

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_ESR1_image.jpg

| image_source = PDB rendering based on 1a52.

| PDB = {{PDB2|1a52}}, {{PDB2|1ere}}, {{PDB2|1err}}, {{PDB2|1g50}}, {{PDB2|1gwq}}, {{PDB2|1gwr}}, {{PDB2|1hcp}}, {{PDB2|1hcq}}, {{PDB2|1l2i}}, {{PDB2|1pcg}}, {{PDB2|1qkt}}, {{PDB2|1qku}}, {{PDB2|1r5k}}, {{PDB2|1sj0}}, {{PDB2|1uom}}, {{PDB2|1x7e}}, {{PDB2|1x7r}}, {{PDB2|1xp1}}, {{PDB2|1xp6}}, {{PDB2|1xp9}}, {{PDB2|1xpc}}, {{PDB2|1xqc}}, {{PDB2|1yim}}, {{PDB2|1yin}}, {{PDB2|1zky}}, {{PDB2|2ayr}}, {{PDB2|2b1v}}, {{PDB2|2b1z}}, {{PDB2|2b23}}, {{PDB2|2bj4}}, {{PDB2|2fai}}, {{PDB2|2g44}}, {{PDB2|2g5o}}, {{PDB2|2i0j}}, {{PDB2|2jf9}}, {{PDB2|2jfa}}, {{PDB2|2ouz}}, {{PDB2|2p15}}, {{PDB2|3erd}}, {{PDB2|3ert}}

| Name = estrogen receptor 1

| HGNCid = 3467

| Symbol = ESR1

| AltSymbols =; ER; DKFZp686N23123; ESR; ESRA; Era; NR3A1

| OMIM = 133430

| ECnumber =

| Homologene = 47906

| MGIid = 1352467

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0003677 |text = DNA binding}} {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003707 |text = steroid hormone receptor activity}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0005496 |text = steroid binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0008289 |text = lipid binding}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016049 |text = cell growth}} {{GNF_GO|id=GO:0016585 |text = chromatin remodeling complex}} {{GNF_GO|id=GO:0030235 |text = nitric-oxide synthase regulator activity}} {{GNF_GO|id=GO:0030284 |text = estrogen receptor activity}} {{GNF_GO|id=GO:0030520 |text = estrogen receptor signaling pathway}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0045839 |text = negative regulation of mitosis}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 2099

| Hs_Ensembl = ENSG00000091831

| Hs_RefseqProtein = NP_000116

| Hs_RefseqmRNA = NM_000125

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 6

| Hs_GenLoc_start = 152170379

| Hs_GenLoc_end = 152466099

| Hs_Uniprot = P03372

| Mm_EntrezGene = 13982

| Mm_Ensembl = ENSMUSG00000019768

| Mm_RefseqmRNA = XM_985634

| Mm_RefseqProtein = XP_990728

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 10

| Mm_GenLoc_start = 5342780

| Mm_GenLoc_end = 5734495

| Mm_Uniprot =

}}

Summary

The estrogen receptor (ESR) is a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding, and activation of transcription. Alternative splicing results in several ESR1 mRNA transcripts, which differ primarily in their 5-prime untranslated regions. The translated receptors show less variability.[supplied by OMIM]

HIF1A

REDIRECT: Protein Redirected to: HIF1A {August 12, 2007 5:36:58 PM PDT}
CREATED: Created new protein page: HIF1A {August 12, 2007 5:37:06 PM PDT}

HLA-B

REDIRECT: Protein Redirected to: HLA-B {August 12, 2007 5:37:06 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:37:15 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: HLA-B. Invoking a Mandantory Inspection. {August 12, 2007 5:37:15 PM PDT}

 {{protein
| Name = major histocompatibility complex, class I, B
| caption =
| image =
| width =
| HGNCid = 4932
| Symbol = HLA-B
| AltSymbols =
| EntrezGene = 3106
| OMIM = 142830
| RefSeq = NM_005514
| UniProt = P01889
| PDB =
| ECnumber =
| Chromosome = 6
| Arm = p
| Band = 21.31
| LocusSupplementaryData =
}}
HLA-B (major histocompatibility complex, class I, B) is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria.
HLA is the human version of the major histocompatibility complex (MHC), a gene family that occurs in many species. Genes in this complex are separated into three basic groups: class I, class II, and class III. In humans, the HLA-B gene and two related genes, HLA-A and HLA-C, are the major genes in MHC class I.
MHC class I genes provide instructions for making proteins that are present on the surface of almost all cells. On the cell surface, these proteins are bound to protein fragments (peptides) that have been exported from within the cell. MHC class I proteins display these peptides to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by destroying the infected cell.
The HLA-B gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign invaders. Hundreds of versions (alleles) of HLA-B are known, each of which is given a particular number (such as HLA-B27). Closely related alleles are categorized together; for example, at least 28 very similar alleles are subtypes of HLA-B27. These subtypes are designated as HLA-B*2701 to HLA-B*2728.
The HLA-B gene is located on the short (p) arm of chromosome 6 at position 21.3, from base pair 31,429,845 to base pair 31,432,923.

Related conditions

Ankylosing spondylitis: A version of the HLA-B gene called HLA-B27 increases the risk of developing ankylosing spondylitis. It is uncertain how HLA-B27 causes this increased risk. Researchers speculate that HLA-B27 may abnormally display to the immune system peptides that trigger arthritis. Other research suggests that joint inflammation characteristic of this disorder may result from improper folding of the HLA-B27 protein or the presence of abnormal forms of the protein on the cell surface. Although most patients with ankylosing spondylitis have the HLA-B27 variation, many people with this particular variation never develop the disorder. Other genetic and environmental factors are likely to affect the chances of developing ankylosing spondylitis and influence its progression.

HLA-B27 is associated with the spondyloarthropathies, a group of disorders that includes ankylosing spondylitis and other inflammatory joint diseases. Some of these diseases are associated with a common skin condition called psoriasis or chronic inflammatory bowel disorders (Crohn's disease and ulcerative colitis). One of the spondyloarthropathies, reactive arthritis, is typically triggered by bacterial infections of the gastrointestinal or genital tract. Following an infection, affected individuals may develop arthritis, back pain, and eye inflammation. Like ankylosing spondylitis, many factors probably contribute to the development of reactive arthritis and other spondyloarthropathies.

Other disorders: Several variations of the HLA-B gene are associated with adverse reactions to certain drugs. For example, two specific versions of this gene are related to increased drug sensitivity among the Han Chinese population. Individuals who have HLA-B*1502 are more likely to experience a severe skin disorder called Stevens-Johnson syndrome in response to carbamazepine (a drug used to treat seizures). Another version, HLA-B*5801, is associated with an increased risk of severe skin reactions in people treated with allopurinol (a drug used to treat gout, which is a form of arthritis caused by uric acid in the joints).

Among people with human immunodeficiency virus (HIV) infection, a version of HLA-B designated HLA-B*5701 is associated with an extreme sensitivity to abacavir. This drug is a treatment for HIV-1 that slows the spread of the virus in the body. People with abacavir hypersensitivity often develop a fever, chills, rash, upset stomach, and other symptoms when treated with this drug.

Several other variations of the HLA-B gene appear to play a role in the progression of HIV infection to acquired immunodeficiency syndrome (AIDS). AIDS is a disease that damages the immune system, preventing it from effectively defending the body against infections. The signs and symptoms of AIDS may not appear until 10 years or more after infection with HIV. Studies suggest that people with HIV infection who have HLA-B27 or HLA-B57 tend to progress more slowly than usual to AIDS. On the other hand, researchers believe that HIV-positive individuals who have HLA-B35 tend to develop the signs and symptoms of AIDS more quickly than usual. Other factors also influence the progression of HIV to AIDS.

Another version of the HLA-B gene, HLA-B53, has been shown to help protect against severe malaria. HLA-B53 is most common in West African populations, where malaria is a frequent cause of death in children. Researchers suggest that this version of the HLA-B gene may help the immune system respond more effectively to the parasite that causes malaria.

References

{{cite journal | author=Brown MA, Crane AM, Wordsworth BP | title=Genetic aspects of susceptibility, severity, and clinical expression in ankylosing spondylitis | journal=Curr Opin Rheumatol | year=2002 | pages=354-60 | volume=14 | issue=4 | id=PMID 12118167}}
{{cite journal | author=Carrington M, O'Brien SJ | title=The influence of HLA genotype on AIDS | journal=Annu Rev Med | year=2003 | pages=535-51 | volume=54 | id=PMID 12525683}}
{{cite journal | author=Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT | title=Medical genetics: a marker for Stevens-Johnson syndrome | journal=Nature | year=2004 | pages=486 | volume=428 | issue=6982 | id=PMID 15057820}}
{{cite journal | author=Colbert RA | title=The immunobiology of HLA-B27: variations on a theme | journal=Curr Mol Med | year=2004 | pages=21-30 | volume=4 | issue=1 | id=PMID 15011956}}
{{cite journal | author=Colmegna I, Cuchacovich R, Espinoza LR | title=HLA-B27-associated reactive arthritis: pathogenetic and clinical considerations | journal=Clin Microbiol Rev | year=2004 | pages=348-69 | volume=17 | issue=2 | id=PMID 15084505}} [http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=15084505 Full text]
{{cite journal | author=Cooke GS, Hill AV | title=Genetics of susceptibility to human infectious disease | journal=Nat Rev Genet | year=2001 | pages=967-77 | volume=2 | issue=12 | id=PMID 11733749}}
{{cite journal | author=Gao X, Nelson GW, Karacki P, Martin MP, Phair J, Kaslow R, Goedert JJ, Buchbinder S, Hoots K, Vlahov D, O'Brien SJ, Carrington M | title=Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS | journal=N Engl J Med | year=2001 | pages=1668-75 | volume=344 | issue=22 | id=PMID 11386265}}
{{cite journal | author=Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD | title=Genetic variations in HLA-B region and hypersensitivity reactions to abacavir | journal=Lancet | year=2002 | pages=1121-2 | volume=359 | issue=9312 | id=PMID 11943262}}
{{cite journal | author=Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, Bennett S, Brewster D, McMichael AJ, Greenwood BM | title=Common west African HLA antigens are associated with protection from severe malaria | journal=Nature | year=1991 | pages=595-600 | volume=352 | issue=6336 | id=PMID 1865923}}
{{cite journal | author=Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, Lin YL, Lan JL, Yang LC, Hong HS, Chen MJ, Lai PC, Wu MS, Chu CY, Wang KH, Chen CH, Fann CS, Wu JY, Chen YT | title=HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol | journal=Proc Natl Acad Sci U S A | year=2005 | pages=4134-9 | volume=102 | issue=11 | id=PMID 15743917}} [http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=15743917 Full text]
{{cite journal | author=Khan MA, Ball EJ | title=Genetic aspects of ankylosing spondylitis | journal=Best Pract Res Clin Rheumatol | year=2002 | pages=675-90 | volume=16 | issue=4 | id=PMID 12406434}}
{{cite journal | author=Khan MA | title=Update on spondyloarthropathies | journal=Ann Intern Med | year=2002 | pages=896-907 | volume=136 | issue=12 | id=PMID 12069564}} [http://www.annals.org/cgi/reprint/136/12/896 Full text (PDF)]
{{cite journal | author=Letvin NL, Walker BD | title=Immunopathogenesis and immunotherapy in AIDS virus infections | journal=Nat Med | year=2003 | pages=861-6 | volume=9 | issue=7 | id=PMID 12835706}}
{{cite journal | author=Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Marincola FM, Martino L, Hallahan CW, Selig SM, Schwartz D, Sullivan J, Connors M | title=HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors | journal=Proc Natl Acad Sci U S A | year=2000 | pages=2709-14 | volume=97 | issue=6 | id=PMID 10694578}} [http://www.pnas.org/cgi/content/full/97/6/2709 Full text]
{{cite journal | author=Sheehan NJ | title=The ramifications of HLA-B27 | journal=J R Soc Med | year=2004 | pages=10-4 | volume=97 | issue=1 | id=PMID 14702356}}

This article incorporates public domain text from [http://ghr.nlm.nih.gov The U.S. National Library of Medicine]

External links

{{OMIM|142830}}
{{EntrezGene|3106}}
{{GeneCard|HLA-B}}
[http://www.anthonynolan.org.uk/HIG/lists/nomenc.html Nomenclature for factors of the HLA system]

Category:Genes

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_HLA-B_image.jpg

| image_source = PDB rendering based on 1a1n.

| PDB = {{PDB2|1a1n}}, {{PDB2|1a9b}}, {{PDB2|1a9e}}, {{PDB2|1agb}}, {{PDB2|1agc}}, {{PDB2|1agd}}, {{PDB2|1age}}, {{PDB2|1agf}}, {{PDB2|1cg9}}, {{PDB2|1e27}}, {{PDB2|1e28}}, {{PDB2|1efx}}, {{PDB2|1hsa}}, {{PDB2|1jgd}}, {{PDB2|1jge}}, {{PDB2|1k5n}}, {{PDB2|1m05}}, {{PDB2|1mi5}}, {{PDB2|1of2}}, {{PDB2|1ogt}}, {{PDB2|1uxs}}, {{PDB2|1uxw}}, {{PDB2|1w0v}}, {{PDB2|1w0w}}, {{PDB2|1xh3}}, {{PDB2|1xr8}}, {{PDB2|1xr9}}, {{PDB2|1zhk}}, {{PDB2|1zhl}}, {{PDB2|1zsd}}, {{PDB2|2a83}}, {{PDB2|2ak4}}, {{PDB2|2axf}}, {{PDB2|2axg}}, {{PDB2|2bsr}}, {{PDB2|2bss}}, {{PDB2|2bst}}, {{PDB2|2cik}}, {{PDB2|2fyy}}, {{PDB2|2fz3}}, {{PDB2|2h6p}}, {{PDB2|2nw3}}, {{PDB2|2nx5}}

| Name = major histocompatibility complex, class I, B

| HGNCid = 4932

| Symbol = HLA-B

| AltSymbols =; HLA B; SPDA1

| OMIM = 142830

| ECnumber =

| Homologene = 83181

| MGIid =

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0002474 |text = antigen processing and presentation of peptide antigen via MHC class I}} {{GNF_GO|id=GO:0003674 |text = molecular_function}} {{GNF_GO|id=GO:0005575 |text = cellular_component}} {{GNF_GO|id=GO:0005624 |text = membrane fraction}} {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0006952 |text = defense response}} {{GNF_GO|id=GO:0006955 |text = immune response}} {{GNF_GO|id=GO:0008150 |text = biological_process}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} {{GNF_GO|id=GO:0019882 |text = antigen processing and presentation}} {{GNF_GO|id=GO:0032393 |text = MHC class I receptor activity}} {{GNF_GO|id=GO:0042612 |text = MHC class I protein complex}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 3106

| Hs_Ensembl = ENSG00000204523

| Hs_RefseqProtein = NP_005505

| Hs_RefseqmRNA = NM_005514

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 6

| Hs_GenLoc_start = 31429622

| Hs_GenLoc_end = 31433001

| Hs_Uniprot = P01889

| Mm_EntrezGene = 547349

| Mm_Ensembl =

| Mm_RefseqmRNA = NM_001025208

| Mm_RefseqProtein = NP_001020379

| Mm_GenLoc_db =

| Mm_GenLoc_chr =

| Mm_GenLoc_start =

| Mm_GenLoc_end =

| Mm_Uniprot =

}}

Summary

HLA-B belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exon 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. Hundreds of HLA-B alleles have been described

IGF1

REDIRECT: Protein Redirected to: Insulin-like growth factor 1 {August 12, 2007 5:37:15 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:37:17 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Insulin-like growth factor 1. Invoking a Mandantory Inspection. {August 12, 2007 5:37:17 PM PDT}

 {{Protein
|Name=insulin-like growth factor 1 (somatomedin C)
|image=IGF-1.png
|caption=
|Symbol=IGF1
|AltSymbols=
|HGNCid=5464
|Chromosome=12
|Arm=q
|Band=22
|LocusSupplementaryData=-q23
|ECnumber=
|OMIM=147440
|EntrezGene=3479
|RefSeq=NM_000618
|UniProt=P01343
|PDB=
}}
Insulin-like growth factor 1 (IGF-1) is a  polypeptide protein hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults.

Production and circulation

IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7649 daltons. IGF-1 is produced primarily by the liver as an endocrine hormone as well as target tissues in a paracrine/autocrine fashion. Production is stimulated by growth hormone and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5b. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio.

Action

Its primary action is mediated by binding to specific IGF receptors present on many cell types in many tissues. The signal is transduced by intracellular events. IGF-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and multiplication and a potent inhibitor of programmed cell death.

Almost every cell in the human body is affected by IGF-1, especially cells in muscle, cartilage, bone, liver, kidney, nerves, skin, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis.

Receptors

IGF-1 binds to at least two cell surface receptors: the IGF-1 receptor (IGFR), and the insulin receptor. The IGF-1 receptor seems to be the "physiologic" receptor - it binds IGF-1 at significantly higher affinity than IGF-1 is bound to the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase - meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the insulin receptor at approximately 0.1x the potency of insulin. Part of this signaling may be via IGF1R/Insulin Receptor heterodimers (the reason for the confusion is that binding studies show that IGF1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF1 in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia).

IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.

Use as a diagnostic test

IGF-1 levels can be measured in the blood in 10-1000 ng/ml amounts. As levels do not fluctuate greatly throughout the day for an individual person, IGF-1 is used by physicians as a screening test for growth hormone deficiency and excess.

Interpretation of IGF-1 levels is complicated by the wide normal ranges, and variations by age, sex, and pubertal stage. Clinically significant conditions and changes may be masked by the wide normal ranges. Sequential management over time is often useful for the management of several types of pituitary disease, undernutrition, and growth problems.

Diseases of deficiency and resistance

Rare diseases characterized by inability to make or respond to IGF-1 produce a distinctive type of growth failure. One such disorder, termed Laron dwarfism does not respond at all to growth hormone treatment due to a lack of GH receptors. The FDA has grouped these diseases into a disorder called severe primary IGF deficiency. Patients with severe primary IGFD typically present with normal to high GH levels, height below -3 standard deviations (SD), and IGF-1 levels below -3SD. Severe primary IGFD includes patients with mutations in the GH receptor, post-receptor mutations or IGF mutations, as previously described. As a result, these patients cannot be expected to respond to GH treatment.

The IGF signaling pathway appears to play a crucial role in cancer. Several studies have shown that increased levels of IGF lead to an increased risk of cancer. Studies done on lung cancer cells show that drugs inhibiting such signaling can be of potential interest in cancer therapy.<ref>{{cite journal |author=Velcheti V, Govindan R |title=Insulin-like growth factor and lung cancer |journal=Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer |volume=1 |issue=7 |pages=607-10 |year=2006 |pmid=17409926 |doi= |url=http://www.jto.org/pt/re/jto/fulltext.01243894-200609000-00002.htm}}</ref>

Factors influencing the levels of IGF-1 in the circulation

Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include an individuals genetic make-up, the time of day, their age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake.<ref>{{cite journal |author=Scarth J |title=Modulation of the growth hormone-insulin-like growth factor (GH-IGF) axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review |journal=Xenobiotica |volume=36 |issue=2-3 |pages=119-218 |year= 2006 |id=PMID 16702112}}</ref> The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals - see also endocrine disruptor.

IGF-1 as a therapeutic agent

IGF-1 has been manufactured recombinantly on a large scale using both yeast and E. coli. Several companies have evaluated IGF-1 in clinical trials for a variety of indications, including growth failure, type 1 diabetes, type 2 diabetes, amyotrophic lateral sclerosis (ALS aka "Lou Gehrig's Disease"), severe burn injury and myotonic muscular dystrophy (MMD). Results of clinical trials evaluating the efficacy of IGF-1 in type 1 diabetes and type 2 diabetes showed great promise in reducing hemoglobin A1C levels, as well as daily insulin consumption. However, the sponsor, Genentech, discontinued the program due to an exacerbation of diabetic retinopathy in patients coupled with a shift in corporate focus towards oncology. Cephalon and Chiron conducted two pivotal clinical studies of IGF-1 for ALS, and although one study demonstrated efficacy, the second was equivocal, and the product has never been approved by the FDA.

However, in the last few years, two additional companies Tercica and Insmed compiled enough clinical trial data to seek FDA approval in the United States. In August 2005, the FDA approved Tercica's IGF-1 drug, Increlex, as replacement therapy for severe primary IGF-1 deficiency based on clinical trial data from 71 patients. In December 2005, the FDA also approved Iplex, Insmed's IGF-1/IGFBP-3 complex. The Insmed drug is injected once a day versus the twice-a-day version that Tercica sells.

By delivering Iplex in a complex, patients can get the same efficacy with regard to growth rates but experience fewer side effects with less severe hypoglycemia. This would seem to make sense, since in the human body 97-99% of IGF-1 is bound to one of six IGF binding proteins. IGFBP-3 is the most abundant of these binding proteins, accounting for approximately 80% of IGF-1 binding.

Insmed was found to infringe on patents licensed by Tercica, which then sought to get a U.S. district court judge to ban sales of Iplex. [http://www.nytimes.com/2007/02/17/business/17patent.html?ref=health] To settle patent infringement charges and resolve all litigation between the two companies, Insmed in March 2007 agreed to withdraw Iplex from the U.S. market, leaving Tercica's Increlex as the sole version of IGF-1 available in the United States. [http://www.nytimes.com/2007/03/07/business/07patent.html?ref=health]

Terminology

IGF-1 has been known as "sulfation factor"<ref>{{cite journal |author=Salmon W, Daughaday W |title=A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro |journal=J Lab Clin Med |volume=49 |issue=6 |pages=825-36 |year=1957 |id=PMID 13429201}}</ref> and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s. It was also known as "somatomedin C" in the 1980s.

Additional images

Image:IGF-1.GIF|IGF-1

</gallery>

References

External links

{{MeshName|Insulin-Like+Growth+Factor+I}}
[http://www.magicfoundation.org/www/docs/978.1035/ IGF-1 for Parents]

Category:Peptide hormones

Category:Growth factors

da:IGF-1

es:Factor de crecimiento insulÃnico tipo 1

fr:IGF-1

nl:IGF1

sr:Ð˜Ð½Ñ�ÑƒÐ»Ð¸Ð½Ñƒ Ñ�Ð»Ð¸Ñ‡Ð°Ð½ Ñ„Ð°ÐºÑ‚Ð¾Ñ€ Ñ€Ð°Ñ�Ñ‚Ð° 1

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_IGF1_image.jpg

| image_source = PDB rendering based on 1bqt.

| PDB = {{PDB2|1bqt}}, {{PDB2|1gzr}}, {{PDB2|1gzy}}, {{PDB2|1gzz}}, {{PDB2|1h02}}, {{PDB2|1h59}}, {{PDB2|1imx}}, {{PDB2|1pmx}}, {{PDB2|1wqj}}, {{PDB2|2dsp}}, {{PDB2|2dsq}}, {{PDB2|2dsr}}, {{PDB2|2gf1}}, {{PDB2|3gf1}}, {{PDB2|3lri}}

| Name = insulin-like growth factor 1 (somatomedin C)

| HGNCid = 5464

| Symbol = IGF1

| AltSymbols =; IGFI

| OMIM = 147440

| ECnumber =

| Homologene = 515

| MGIid = 96432

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0001501 |text = skeletal development}} {{GNF_GO|id=GO:0005159 |text = insulin-like growth factor receptor binding}} {{GNF_GO|id=GO:0005179 |text = hormone activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0006260 |text = DNA replication}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006928 |text = cell motility}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007265 |text = Ras protein signal transduction}} {{GNF_GO|id=GO:0007399 |text = nervous system development}} {{GNF_GO|id=GO:0007517 |text = muscle development}} {{GNF_GO|id=GO:0007605 |text = sensory perception of sound}} {{GNF_GO|id=GO:0008083 |text = growth factor activity}} {{GNF_GO|id=GO:0008284 |text = positive regulation of cell proliferation}} {{GNF_GO|id=GO:0009441 |text = glycolate metabolic process}} {{GNF_GO|id=GO:0009887 |text = organ morphogenesis}} {{GNF_GO|id=GO:0010001 |text = glial cell differentiation}} {{GNF_GO|id=GO:0018445 |text = prothoracicotrophic hormone activity}} {{GNF_GO|id=GO:0048009 |text = insulin-like growth factor receptor signaling pathway}} {{GNF_GO|id=GO:0048468 |text = cell development}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 3479

| Hs_Ensembl = ENSG00000017427

| Hs_RefseqProtein = NP_000609

| Hs_RefseqmRNA = NM_000618

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 12

| Hs_GenLoc_start = 101313809

| Hs_GenLoc_end = 101398471

| Hs_Uniprot = P01343

| Mm_EntrezGene = 16000

| Mm_Ensembl = ENSMUSG00000020053

| Mm_RefseqmRNA = NM_010512

| Mm_RefseqProtein = NP_034642

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 10

| Mm_GenLoc_start = 87288867

| Mm_GenLoc_end = 87361600

| Mm_Uniprot =

}}

Summary

The somatomedins, or insulin-like growth factors (IGFs), comprise a family of peptides that play important roles in mammalian growth and development. IGF1 mediates many of the growth-promoting effects of growth hormone (GH; MIM 139250). Early studies showed that growth hormone did not directly stimulate the incorporation of sulfate into cartilage, but rather acted through a serum factor, termed 'sulfation factor,' which later became known as 'somatomedin' (Daughaday et al., 1972). Three main somatomedins have been characterized: somatomedin C (IGF1), somatomedin A (IGF2; MIM 147470), and somatomedin B (MIM 193190) (Rotwein, 1986; Rosenfeld, 2003).[supplied by OMIM]

IL10

REDIRECT: Protein Redirected to: Interleukin_10 {August 12, 2007 5:37:25 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:37:27 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Interleukin_10. Invoking a Mandantory Inspection. {August 12, 2007 5:37:27 PM PDT}

 {{protein
| Name = interleukin 10
| caption = Crystal structure of monomeric human IL-10
| image = IL10_Crystal_Structure.rsh.png
| width = 250 px
| HGNCid = 5962
| Symbol = IL10
| AltSymbols =
| EntrezGene = 3586
| OMIM = 124092
| RefSeq = NM_000572
| UniProt = P22301
| PDB = 2H24
| ECnumber =
| Chromosome = 1
| Arm = q
| Band = 31
| LocusSupplementaryData = -q32
}}
Interleukin-10 (IL-10 or IL10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine.

Function

It is capable of inhibiting synthesis of pro-inflammatory cytokines like Interferon-gamma, IL-2, IL-3, TNFÎ± and GM-CSF made by cells such as macrophages and the Type 1 T helper cells.

IL-10 also displays potent abilities to suppress the antigen presentation capactiy of antigen presenting cells.

However, it is also stimulatory towards certain T cells, mast cells and B cells.

Expression

It is mainly expressed in monocytes and Type 2 T helper cells (TH2), mast cells and also in a certain subset of activated T cells and B cells.

It is released by cytotoxic T-cells to inhibit the actions of NK cells during the immune response to viral infection.

Gene and Protein Structure

In humans, the IL-10 gene is located in chromosome 1 and consists of 5 exons.

The IL-10 protein is a homodimer . Each subunit is 178 amino acids long.

External links

{{MeshName|Interleukin-10}}

nl:interleukine-10

pl:Interleukina 10

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_IL10_image.jpg

| image_source = PDB rendering based on 1ilk.

| PDB = {{PDB2|1ilk}}, {{PDB2|1inr}}, {{PDB2|1j7v}}, {{PDB2|1lk3}}, {{PDB2|1vlk}}, {{PDB2|1y6k}}, {{PDB2|1y6m}}, {{PDB2|1y6n}}, {{PDB2|2h24}}, {{PDB2|2ilk}}

| Name = interleukin 10

| HGNCid = 5962

| Symbol = IL10

| AltSymbols =; CSIF; IL-10; IL10A; MGC126450; MGC126451; TGIF

| OMIM = 124092

| ECnumber =

| Homologene = 478

| MGIid = 96537

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0005125 |text = cytokine activity}} {{GNF_GO|id=GO:0005141 |text = interleukin-10 receptor binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006954 |text = inflammatory response}} {{GNF_GO|id=GO:0006955 |text = immune response}} {{GNF_GO|id=GO:0007253 |text = cytoplasmic sequestering of NF-kappaB}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0030097 |text = hemopoiesis}} {{GNF_GO|id=GO:0030183 |text = B cell differentiation}} {{GNF_GO|id=GO:0030595 |text = leukocyte chemotaxis}} {{GNF_GO|id=GO:0042092 |text = T-helper 2 type immune response}} {{GNF_GO|id=GO:0042100 |text = B cell proliferation}} {{GNF_GO|id=GO:0042130 |text = negative regulation of T cell proliferation}} {{GNF_GO|id=GO:0042742 |text = defense response to bacterium}} {{GNF_GO|id=GO:0045019 |text = negative regulation of nitric oxide biosynthetic process}} {{GNF_GO|id=GO:0045077 |text = negative regulation of interferon-gamma biosynthetic process}} {{GNF_GO|id=GO:0045191 |text = regulation of isotype switching}} {{GNF_GO|id=GO:0045347 |text = negative regulation of MHC class II biosynthetic process}} {{GNF_GO|id=GO:0045348 |text = positive regulation of MHC class II biosynthetic process}} {{GNF_GO|id=GO:0045355 |text = negative regulation of interferon-alpha biosynthetic process}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 3586

| Hs_Ensembl = ENSG00000136634

| Hs_RefseqProtein = NP_000563

| Hs_RefseqmRNA = NM_000572

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 1

| Hs_GenLoc_start = 205007570

| Hs_GenLoc_end = 205012462

| Hs_Uniprot = P22301

| Mm_EntrezGene = 16153

| Mm_Ensembl = ENSMUSG00000016529

| Mm_RefseqmRNA = NM_010548

| Mm_RefseqProtein = NP_034678

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 1

| Mm_GenLoc_start = 132847393

| Mm_GenLoc_end = 132852516

| Mm_Uniprot =

}}

Summary

The protein encoded by this gene is a cytokine produced primarily by monocytes and to a lesser extent by lymphocytes. This cytokine has pleiotropic effects in immunoregulation and inflammation. It down-regulates the expression of Th1 cytokines, MHC class II Ags, and costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. This cytokine can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract.

IL1B

REDIRECT: Protein Redirected to: IL1B {August 12, 2007 5:37:17 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:37:20 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: IL1B. Invoking a Mandantory Inspection. {August 12, 2007 5:37:20 PM PDT}

 {{protein
| Name = interleukin 1, beta
| caption =
| image =
| width =
| HGNCid = 5992
| Symbol = IL1B
| AltSymbols =
| EntrezGene = 3553
| OMIM = 147720
| RefSeq = NM_000576
| UniProt = P01584
| PDB =
| ECnumber =
| Chromosome = 2
| Arm = q
| Band = 13
| LocusSupplementaryData = -q21
}}
Interleukin-1 beta is a cytokine. IL-1Î² precursor is cleaved by caspase 1 (interleukin 1 beta convertase). Cytosolic thiol protease cleaves the product to form mature IL-1Î².
{{chem-stub}}

Appended Protein Page ******

<!-- BOT: MANUAL_INSPECTION_REQUIRED = NO - change this option to YES to have the protein box bot require an operator inspection before updating occurs.  -->
<!-- BOT: PROTEIN BOX UPDATE = YES - This protein box is automatically updated by protein box bot. Change the update option to NO to have the bot skip updating this protein box -->
{{GNF_Protein_box
| image = PBB_Protein_IL1B_image.jpg
| image_source = PDB rendering based on 1hib.
| PDB = {{PDB2|1hib}}, {{PDB2|1i1b}}, {{PDB2|1iob}}, {{PDB2|1itb}}, {{PDB2|1l2h}}, {{PDB2|1s0l}}, {{PDB2|1t4q}}, {{PDB2|1too}}, {{PDB2|1tp0}}, {{PDB2|1twe}}, {{PDB2|1twm}}, {{PDB2|21bi}}, {{PDB2|2i1b}}, {{PDB2|2nvh}}, {{PDB2|31bi}}, {{PDB2|41bi}}, {{PDB2|4i1b}}, {{PDB2|5i1b}}, {{PDB2|6i1b}}, {{PDB2|7i1b}}, {{PDB2|9ilb}}
| Name = interleukin 1, beta
| HGNCid = 5992
| Symbol = IL1B
| AltSymbols =; IL-1; IL1-BETA; IL1F2
| OMIM = 147720
| ECnumber =
| Homologene = 481
| MGIid = 96543
| GeneAtlas_image =
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = ~~~~~
| Function = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}} {{GNF_GO|id=GO:0001660 |text = fever}} {{GNF_GO|id=GO:0004871 |text = signal transducer activity}} {{GNF_GO|id=GO:0005149 |text = interleukin-1 receptor binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0006954 |text = inflammatory response}} {{GNF_GO|id=GO:0006955 |text = immune response}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0019735 |text = antimicrobial humoral response}} {{GNF_GO|id=GO:0030593 |text = neutrophil chemotaxis}} {{GNF_GO|id=GO:0045080 |text = positive regulation of chemokine biosynthetic process}} {{GNF_GO|id=GO:0045410 |text = positive regulation of interleukin-6 biosynthetic process}} {{GNF_GO|id=GO:0050900 |text = leukocyte migration}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 3553
| Hs_Ensembl = ENSG00000125538
| Hs_RefseqProtein = NP_000567
| Hs_RefseqmRNA = NM_000576
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 2
| Hs_GenLoc_start = 113303808
| Hs_GenLoc_end = 113310827
| Hs_Uniprot = P01584
| Mm_EntrezGene = 16176
| Mm_Ensembl = ENSMUSG00000027398
| Mm_RefseqmRNA = NM_008361
| Mm_RefseqProtein = NP_032387
| Mm_GenLoc_db =
| Mm_GenLoc_chr = 2
| Mm_GenLoc_start = 129056011
| Mm_GenLoc_end = 129062561
| Mm_Uniprot =
}}
}}
<!-- BOT: SUMMARY BEGIN UPDATE = YES - This summary is automatically updated by protein box bot.  Change the update option to NO to have the bot skip updating this summary -->

Summary

The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine is produced by activated macrophages as a proprotein, which is proteolytically processed to its active form by caspase 1 (CASP1/ICE). This cytokine is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis. The induction of cyclooxygenase-2 (PTGS2/COX2) by this cytokine in the central nervous system (CNS) is found to contribute to inflammatory pain hypersensitivity. This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2.

IL6

REDIRECT: Protein Redirected to: Interleukin-6 {August 12, 2007 5:37:20 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:37:22 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Interleukin-6. Invoking a Mandantory Inspection. {August 12, 2007 5:37:22 PM PDT}

 #REDIRECT Interleukin 6

Appended Protein Page ******

<!-- BOT: MANUAL_INSPECTION_REQUIRED = NO - change this option to YES to have the protein box bot require an operator inspection before updating occurs.  -->
<!-- BOT: PROTEIN BOX UPDATE = YES - This protein box is automatically updated by protein box bot. Change the update option to NO to have the bot skip updating this protein box -->
{{GNF_Protein_box
| image = PBB_Protein_IL6_image.jpg
| image_source = PDB rendering based on 1alu.
| PDB = {{PDB2|1alu}}, {{PDB2|1il6}}, {{PDB2|1p9m}}, {{PDB2|2il6}}
| Name = interleukin 6 (interferon, beta 2)
| HGNCid = 6018
| Symbol = IL6
| AltSymbols =; HGF; BSF2; HSF; IFNB2; IL-6
| OMIM = 147620
| ECnumber =
| Homologene = 502
| MGIid = 96559
| GeneAtlas_image =
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = ~~~~~
| Function = {{GNF_GO|id=GO:0001781 |text = neutrophil apoptosis}} {{GNF_GO|id=GO:0005125 |text = cytokine activity}} {{GNF_GO|id=GO:0005138 |text = interleukin-6 receptor binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0006953 |text = acute-phase response}} {{GNF_GO|id=GO:0006959 |text = humoral immune response}} {{GNF_GO|id=GO:0007166 |text = cell surface receptor linked signal transduction}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0008284 |text = positive regulation of cell proliferation}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0043066 |text = negative regulation of apoptosis}} {{GNF_GO|id=GO:0045079 |text = negative regulation of chemokine biosynthetic process}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 3569
| Hs_Ensembl = ENSG00000136244
| Hs_RefseqProtein = NP_000591
| Hs_RefseqmRNA = NM_000600
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 7
| Hs_GenLoc_start = 22732028
| Hs_GenLoc_end = 22738091
| Hs_Uniprot = P05231
| Mm_EntrezGene = 16193
| Mm_Ensembl = ENSMUSG00000025746
| Mm_RefseqmRNA = NM_031168
| Mm_RefseqProtein = NP_112445
| Mm_GenLoc_db =
| Mm_GenLoc_chr = 5
| Mm_GenLoc_start = 30343948
| Mm_GenLoc_end = 30350755
| Mm_Uniprot =
}}
}}
<!-- BOT: SUMMARY BEGIN UPDATE = YES - This summary is automatically updated by protein box bot.  Change the update option to NO to have the bot skip updating this summary -->
<!-- No Summary Available -->
<!-- BOT: SUMMARY END -->

IL8

REDIRECT: Protein Redirected to: Interleukin_8 {August 12, 2007 5:37:22 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:37:25 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Interleukin_8. Invoking a Mandantory Inspection. {August 12, 2007 5:37:25 PM PDT}

 {{protein
| Name = interleukin 8
| caption = Solution structure of human IL-8
| image = IL8_Solution_Structure.rsh.png
| width = 250 px
| HGNCid = 6025
| Symbol = IL8
| AltSymbols =
| EntrezGene = 3576
| OMIM = 146930
| RefSeq = NM_000584
| UniProt = P10145
| PDB = 1IL8
| ECnumber =
| Chromosome = 4
| Arm = q
| Band = 13
| LocusSupplementaryData = -q21
}}
Interleukin-8 (IL-8) is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies<ref>Wolff B, Burns AR, Middleton J, Rot A. Endothelial cell "memory" of inflammatory stimulation: human venular endothelial cells store interleukin 8 in Weibel-Palade bodies. J Exp Med. 1998 Nov 2;188(9):1757-62. PMID 9802987</ref><ref>Utgaard JO, Jahnsen FL, Bakka A, Brandtzaeg P, Haraldsen G. Rapid secretion of prestored interleukin 8 from Weibel-Palade bodies of microvascular endothelial cells. J Exp Med. 1998 Nov 2;188(9):1751-6. PMID 9802986</ref>.

Function

When first encountering an antigen, the primary cells to encounter it are the macrophages who phagocytose the particle. Upon processing, they release chemokines to signal other immune cells to come in to the site of inflammation. IL-8 is one such chemokine. It serves as a chemical signal that attracts neutrophils at the site of inflammation, and therefore is also known as Neutrophil Chemotactic Factor.

Clinical significance

If a pregnant mother has high levels of interleukin-8, she has a higher risk of inducing schizophrenia in her offspring.<ref>Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, Perrin M, Gorman JM, Susser ES. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry. 2004 May;161(5):889-95. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15121655 Abstract] [http://ajp.psychiatryonline.org/cgi/content/full/161/5/889#SEC3 fulltext]</ref> High levels of Interleukin 8 have been shown to reduce the chance of good treatment responses to antipsychotic medication in schizophrenia.<ref>Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC. Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J Clin Psychiatry. 2004 Jul;65(7):940-7.</ref>

Interleukin-8 is often associated with inflammation.

Nomenclature

IL-8 was renamed CXCL8 by the Chemokine Nomenclature Subcommittee of the Nomenclature Committee of the International Union of Immunological Societies, although its approved gene symbol remains IL8.

References

</div>

pl:Interleukina 8

zh:ç™½ç»†èƒžä»‹ç´ -8

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_IL8_image.jpg

| image_source = PDB rendering based on 1icw.

| PDB = {{PDB2|1icw}}, {{PDB2|1ikl}}, {{PDB2|1ikm}}, {{PDB2|1il8}}, {{PDB2|1ilp}}, {{PDB2|1ilq}}, {{PDB2|1qe6}}, {{PDB2|2il8}}, {{PDB2|3il8}}

| Name = interleukin 8

| HGNCid = 6025

| Symbol = IL8

| AltSymbols =; 3-10C; AMCF-I; CXCL8; GCP-1; GCP1; K60; LECT; LUCT; LYNAP; MDNCF; MONAP; NAF; NAP-1; NAP1; SCYB8; TSG-1; b-ENAP

| OMIM = 146930

| ECnumber =

| Homologene = 47937

| MGIid =

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0001525 |text = angiogenesis}} {{GNF_GO|id=GO:0005153 |text = interleukin-8 receptor binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0006928 |text = cell motility}} {{GNF_GO|id=GO:0006935 |text = chemotaxis}} {{GNF_GO|id=GO:0006954 |text = inflammatory response}} {{GNF_GO|id=GO:0006955 |text = immune response}} {{GNF_GO|id=GO:0007050 |text = cell cycle arrest}} {{GNF_GO|id=GO:0007186 |text = G-protein coupled receptor protein signaling pathway}} {{GNF_GO|id=GO:0007242 |text = intracellular signaling cascade}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0008009 |text = chemokine activity}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0019722 |text = calcium-mediated signaling}} {{GNF_GO|id=GO:0030155 |text = regulation of cell adhesion}} {{GNF_GO|id=GO:0030593 |text = neutrophil chemotaxis}} {{GNF_GO|id=GO:0042119 |text = neutrophil activation}} {{GNF_GO|id=GO:0045091 |text = regulation of retroviral genome replication}} {{GNF_GO|id=GO:0050930 |text = induction of positive chemotaxis}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 3576

| Hs_Ensembl = ENSG00000169429

| Hs_RefseqProtein = NP_000575

| Hs_RefseqmRNA = NM_000584

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 4

| Hs_GenLoc_start = 74825139

| Hs_GenLoc_end = 74828295

| Hs_Uniprot = P10145

| Mm_EntrezGene =

| Mm_Ensembl =

| Mm_RefseqmRNA =

| Mm_RefseqProtein =

| Mm_GenLoc_db =

| Mm_GenLoc_chr =

| Mm_GenLoc_start =

| Mm_GenLoc_end =

| Mm_Uniprot =

}}

Summary

The protein encoded by this gene is a member of the CXC chemokine family. This chemokine is one of the major mediators of the inflammatory response. This chemokine is secreted by several cell types. It functions as a chemoattractant, and is also a potent angiogenic factor. This gene is believed to play a role in the pathogenesis of bronchiolitis, a common respiratory tract disease caused by viral infection. This gene and other ten members of the CXC chemokine gene family form a chemokine gene cluster in a region mapped to chromosome 4q.

ITGB1

REDIRECT: Protein Redirected to: CD29 {August 12, 2007 5:37:27 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:37:30 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: CD29. Invoking a Mandantory Inspection. {August 12, 2007 5:37:30 PM PDT}

 {{protein
|Name=integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12)
|caption=
|image=
|width=
|HGNCid=6153
|Symbol=ITGB1
|AltSymbols=FNRB, MSK12, MDF2
|EntrezGene=3688
|OMIM=135630
|RefSeq=NM_002211
|UniProt=P05556
|PDB=
|ECnumber=
|Chromosome=10
|Arm=p
|Band=11.2
|LocusSupplementaryData=
}}
CD29 is an integrin unit associated with very late antigen receptors.

External links

{{MeshName|CD29+Antigen}}

Appended Protein Page ******

{{GNF_Protein_box

| image =

| image_source =

| PDB =

| Name = integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12)

| HGNCid = 6153

| Symbol = ITGB1

| AltSymbols =; CD29; FNRB; GPIIA; MDF2; MSK12; VLAB

| OMIM = 135630

| ECnumber =

| Homologene = 22999

| MGIid = 96610

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0001726 |text = ruffle}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005783 |text = endoplasmic reticulum}} {{GNF_GO|id=GO:0006968 |text = cellular defense response}} {{GNF_GO|id=GO:0007155 |text = cell adhesion}} {{GNF_GO|id=GO:0007156 |text = homophilic cell adhesion}} {{GNF_GO|id=GO:0007160 |text = cell-matrix adhesion}} {{GNF_GO|id=GO:0007229 |text = integrin-mediated signaling pathway}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0008305 |text = integrin complex}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} {{GNF_GO|id=GO:0016477 |text = cell migration}} {{GNF_GO|id=GO:0042802 |text = identical protein binding}} {{GNF_GO|id=GO:0046982 |text = protein heterodimerization activity}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 3688

| Hs_Ensembl = ENSG00000150093

| Hs_RefseqProtein = NP_391988

| Hs_RefseqmRNA = NM_033668

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 10

| Hs_GenLoc_start = 33229326

| Hs_GenLoc_end = 33287204

| Hs_Uniprot = P05556

| Mm_EntrezGene = 16412

| Mm_Ensembl = ENSMUSG00000025809

| Mm_RefseqmRNA = NM_010578

| Mm_RefseqProtein = NP_034708

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 8

| Mm_GenLoc_start = 131591503

| Mm_GenLoc_end = 131618179

| Mm_Uniprot =

}}

Summary

Integrins are heterodimeric proteins made up of alpha and beta subunits. At least 18 alpha and 8 beta subunits have been described in mammals. Integrin family members are membrane receptors involved in cell adhesion and recognition in a variety of processes including embryogenesis, hemostasis, tissue repair, immune response and metatastatic diffusion of tumor cells. The protein encoded by this gene is a beta subunit. Six alternatively spliced variants have been found for this gene which encode five proteins with alternate carboxy termini.

MAPK1

REDIRECT: Protein Redirected to: MAPK1 {August 12, 2007 5:38:13 PM PDT}
CREATED: Created new protein page: MAPK1 {August 12, 2007 5:38:21 PM PDT}

MMP9

REDIRECT: Protein Redirected to: MMP9 {August 12, 2007 5:37:30 PM PDT}
CREATED: Created new protein page: MMP9 {August 12, 2007 5:37:37 PM PDT}

NFKB1

REDIRECT: Protein Redirected to: NFKB1 {August 12, 2007 5:37:37 PM PDT}
CREATED: Created new protein page: NFKB1 {August 12, 2007 5:37:51 PM PDT}

PPARG

REDIRECT: Protein Redirected to: PPARG {August 12, 2007 5:37:51 PM PDT}
CREATED: Created new protein page: PPARG {August 12, 2007 5:38:05 PM PDT}

PRKCA

REDIRECT: Protein Redirected to: PKC-alpha {August 12, 2007 5:38:05 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:38:13 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: PKC-alpha. Invoking a Mandantory Inspection. {August 12, 2007 5:38:13 PM PDT}

 #REDIRECT PKC alpha

Appended Protein Page ******

<!-- BOT: MANUAL_INSPECTION_REQUIRED = NO - change this option to YES to have the protein box bot require an operator inspection before updating occurs.  -->
<!-- BOT: PROTEIN BOX UPDATE = YES - This protein box is automatically updated by protein box bot. Change the update option to NO to have the bot skip updating this protein box -->
{{GNF_Protein_box
| image = PBB_Protein_PRKCA_image.jpg
| image_source = PDB rendering based on 1dsy.
| PDB = {{PDB2|1dsy}}
| Name = protein kinase C, alpha
| HGNCid = 9393
| Symbol = PRKCA
| AltSymbols =; PRKACA; AAG6; MGC129900; MGC129901; PKC-alpha; PKCA
| OMIM = 176960
| ECnumber =
| Homologene = 55679
| MGIid = 97595
| GeneAtlas_image =
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = ~~~~~
| Function = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}} {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0000188 |text = inactivation of MAPK activity}} {{GNF_GO|id=GO:0001933 |text = negative regulation of protein amino acid phosphorylation}} {{GNF_GO|id=GO:0001934 |text = positive regulation of protein amino acid phosphorylation}} {{GNF_GO|id=GO:0002026 |text = cardiac inotropy}} {{GNF_GO|id=GO:0004698 |text = calcium-dependent protein kinase C activity}} {{GNF_GO|id=GO:0005509 |text = calcium ion binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0005624 |text = membrane fraction}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005739 |text = mitochondrion}} {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0006469 |text = negative regulation of protein kinase activity}} {{GNF_GO|id=GO:0006874 |text = cellular calcium ion homeostasis}} {{GNF_GO|id=GO:0006937 |text = regulation of muscle contraction}} {{GNF_GO|id=GO:0007166 |text = cell surface receptor linked signal transduction}} {{GNF_GO|id=GO:0007242 |text = intracellular signaling cascade}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0008624 |text = induction of apoptosis by extracellular signals}} {{GNF_GO|id=GO:0008629 |text = induction of apoptosis by intracellular signals}} {{GNF_GO|id=GO:0016740 |text = transferase activity}} {{GNF_GO|id=GO:0019992 |text = diacylglycerol binding}} {{GNF_GO|id=GO:0030593 |text = neutrophil chemotaxis}} {{GNF_GO|id=GO:0046325 |text = negative regulation of glucose import}} {{GNF_GO|id=GO:0046627 |text = negative regulation of insulin receptor signaling pathway}} {{GNF_GO|id=GO:0050729 |text = positive regulation of inflammatory response}} {{GNF_GO|id=GO:0050730 |text = regulation of peptidyl-tyrosine phosphorylation}} {{GNF_GO|id=GO:0050930 |text = induction of positive chemotaxis}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 5578
| Hs_Ensembl = ENSG00000154229
| Hs_RefseqProtein = NP_002728
| Hs_RefseqmRNA = NM_002737
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 17
| Hs_GenLoc_start = 61729388
| Hs_GenLoc_end = 62237324
| Hs_Uniprot = P17252
| Mm_EntrezGene = 18750
| Mm_Ensembl = ENSMUSG00000050965
| Mm_RefseqmRNA = NM_011101
| Mm_RefseqProtein = NP_035231
| Mm_GenLoc_db =
| Mm_GenLoc_chr = 11
| Mm_GenLoc_start = 107754338
| Mm_GenLoc_end = 108159844
| Mm_Uniprot =
}}
}}
<!-- BOT: SUMMARY BEGIN UPDATE = YES - This summary is automatically updated by protein box bot.  Change the update option to NO to have the bot skip updating this summary -->

Summary

Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This kinase has been reported to play roles in many different cellular processes, such as cell adhesion, cell transformation, cell cycle checkpoint, and cell volume control. Knockout studies in mice suggest that this kinase may be a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes.

PTGS2

REDIRECT: Protein Redirected to: PTGS2 {August 12, 2007 5:38:21 PM PDT}
CREATED: Created new protein page: PTGS2 {August 12, 2007 5:38:34 PM PDT}

RB1

REDIRECT: Protein Redirected to: Retinoblastoma protein {August 12, 2007 5:38:34 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:38:43 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Retinoblastoma protein. Invoking a Mandantory Inspection. {August 12, 2007 5:38:43 PM PDT}

 {{protein
|Name=retinoblastoma 1 (including osteosarcoma)
|caption=
|image=
|width=
|HGNCid=9884
|Symbol=RB1
|AltSymbols=OSRC
|EntrezGene=5925
|OMIM=180200
|RefSeq=NM_000321
|UniProt=P06400
|PDB=
|ECnumber=
|Chromosome=13
|Arm=q
|Band=14.2
|LocusSupplementaryData=
}}
The retinoblastoma protein, also called pRb or Rb, is a tumor suppressor protein found to be dysfunctional in a number of types of cancer.<ref name="Murphree1984">Murphree A.L. and Benedict W.F. 1984. Retinoblastoma: clues to human oncogenesis in Science, 223(4640): 1028-1033. {{Entrez Pubmed|6320372}} Retrieved on January 24, 2007.</ref> pRb was so named because retinoblastoma cancer results when the protein is inactivated by a mutation in both alleles of the RB1 gene that codes for it. The "p" in pRb stands for protein and is a way to distinguish it from the gene, Rb.  pRb is usually present as a phosphoprotein inside cells and is a target for phosphorylation by several kinases as described below. One highly studied function of pRb is to prevent the cell from dividing or progressing through the cell cycle.  Thus, when pRb is ineffective at this role, mutated cells can continue to divide and may become cancerous.
pRb is a member of the 'Pocket protein family', because it has a pocket to which proteins can bind.<ref name="Korenjak and Brehm">Korenjak M. and Brehm A.  2005.  [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS0-4GSJXD8-1&_coverDate=10%2F31%2F2005&_alid=324524977&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=6248&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=433dbaa00425e7b5ca02f73279fbc321 E2Fâ€“Rb complexes regulating transcription of genes important for differentiation and development].  Current Opinion in Genetics & Development, 15(5): 520-527.</ref><ref name="MÃ¼nger and Howley">MÃ¼nger K. and Howley P.M.  2002. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T32-46W13SB-2&_coverDate=11%2F30%2F2002&_alid=324525784&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4934&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=e7d4057a8f6b3c57fee07e374e77fd5d Human papillomavirus immortalization and transformation functions]. Virus Research, 89: 213â€“228. </ref>  Oncogenic proteins such as those produced by cells infected by high-risk types of human papillomaviruses can bind and inactivate pRb, which can lead to cancer.

Cell cycle suppression

pRb prevents the cell from replicating damaged DNA by preventing its progression through the cell cycle into its S, or synthesis phase or progressing through G1, or first gap phase.<ref name="Das">Das S.K., Hashimoto T., Shimizu K., Yoshida T., Sakai T., Sowa Y., Komoto A., and Kanazawa K. 2005. Fucoxanthin induces cell cycle arrest at G0/G1 phase in human colon carcinoma cells through up-regulation of p21WAF1/Cip1. Biochimica et Biophysica Acta, 1726(3):328-335. PMID 16236452. Retrieved on January 24, 2007.</ref> pRb binds and inhibits transcription factors of the E2F family. E2F transcription factors are dimers of an E2F protein and a DP protein.<ref name="Wu1995"> Wu C.L., Zukerberg L.R., Ngwu C., Harlow E. and Lees J.A. 1995. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=7739537 In vivo association of E2F and DP family proteins.] Molecular and Cellular Biology 15(5): 2536-2546. {{Entrez Pubmed|7739537}} Retrieved on January 24, 2007.</ref> The transcription activating complexes of E2 promoter-bindingâ€“protein-dimerization partners (E2F-DP) can push a cell into S phase.<ref name="Funk">Funk J.O., Waga S., Harry J.B., Espling E., Stillman B., and Galloway D.A. 1997. [http://www.genesdev.org/cgi/content/full/11/16/2090 Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein]. Trends in Genetics, 13(12): 474.</ref><ref name="De Veylder">De Veylder L., JoubÃ¨s J., and InzÃ© D. 2003. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS4-49KH3G2-1&_coverDate=12%2F31%2F2003&_alid=324521740&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=6252&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=40e5304bd36a43ee0f9ef82ab574339d Plant cell cycle transitions]. Current Opinion in Plant Biology. 6(6): 536-543. </ref><ref name="de Jager">de Jager S.M., Maughan S., Dewitte W., Scofield S., and Murray J.A.H. 2005. [http://www.biot.cam.ac.uk/jahm/pdf_files/SCDB385.pdf The developmental context of cell-cycle control in plants]. Seminars in Cell & Developmental Biology. 16(3): 385-396. PMID 15840447. Retrieved on January 24, 2007.</ref><ref name="Greenblatt">Greenblatt R.J. 2005. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T5D-4H6P7Y9-1&_user=10&_handle=V-WA-A-W-W-MsSAYZA-UUA-U-AABAVZDCWU-AAWEUVYBWU-BEAYVEYEY-W-U&_fmt=summary&_coverDate=09%2F15%2F2005&_rdoc=1&_orig=browse&_srch=%23toc%235000%232005%23999729981%23607092!&_cdi=5000&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=42b5289fd6b206fd7ae9269741210c39 Human papillomaviruses: Diseases, diagnosis, and a possible vaccine]. Clinical Microbiology Newsletter, 27(18): 139-145. doi:10.1016/j.clinmicnews.2005.09.001. Retrieved on January 24, 2007. </ref><ref name="Sinal and Woods">Sinal S.H. and Woods C.R. 2005. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16210110&query_hl=8 Human papillomavirus infections of the genital and respiratory tracts in young children]. Seminars in Pediatric Infectious Diseases, 16(4): 306-316. PMID 16210110. Retrieved on January 24, 2007.</ref> As long as E2F-DP is inactivated, the cell remains stalled in the G1 phase. When pRb is bound to E2F, the complex acts as a growth suppressor and prevents progression through the cell cycle.<ref name="MÃ¼nger and Howley"/> The pRb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, further suppressing DNA synthesis.

Activation and inactivation

pRb can actively inhibit cell cycle progression when it is dephosphorylated while this function is inactivated when pRb is phosphorylated. pRb is activated near the end of mitosis (M phase) when a phosphatase dephosphorylates it, allowing it to bind E2F.<ref name="MÃ¼nger and Howley"/><ref name="Vietri2006">Vietri M., Bianchi M., Ludlow J.W., Mittnacht S. and Villa-Moruzzi E. 2006. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16466572 Direct interaction between the catalytic subunit of Protein Phosphatase 1 and pRb.] Cancer cell international, 6(3): 3 {{Entrez Pubmed|16466572}} Retrieved on January 24, 2007.</ref>

When it is time for a cell to enter S phase, complexes of cyclin-dependent kinases (CDK) and cyclins phosphorylate pRb, inhibiting its activity.<ref name="Korenjak and Brehm"/><ref name="MÃ¼nger and Howley"/><ref name="Das"/><ref name="Bartkova">Bartkova J., GrÃ¸n B., Dabelsteen E., and Bartek J. 2003. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T4J-481FJ6W-4&_coverDate=02%2F28%2F2003&_alid=324520285&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4976&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=cefdf7198634e1b85780e1e5bb17bd00 Cell-cycle regulatory proteins in human wound healing]. Archives of Oral Biology, 48(2): 125-132. PMID 12642231. Retrieved on January 24, 2007.</ref> The initial phosphorylation is performed by Cyclin D/CDK4,6 and followed by additional phosphorylation by Cyclin E/CDK2. pRb remains phosphorylated throughout S, G2 and M phases.<ref name="MÃ¼nger and Howley"/>

Phosphorylation of pRb allows E2F-DP to dissociate from pRb and become active.<ref name="MÃ¼nger and Howley"/><ref name="De Veylder"/><ref name="Das"/> When E2F is freed it activates factors like cyclins (e.g. Cyclin E and A), which push the cell through the cell cycle by activating cyclin-dependent kinases, and a molecule called proliferating cell nuclear antigen, or PCNA, which speeds DNA replication and repair by helping to attach polymerase to DNA.<ref name="Funk"/><ref name="Das"/><ref name="Greenblatt"/>

References

External links

{{MeshName|Retinoblastoma+genes}}

Category:DNA replication

Category:Proteins

es:ProteÃna del retinoblastoma

it:Proteina del retinoblastoma

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_RB1_image.jpg

| image_source = PDB rendering based on 1ad6.

| PDB = {{PDB2|1ad6}}, {{PDB2|1gh6}}, {{PDB2|1gux}}, {{PDB2|1o9k}}, {{PDB2|2aze}}

| Name = retinoblastoma 1 (including osteosarcoma)

| HGNCid = 9884

| Symbol = RB1

| AltSymbols =; OSRC; RB

| OMIM = 180200

| ECnumber =

| Homologene = 272

| MGIid = 97874

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000075 |text = cell cycle checkpoint}} {{GNF_GO|id=GO:0000082 |text = G1/S transition of mitotic cell cycle}} {{GNF_GO|id=GO:0000122 |text = negative regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0000279 |text = M phase}} {{GNF_GO|id=GO:0000785 |text = chromatin}} {{GNF_GO|id=GO:0003674 |text = molecular_function}} {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003713 |text = transcription coactivator activity}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005667 |text = transcription factor complex}} {{GNF_GO|id=GO:0005819 |text = spindle}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006469 |text = negative regulation of protein kinase activity}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007050 |text = cell cycle arrest}} {{GNF_GO|id=GO:0008134 |text = transcription factor binding}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0016564 |text = transcription repressor activity}} {{GNF_GO|id=GO:0019900 |text = kinase binding}} {{GNF_GO|id=GO:0030308 |text = negative regulation of cell growth}} {{GNF_GO|id=GO:0030521 |text = androgen receptor signaling pathway}} {{GNF_GO|id=GO:0043550 |text = regulation of lipid kinase activity}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0050681 |text = androgen receptor binding}} {{GNF_GO|id=GO:0051146 |text = striated muscle cell differentiation}} {{GNF_GO|id=GO:0051301 |text = cell division}} {{GNF_GO|id=GO:0051318 |text = G1 phase}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 5925

| Hs_Ensembl = ENSG00000139687

| Hs_RefseqProtein = NP_000312

| Hs_RefseqmRNA = NM_000321

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 13

| Hs_GenLoc_start = 47775912

| Hs_GenLoc_end = 47954123

| Hs_Uniprot = P06400

| Mm_EntrezGene = 19645

| Mm_Ensembl = ENSMUSG00000022105

| Mm_RefseqmRNA = NM_009029

| Mm_RefseqProtein = NP_033055

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 14

| Mm_GenLoc_start = 71929657

| Mm_GenLoc_end = 72059946

| Mm_Uniprot =

}}

Summary

Retinoblastoma (RB) is an embryonic malignant neoplasm of retinal origin. It almost always presents in early childhood and is often bilateral. Spontaneous regression ('cure') occurs in some cases.[supplied by OMIM]

SRC

REDIRECT: Protein Redirected to: Src_(gene) {August 12, 2007 5:38:43 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:38:46 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Src_(gene). Invoking a Mandantory Inspection. {August 12, 2007 5:38:46 PM PDT}

 Src is a family of proto-oncogenic tyrosine kinases originally discovered by J. Michael Bishop and Harold E. Varmus.  The discovery of Src family proteins has been instrumental to the modern understanding of cancer as a disease where normally healthy cellular signalling has gone awry.

v-src

Francis Peyton Rous was credited with being the first to come up with the idea that viruses could cause cancer. In 1911 he performed an experiment where he removed a type of tumor called a fibrosarcoma from chickens, ground them up, and used centrifugation to remove cells and debris. He injected the remaining liquid into healthy chicks and found that the chicks developed sarcomas. The causative agent in the liquid was later found to be a virus that was called the Rous sarcoma virus (RSV).

Later work by others showed that RSV was a type of retrovirus. Non-cancer-forming retroviruses contain 3 genes, called gag, pol, and env. Some tumor-inducing retroviruses (such as RSV), however, contain a gene called v-src (viral-sarcoma). It was found that the v-src gene in RSV is required for the formation of cancer and that the other genes have no role in oncogenesis.<ref name="v-src">{{cite journal |author=Stehelin D, Fujita DJ, Padgett T, Varmus HE, Bishop JM. |title=Detection and enumeration of transformation-defective strains of avian sarcoma virus with molecular hybridization. |journal= Virology |volume=76 |issue=2 |pages=675-84 |year=1977 |pmid=190771}}</ref>

Src tyrosine kinases transmit integrin-dependent signals central to cell movement and proliferation. Hallmarks of v-src induced transformation are rounding of the cell and the formation of actin rich podosomes on the basal surface of the cell. These structures are correlated with increased invasiveness, a process thought to be essential for metastasis.

v-src lacks the C-terminal inhibitory phosphorylation site, and is therefore constitutively active as opposed to normal src (c-src) which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-src is therefore an instructive example of an oncogene whereas c-src is a proto-oncogene.

c-src

{{ProteinShort | Name = pp60c-src | caption = | image = | width = | HGNCid = 11283 | Symbol = SRC | AltSymbols = | EntrezGene = 6714 | OMIM = 190090 | RefSeq = NM_005417 | UniProt = P12931 | PDB = | ECnumber = | Chromosome = | Arm = | Band = | LocusSupplementaryData = }}

In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens contain a gene that is structurally closely-related to v-src.<ref name="v-src">{{cite journal |author=Tal J, Fujita DJ, Kawai S, Varmus HE, Bishop JM |title=Purification of DNA complementary to the env gene of avian sarcoma virus and analysis of relationships among the env genes of avian leukosis-sarcoma viruses. |journal= J Virol. |volume=21 |issue=2 |pages=497-505 |year=1977 |pmid=189084}}</ref> The normal cellular gene was called c-src (cellular-src).<ref name="srconcogene">{{cite journal |author=Oppermann H, Levinson AD, Varmus HE, Levintow L, Bishop JM |title=Uninfected vertebrate cells contain a protein that is closely related to the product of the avian sarcoma virus transforming gene (src). |journal=Proc Natl Acad Sci U S A. |volume=76 |issue=4 |pages=1804-8 |year=1979 |pmid=221907}}</ref> This discovery changed the current thinking about cancer from a model wherein cancer is caused by a foreign substance (a viral gene) to one where a gene that is normally present in the cell can cause cancer. It is believed that at one point an ancestral virus mistakenly incorporated the c-src gene of its cellular host. At some point, the normal gene became mutated into an abnormally-functioning oncogene, as is now observed in RSV. Once the oncogene is transfected back into a normal host, it can lead to cancer.

src: The transforming (sarcoma inducing) gene of Rous sarcoma virus. The protein product is pp60vsrc, a cytoplasmic protein with tyrosine-specific protein kinase activity ({{EC number|2.7.10.2}}), that associates with the cytoplasmic face of the plasma membrane. The protein consists of 3 domains, an N-terminal SH3 domain, a central SH2 domain and a Tyrosine kinase domain. The SH2 and SH3 domains cooperate in the auto-inhibition of the kinase domain. c-Src is phosphorylated on an inhibitory tyrosine near the c-terminus of the protein. This produces a binding site for the SH2 domain which, when bound, facilitates binding of the SH3 domain to a low affinity polyproline site within the linker between the SH2 domain and the Kinase domain. Binding of the SH3 domain results in misalignment of residues within the kinase domain's active site inactivating the enzyme. This allows for multiple mechanism for c-Src activation: dephosphorylation of the C-terminal tyrosine by a protein tyrosine phosphatase, binding of the SH2 domain by a competitive phospho-tyrosine residue, as seen in the case of c-Src binding to Focal Adhesion Kinase, or competitive binding of a polyproline binding site to the SH3 domain, as seen in the case of the HIV NEF protein.

Src Family Kinases

The Src family includes nine members: Src, Lck, Hck, Fyn, Blk, Lyn, Fgr, Yes, and Yrk.

External links

[http://vega.sanger.ac.uk/Homo_sapiens/geneview?db=core;gene=OTTHUMG00000032417 Vega geneview]
{{MeshName|src-Family+Kinases}}
{{MeshName|src+Gene}}

References

Lodish, Harvey; Burk, Arnold; Zipurksy, Lawrence, et al. "Cancer" in Molecular Cell Biology. 4th edition. 2000. ISBN 0-7167-3706-X. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=mcb.section.7090]

Category:Oncogenes

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_SRC_image.jpg

| image_source = PDB rendering based on 1a07.

| PDB = {{PDB2|1a07}}, {{PDB2|1a08}}, {{PDB2|1a09}}, {{PDB2|1a1a}}, {{PDB2|1a1b}}, {{PDB2|1a1c}}, {{PDB2|1a1e}}, {{PDB2|1bkl}}, {{PDB2|1bkm}}, {{PDB2|1f1w}}, {{PDB2|1f2f}}, {{PDB2|1fmk}}, {{PDB2|1hcs}}, {{PDB2|1hct}}, {{PDB2|1is0}}, {{PDB2|1kc2}}, {{PDB2|1ksw}}, {{PDB2|1nlo}}, {{PDB2|1nlp}}, {{PDB2|1nzl}}, {{PDB2|1nzv}}, {{PDB2|1o41}}, {{PDB2|1o42}}, {{PDB2|1o43}}, {{PDB2|1o44}}, {{PDB2|1o45}}, {{PDB2|1o46}}, {{PDB2|1o47}}, {{PDB2|1o48}}, {{PDB2|1o49}}, {{PDB2|1o4a}}, {{PDB2|1o4b}}, {{PDB2|1o4c}}, {{PDB2|1o4d}}, {{PDB2|1o4e}}, {{PDB2|1o4f}}, {{PDB2|1o4g}}, {{PDB2|1o4h}}, {{PDB2|1o4i}}, {{PDB2|1o4j}}, {{PDB2|1o4k}}, {{PDB2|1o4l}}, {{PDB2|1o4m}}, {{PDB2|1o4n}}, {{PDB2|1o4o}}, {{PDB2|1o4p}}, {{PDB2|1o4q}}, {{PDB2|1o4r}}, {{PDB2|1p13}}, {{PDB2|1prl}}, {{PDB2|1prm}}, {{PDB2|1qwe}}, {{PDB2|1qwf}}, {{PDB2|1rlp}}, {{PDB2|1rlq}}, {{PDB2|1sha}}, {{PDB2|1shb}}, {{PDB2|1shd}}, {{PDB2|1skj}}, {{PDB2|1spr}}, {{PDB2|1sps}}, {{PDB2|1srl}}, {{PDB2|1srm}}, {{PDB2|1y57}}, {{PDB2|1yi6}}, {{PDB2|1yoj}}, {{PDB2|1yol}}, {{PDB2|1yom}}, {{PDB2|2bdf}}, {{PDB2|2bdj}}, {{PDB2|2h8h}}, {{PDB2|2hwo}}, {{PDB2|2hwp}}, {{PDB2|2oiq}}, {{PDB2|2ptk}}, {{PDB2|2src}}

| Name = v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)

| HGNCid = 11283

| Symbol = SRC

| AltSymbols =; ASV; SRC1; c-SRC; p60-Src

| OMIM = 190090

| ECnumber =

| Homologene = 21120

| MGIid = 98397

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004713 |text = protein-tyrosine kinase activity}} {{GNF_GO|id=GO:0005070 |text = SH3/SH2 adaptor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0007172 |text = signal complex assembly}} {{GNF_GO|id=GO:0007243 |text = protein kinase cascade}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} {{GNF_GO|id=GO:0016740 |text = transferase activity}} {{GNF_GO|id=GO:0042169 |text = SH2 domain binding}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 6714

| Hs_Ensembl = ENSG00000197122

| Hs_RefseqProtein = NP_005408

| Hs_RefseqmRNA = NM_005417

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 20

| Hs_GenLoc_start = 35406502

| Hs_GenLoc_end = 35467239

| Hs_Uniprot = P12931

| Mm_EntrezGene = 20779

| Mm_Ensembl = ENSMUSG00000027646

| Mm_RefseqmRNA = NM_001025395

| Mm_RefseqProtein = NP_001020566

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 2

| Mm_GenLoc_start = 157115730

| Mm_GenLoc_end = 157163279

| Mm_Uniprot =

}}

Summary

This gene is highly similar to the v-src gene of Rous sarcoma virus. This proto-oncogene may play a role in the regulation of embryonic development and cell growth. The protein encoded by this gene is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase. Mutations in this gene could be involved in the malignant progression of colon cancer. Two transcript variants encoding the same protein have been found for this gene.

TGFB1

REDIRECT: Protein Redirected to: TGFB1 {August 12, 2007 5:38:46 PM PDT}
CREATED: Created new protein page: TGFB1 {August 12, 2007 5:38:53 PM PDT}

TNF

REDIRECT: Protein Redirected to: TNF-alpha {August 12, 2007 5:38:53 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:39:03 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: TNF-alpha. Invoking a Mandantory Inspection. {August 12, 2007 5:39:03 PM PDT}

 #REDIRECT Tumor necrosis factor-alpha {{R from abbreviation}}

Appended Protein Page ******

<!-- BOT: MANUAL_INSPECTION_REQUIRED = NO - change this option to YES to have the protein box bot require an operator inspection before updating occurs.  -->
<!-- BOT: PROTEIN BOX UPDATE = YES - This protein box is automatically updated by protein box bot. Change the update option to NO to have the bot skip updating this protein box -->
{{GNF_Protein_box
| image = PBB_Protein_TNF_image.jpg
| image_source = PDB rendering based on 1a8m.
| PDB = {{PDB2|1a8m}}, {{PDB2|1tnf}}, {{PDB2|2az5}}, {{PDB2|2tun}}, {{PDB2|4tsv}}, {{PDB2|5tsw}}
| Name = tumor necrosis factor (TNF superfamily, member 2)
| HGNCid = 11892
| Symbol = TNF
| AltSymbols =; DIF; TNF-alpha; TNFA; TNFSF2
| OMIM = 191160
| ECnumber =
| Homologene = 496
| MGIid = 104798
| GeneAtlas_image =
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = ~~~~~
| Function = {{GNF_GO|id=GO:0000060 |text = protein import into nucleus, translocation}} {{GNF_GO|id=GO:0000122 |text = negative regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0001932 |text = regulation of protein amino acid phosphorylation}} {{GNF_GO|id=GO:0005125 |text = cytokine activity}} {{GNF_GO|id=GO:0005164 |text = tumor necrosis factor receptor binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0005625 |text = soluble fraction}} {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0006006 |text = glucose metabolic process}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006959 |text = humoral immune response}} {{GNF_GO|id=GO:0007159 |text = leukocyte adhesion}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0008625 |text = induction of apoptosis via death domain receptors}} {{GNF_GO|id=GO:0009615 |text = response to virus}} {{GNF_GO|id=GO:0009887 |text = organ morphogenesis}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} {{GNF_GO|id=GO:0042127 |text = regulation of cell proliferation}} {{GNF_GO|id=GO:0042742 |text = defense response to bacterium}} {{GNF_GO|id=GO:0043123 |text = positive regulation of I-kappaB kinase/NF-kappaB cascade}} {{GNF_GO|id=GO:0045123 |text = cellular extravasation}} {{GNF_GO|id=GO:0045670 |text = regulation of osteoclast differentiation}} {{GNF_GO|id=GO:0045941 |text = positive regulation of transcription}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0045994 |text = positive regulation of translational initiation by iron}} {{GNF_GO|id=GO:0046325 |text = negative regulation of glucose import}} {{GNF_GO|id=GO:0046330 |text = positive regulation of JNK cascade}} {{GNF_GO|id=GO:0051023 |text = regulation of immunoglobulin secretion}} {{GNF_GO|id=GO:0051092 |text = activation of NF-kappaB transcription factor}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 7124
| Hs_Ensembl = ENSG00000204490
| Hs_RefseqProtein = NP_000585
| Hs_RefseqmRNA = NM_000594
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 6
| Hs_GenLoc_start = 31651314
| Hs_GenLoc_end = 31654092
| Hs_Uniprot = P01375
| Mm_EntrezGene = 21926
| Mm_Ensembl = ENSMUSG00000024401
| Mm_RefseqmRNA = NM_013693
| Mm_RefseqProtein = NP_038721
| Mm_GenLoc_db =
| Mm_GenLoc_chr = 17
| Mm_GenLoc_start = 34807442
| Mm_GenLoc_end = 34810048
| Mm_Uniprot =
}}
}}
<!-- BOT: SUMMARY BEGIN UPDATE = YES - This summary is automatically updated by protein box bot.  Change the update option to NO to have the bot skip updating this summary -->

Summary

This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, and cancer. Knockout studies in mice also suggested the neuroprotective function of this cytokine.

TP53

REDIRECT: Protein Redirected to: TP53 {August 12, 2007 5:39:03 PM PDT}
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 {{Merge|p53|date=August 2007}}
TP53 is a tumor suppressor gene that is named after, and provides instructions for making, a protein called tumor protein 53 (TP53). Through the effect of the protein that it produces, TP53 is a tumor suppressor gene, which means that it regulates the cycle of cell division by keeping cells from growing and dividing too fast or in an uncontrolled way.
The p53 tumor protein is located in the nucleus of cells throughout the body and can bind directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the cell will undergo programmed cell death (apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, the p53 tumor protein prevents the cell from dividing and signals it to undergo apoptosis. This process prevents cells with mutated or damaged DNA from dividing, which helps prevent the development of tumors.
Because the p53 tumor protein is essential for regulating cell division, it has been nicknamed the "guardian of the genome."
The TP53 gene is located on the short (p) arm of chromosome 17 at position 13.1, from base pair 7,512,463 to base pair 7,531,641.

Related conditions

Bladder cancer: Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the TP53 gene have been found in some cases of bladder cancer. Most of these mutations replace one amino acid (a building block of proteins) with another amino acid in the p53 tumor protein. The altered protein cannot bind to DNA correctly, which prevents the protein from effectively regulating cell growth and division. As a result, DNA damage accumulates in cells and they divide in an uncontrolled way, leading to a cancerous tumor. Mutations in the TP53 gene may also help predict whether bladder cancer will progress and spread to nearby tissues and whether the disease will recur after treatment.

Li-Fraumeni syndrome: More than 55 different inherited mutations in the TP53 gene have been found in individuals with Li-Fraumeni syndrome. Many of these changes involve the substitution of one amino acid for another amino acid in the part of p53 tumor protein that binds to DNA. Other types of mutations include deletions of small amounts of DNA within the gene. Mutations in the TP53 gene lead to a version of the p53 tumor protein that cannot regulate cell growth and division. The altered protein is unable to signal cells with mutated or damaged DNA to undergo apoptosis. As a result, such cells continue to divide and can form tumors.

Other cancers: Somatic mutations in the TP53 gene are the most common genetic changes found in human cancer, occurring in about half of all cancers. For example, TP53 gene mutations have been identified in several types of brain tumor, a type of bone cancer called osteosarcoma, a cancer of muscle tissue called rhabdomyosarcoma, and adrenocortical carcinoma (a cancer of the outer layer of the adrenal glands, which are small glands located on top of each kidney). Most TP53 gene mutations substitute one amino acid for another in the p53 tumor protein, which leads to the production of an altered version of the protein that cannot effectively bind to DNA. This altered protein can build up in nuclei of cells, preventing the cells from undergoing apoptosis in response to DNA damage. Instead, these damaged cells continue to grow and divide in an unregulated way, which can lead to cancerous tumors.

References

{{cite journal | author=Borresen-Dale AL | title=TP53 and breast cancer | journal=Hum Mutat | year=2003 | pages=292-300 | volume=21 | issue=3 | id=PMID 12619115}}
{{cite journal | author=Lorenzo Romero JG, Salinas Sanchez AS, Gimenez Bachs JM, Sanchez Sanchez F, Escribano Martinez J, Hernandez Millan IR, Segura Martin M, Virseda Rodriguez JA | title=p53 Gene mutations in superficial bladder cancer | journal=Urol Int | year=2004 | pages=212-8 | volume=73 | issue=3 | id=PMID 15539839}}
{{cite journal | author=Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA | title=Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype | journal=Cancer Res | year=2003 | pages=6643-50 | volume=63 | issue=20 | id=PMID 14583457}}
{{cite journal | author=Sengupta S, Harris CC | title=p53: traffic cop at the crossroads of DNA repair and recombination | journal=Nat Rev Mol Cell Biol | year=2005 | pages=44-55 | volume=6 | issue=1 | id=PMID 15688066}}
{{cite journal | author=Smith ND, Rubenstein JN, Eggener SE, Kozlowski JM | title=The p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer | journal=J Urol | year=2003 | pages=1219-28 | volume=169 | issue=4 | id=PMID 12629332}}
{{cite journal | author=Soussi T, Beroud C | title=Significance of TP53 mutations in human cancer: a critical analysis of mutations at CpG dinucleotides | journal=Hum Mutat | year=2003 | pages=192-200 | volume=21 | issue=3 | id=PMID 12619105}}
{{cite journal | author=Soussi T, Lozano G | title=p53 mutation heterogeneity in cancer | journal=Biochem Biophys Res Commun | year=2005 | pages=834-42 | volume=331 | issue=3 | id=PMID 15865939}}
{{cite journal | author=Varley J | title=TP53, hChk2, and the Li-Fraumeni syndrome | journal=Methods Mol Biol | year=2003 | pages=117-29 | volume=222 | id=PMID 12710683}}
{{cite journal | author=Varley JM | title=Germline TP53 mutations and Li-Fraumeni syndrome | journal=Hum Mutat | year=2003 | pages=313-20 | volume=21 | issue=3 | id=PMID 12619118}}
{{cite journal | author=Vousden KH, Lu X | title=Live or let die: the cell's response to p53 | journal=Nat Rev Cancer | year=2002 | pages=594-604 | volume=2 | issue=8 | id=PMID 12154352}}
{{cite journal | author=Vousden KH, Prives C | title=P53 and prognosis: new insights and further complexity | journal=Cell | year=2005 | pages=7-10 | volume=120 | issue=1 | id=PMID 15652475}}
{{cite journal | author=Zamzami N, Kroemer G | title=p53 in apoptosis control: an introduction | journal=Biochem Biophys Res Commun | year=2005 | pages=685-7 | volume=331 | issue=3 | id=PMID 15865922}}

Category:Tumor suppressor genes

ur:p53 (ÙˆØ±Ø§Ø«Û�)

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_TP53_image.jpg

| image_source = PDB rendering based on 1a1u.

| PDB = {{PDB2|1a1u}}, {{PDB2|1aie}}, {{PDB2|1c26}}, {{PDB2|1gzh}}, {{PDB2|1hs5}}, {{PDB2|1kzy}}, {{PDB2|1olg}}, {{PDB2|1olh}}, {{PDB2|1pes}}, {{PDB2|1pet}}, {{PDB2|1sae}}, {{PDB2|1saf}}, {{PDB2|1sag}}, {{PDB2|1sah}}, {{PDB2|1sai}}, {{PDB2|1saj}}, {{PDB2|1sak}}, {{PDB2|1sal}}, {{PDB2|1tsr}}, {{PDB2|1tup}}, {{PDB2|1uol}}, {{PDB2|1ycs}}, {{PDB2|2ac0}}, {{PDB2|2ady}}, {{PDB2|2ahi}}, {{PDB2|2ata}}, {{PDB2|2b3g}}, {{PDB2|2bim}}, {{PDB2|2bin}}, {{PDB2|2bio}}, {{PDB2|2bip}}, {{PDB2|2biq}}, {{PDB2|2fej}}, {{PDB2|2gs0}}, {{PDB2|2h1l}}, {{PDB2|2j1w}}, {{PDB2|2j1x}}, {{PDB2|2j1y}}, {{PDB2|2j1z}}, {{PDB2|2j20}}, {{PDB2|2j21}}, {{PDB2|2ocj}}, {{PDB2|3sak}}

| Name = tumor protein p53 (Li-Fraumeni syndrome)

| HGNCid = 11998

| Symbol = TP53

| AltSymbols =; LFS1; TRP53; p53

| OMIM = 191170

| ECnumber =

| Homologene = 460

| MGIid = 98834

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000060 |text = protein import into nucleus, translocation}} {{GNF_GO|id=GO:0000739 |text = DNA strand annealing activity}} {{GNF_GO|id=GO:0001701 |text = in utero embryonic development}} {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0004518 |text = nuclease activity}} {{GNF_GO|id=GO:0005507 |text = copper ion binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0005626 |text = insoluble fraction}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005654 |text = nucleoplasm}} {{GNF_GO|id=GO:0005657 |text = replication fork}} {{GNF_GO|id=GO:0005730 |text = nucleolus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005739 |text = mitochondrion}} {{GNF_GO|id=GO:0005829 |text = cytosol}} {{GNF_GO|id=GO:0006284 |text = base-excision repair}} {{GNF_GO|id=GO:0006289 |text = nucleotide-excision repair}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006461 |text = protein complex assembly}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0006917 |text = induction of apoptosis}} {{GNF_GO|id=GO:0006974 |text = response to DNA damage stimulus}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007050 |text = cell cycle arrest}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0007569 |text = cell aging}} {{GNF_GO|id=GO:0008104 |text = protein localization}} {{GNF_GO|id=GO:0008156 |text = negative regulation of DNA replication}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0008635 |text = caspase activation via cytochrome c}} {{GNF_GO|id=GO:0009411 |text = response to UV}} {{GNF_GO|id=GO:0009792 |text = embryonic development ending in birth or egg hatching}} {{GNF_GO|id=GO:0010165 |text = response to X-ray}} {{GNF_GO|id=GO:0016363 |text = nuclear matrix}} {{GNF_GO|id=GO:0019899 |text = enzyme binding}} {{GNF_GO|id=GO:0030154 |text = cell differentiation}} {{GNF_GO|id=GO:0030308 |text = negative regulation of cell growth}} {{GNF_GO|id=GO:0031571 |text = G1 DNA damage checkpoint}} {{GNF_GO|id=GO:0042127 |text = regulation of cell proliferation}} {{GNF_GO|id=GO:0042771 |text = DNA damage response, signal transduction by p53 class mediator resulting in induction of apoptosis}} {{GNF_GO|id=GO:0043066 |text = negative regulation of apoptosis}} {{GNF_GO|id=GO:0045941 |text = positive regulation of transcription}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}} {{GNF_GO|id=GO:0046902 |text = regulation of mitochondrial membrane permeability}} {{GNF_GO|id=GO:0046982 |text = protein heterodimerization activity}} {{GNF_GO|id=GO:0047485 |text = protein N-terminus binding}} {{GNF_GO|id=GO:0048147 |text = negative regulation of fibroblast proliferation}} {{GNF_GO|id=GO:0051097 |text = negative regulation of helicase activity}} {{GNF_GO|id=GO:0051262 |text = protein tetramerization}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 7157

| Hs_Ensembl = ENSG00000141510

| Hs_RefseqProtein = NP_000537

| Hs_RefseqmRNA = NM_000546

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 17

| Hs_GenLoc_start = 7512464

| Hs_GenLoc_end = 7531642

| Hs_Uniprot = P04637

| Mm_EntrezGene = 22059

| Mm_Ensembl = ENSMUSG00000059552

| Mm_RefseqmRNA = NM_011640

| Mm_RefseqProtein = NP_035770

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 11

| Mm_GenLoc_start = 69396600

| Mm_GenLoc_end = 69407992

| Mm_Uniprot =

}}

Summary

Tumor protein p53, a nuclear protein, plays an essential role in the regulation of cell cycle, specifically in the transition from G0 to G1. It is found in very low levels in normal cells, however, in a variety of transformed cell lines, it is expressed in high amounts, and believed to contribute to transformation and malignancy. p53 is a DNA-binding protein containing DNA-binding, oligomerization and transcription activation domains. It is postulated to bind as a tetramer to a p53-binding site and activate expression of downstream genes that inhibit growth and/or invasion, and thus function as a tumor suppressor. Mutants of p53 that frequently occur in a number of different human cancers fail to bind the consensus DNA binding site, and hence cause the loss of tumor suppressor activity. Alterations of the TP53 gene occur not only as somatic mutations in human malignancies, but also as germline mutations in some cancer-prone families with Li-Fraumeni syndrome.

VEGFA

REDIRECT: Protein Redirected to: Vascular endothelial growth factor {August 12, 2007 5:39:07 PM PDT}
NO JOB: Both updates are turned off with errors. {August 12, 2007 5:39:10 PM PDT}
BAD FORMAT: There is a problem with the BOT commands for this protein: Vascular endothelial growth factor. Invoking a Mandantory Inspection. {August 12, 2007 5:39:10 PM PDT}

 {{protein
| Name = vascular endothelial growth factor
| caption =
| image =
| width =
| HGNCid = 12680
| Symbol = VEGF
| AltSymbols =
| EntrezGene = 7422
| OMIM = 192240
| RefSeq = NM_001025366
| UniProt = P15692
| PDB =
| ECnumber =
| Chromosome = 6
| Arm = p
| Band = 21
| LocusSupplementaryData = -p12
}}
Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). As its name implies, VEGF activity has been mostly studied on cells of the vascular endothelium, although it does have effects on a  number of other cell types (e.g. stimulation monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells ). In vitro, VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.

Classification

Image:VEGF isoforms.png

The broad term 'VEGF' covers a number of proteins from two families, that result from alternate splicing of mRNA from a single, 8 exon, VEGF gene. The two different familes are referred to according to their terminal exon (exon 8) splice site - the proximal splice site (denoted VEGFxxx) or distal splice site (VEGFxxxb). In addition, alternate splicing of exon 6 and 7 alters their heparin binding affinity, and amino acid number (in humans: VEGF121, VEGF121b, VEGF145, VEGF165, VEGF165b, VEGF189, VEGF206; the rodent orthologs of these proteins contain one fewer amino acid). These domains have important functional consequences for the VEGF splice variants as the terminal (exon 8) splice site determines whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed in normal tissues). In addition inclusion or exclusion of exons 6 and 7 mediate interactions with heparan sulfate proteoglycans (HSPGs) and neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate the VEGF signaling receptors (VEGFRs).

Function

Image:VEGF Vammin.png

The VEGF splice variants are released from cells as glycosylated disulfide-bonded dimers. Structurally VEGF belongs to the PDGF family of cystine-knot growth factors. Subsequently, several closely-related proteins were discovered (Placenta growth factor (PlGF), VEGF-B, VEGF-C and VEGF-D) which together comprise the VEGF sub-family of growth factors. VEGF is sometimes referred to as VEGF-A to differentiate it from these related growth factors. A number of VEGF-related proteins have also been discovered encoded by viruses (VEGF-E) and in the venom of some snakes (VEGF-F).

All members of the VEGF family stimulate cellular responses by binding to tyrosine kinase receptors (the VEGFRs) on the cell surface, causing them to dimerize and become activated through transphosphorylation, although to different sites, times and extents. The VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). VEGF-C and VEGF-D, but not VEGF-A, are ligands for a third receptor (VEGFR-3),which mediates lymphangiogenesis.

Production

VEGFxxx production can be induced in cells that are not receiving enough oxygen. When a cell is deficient in oxygen, it produces HIF, Hypoxia Inducible Factor, a transcription factor. HIF stimulates the release of VEGFxxx, among other functions (including modulation of erythropoeisis). Circulating VEGFxxx then binds to VEGF Receptors on endothelial cells, triggering a Tyrosine Kinase Pathway leading to angiogenesis.

Clinical significance

VEGFxxx has been implicated with poor prognosis in breast cancer. Numerous studies show a decreased OS and DFS in those tumors overexpressing VEGF. The overexpression of VEGFxxx may be an early step in the process of metastasis, a step that is involved in the "angiogenic" switch. Although VEGFxxx has been correlated with poor survival, its exact mechanism of action in the progression of tumors remains unclear.

VEGFxxx is also released in rheumatoid arthritis in response to TNF-Î±, increasing endothelial permeability and swelling and also stimulating angiogenesis (formation of capillaries).

VEGFxxx is also important in diabetic retinopathy. The microcirculatory problems in the retina of people with diabetes can cause retinal ischaemia, which results in the release of VEGFxxx, and a switch in the balance of pro-angiogenic VEGFxxx isoforms over the normally expressed VEGFxxxb isoforms. VEGFxxx may then cause the creation of new blood vessels in the retina and elsewhere in the eye, heralding changes which may threaten the sight.

Once released, VEGFxxx may elicit several responses. It may cause a cell to survive, move, or further differentiate. Hence, VEGF is a potential target for the treatment of cancer. The first anti-VEGF drug, a monoclonal antibody named bevacizumab, was approved in 2004. Approximately 10-15% of patients benefit from bevacizumab therapy, although biomarkers for bevacizumab efficacy are not yet known.

Current studies show that VEGFs are not the only promoters of angiogenesis. In particular FGF2 and HGF [http://www.healthvalue.net/cmettherapies.html] are potent angiogenic factors.

Patients suffering from pulmonary emphysema have been found to have decreased levels of VEGF in the pulmonary arteries.

Anti VEGF therapies

Anti VEGF therapies [http://www.healthvalue.net/VEGF2engl.html] are important advances in the treatment of certain cancers. They can be monoclonals such as Bevacizumab, or oral small molecules that inhibit the tyrosine kinases stimulated by VEGF : Sunitinib, Sorafenib, Axitinib, Pazopanib. The first two are commercialized. The last two are in clinical trials presented (June 07) at ASCO.

External links

[http://www.therapeuticangiogenesis.com TherapeuticAngiogenesis.com]
[http://www.researchvegf.com ResearchVEGF.com]
{{MeshName|Vascular+Endothelial+Growth+Factors}}
[http://www.exactantigen.com/review/vegf.html VEGF antibody]

Category:Angiology

Category:Growth factors

de:Vascular Endothelial Growth Factor

es:VEGF

fr:Vascular endothelial growth factor

ja:è¡€ç®¡å†…çš®ç´°èƒžå¢—æ®–å› å�

pl:VEGF

fi:VEGF

sv:VaskulÃ¤r endotelcellstillvÃ¤xtfaktor

zh:è¡€ç®¡å†…çš®ç”Ÿé•¿å› å�

Appended Protein Page ******

{{GNF_Protein_box

| image = PBB_Protein_VEGFA_image.jpg

| image_source = PDB rendering based on 1bj1.

| PDB = {{PDB2|1bj1}}, {{PDB2|1cz8}}, {{PDB2|1flt}}, {{PDB2|1kat}}, {{PDB2|1kmx}}, {{PDB2|1mjv}}, {{PDB2|1mkg}}, {{PDB2|1mkk}}, {{PDB2|1qty}}, {{PDB2|1tzh}}, {{PDB2|1tzi}}, {{PDB2|1vgh}}, {{PDB2|1vpf}}, {{PDB2|1vpp}}, {{PDB2|2fjg}}, {{PDB2|2fjh}}, {{PDB2|2vgh}}, {{PDB2|2vpf}}

| Name = vascular endothelial growth factor A

| HGNCid = 12680

| Symbol = VEGFA

| AltSymbols =; MGC70609; VEGF; VEGF-A; VPF

| OMIM = 192240

| ECnumber =

| Homologene = 2534

| MGIid = 103178

| GeneAtlas_image =

| DateOfBotUpdate = ~~~~~

| Function = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}} {{GNF_GO|id=GO:0001525 |text = angiogenesis}} {{GNF_GO|id=GO:0001570 |text = vasculogenesis}} {{GNF_GO|id=GO:0001666 |text = response to hypoxia}} {{GNF_GO|id=GO:0005172 |text = vascular endothelial growth factor receptor binding}} {{GNF_GO|id=GO:0005578 |text = proteinaceous extracellular matrix}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0007399 |text = nervous system development}} {{GNF_GO|id=GO:0007498 |text = mesoderm development}} {{GNF_GO|id=GO:0008083 |text = growth factor activity}} {{GNF_GO|id=GO:0008201 |text = heparin binding}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016477 |text = cell migration}} {{GNF_GO|id=GO:0030324 |text = lung development}} {{GNF_GO|id=GO:0030855 |text = epithelial cell differentiation}} {{GNF_GO|id=GO:0030949 |text = positive regulation of vascular endothelial growth factor receptor signaling pathway}} {{GNF_GO|id=GO:0042462 |text = eye photoreceptor cell development}} {{GNF_GO|id=GO:0042803 |text = protein homodimerization activity}} {{GNF_GO|id=GO:0050679 |text = positive regulation of epithelial cell proliferation}} {{GNF_GO|id=GO:0050840 |text = extracellular matrix binding}} {{GNF_GO|id=GO:0050930 |text = induction of positive chemotaxis}}

| Orthologs = {{GNF_Ortholog_box

| Hs_EntrezGene = 7422

| Hs_Ensembl = ENSG00000112715

| Hs_RefseqProtein = NP_001020537

| Hs_RefseqmRNA = NM_001025366

| Hs_GenLoc_db =

| Hs_GenLoc_chr = 6

| Hs_GenLoc_start = 43845924

| Hs_GenLoc_end = 43862202

| Hs_Uniprot = P15692

| Mm_EntrezGene = 22339

| Mm_Ensembl = ENSMUSG00000023951

| Mm_RefseqmRNA = NM_001025250

| Mm_RefseqProtein = NP_001020421

| Mm_GenLoc_db =

| Mm_GenLoc_chr = 17

| Mm_GenLoc_start = 45480574

| Mm_GenLoc_end = 45495331

| Mm_Uniprot =

}}

Summary

This gene is a member of the PDGF/VEGF growth factor family and encodes a protein that is often found as a disulfide linked homodimer. This protein is a glycosylated mitogen that specifically acts on endothelial cells and has various effects, including mediating increased vascular permeability, inducing angiogenesis, vasculogenesis and endothelial cell growth, promoting cell migration, and inhibiting apoptosis. Elevated levels of this protein is linked to POEMS syndrome, also known as Crow-Fukase syndrome. Mutations in this gene have been associated with proliferative and nonproliferative diabetic retinopathy. Alternate transcriptional splice variants, encoding either freely secreted or cell-associated isoforms, have been characterized. There is also evidence for the use of non-AUG (CUG) translation initiation sites upstream of, and in-frame with the first AUG, leading to additional isoforms.

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Function

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Alzheimer's Disease (AD)

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Role in Liver Biology

Interactions of beta-catenin with other proteins

The Role of Beta-Catenin in The Wnt Signaling Pathway

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