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[edit] Protein Status Log - Date: 09:08, 12 August 2007 (UTC)
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AKT1
- REDIRECT: Protein Redirected to: AKT {August 12, 2007 2:05:25 AM PDT}
- NO JOB: Both updates are turned off with errors. {August 12, 2007 2:05:30 AM PDT}
- BAD FORMAT: There is a problem with the BOT commands for this protein: AKT. Invoking a Mandantory Inspection. {August 12, 2007 2:05:30 AM PDT}
{{protein
|Name=v-akt murine thymoma viral oncogene homolog 1
|caption=
|image=
|width=
|HGNCid=391
|Symbol=AKT1
|AltSymbols=
|EntrezGene=207
|OMIM=164730
|RefSeq=NM_005163
|UniProt=P31749
|PDB=
|ECnumber=
|Chromosome=14
|Arm=q
|Band=32.32
|LocusSupplementaryData=-32.33
}}
{{protein
|Name=v-akt murine thymoma viral oncogene homolog 2
|caption=
|image=
|width=
|HGNCid=392
|Symbol=AKT2
|AltSymbols=
|EntrezGene=208
|OMIM=164731
|RefSeq=NM_001626
|UniProt=P31751
|PDB=
|ECnumber=
|Chromosome=19
|Arm=q
|Band=13.1
|LocusSupplementaryData=-13.2
}}
{{protein
|Name=v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma)
|caption=
|image=
|width=
|HGNCid=393
|Symbol=AKT3
|AltSymbols=
|EntrezGene=10000
|OMIM=
|RefSeq=NM_181690
|UniProt=Q9Y243
|PDB=
|ECnumber=
|Chromosome=1
|Arm=q
|Band=43
|LocusSupplementaryData=-44
}}
'''Akt1''', also known as "Akt" or [[protein kinase]] B (PKB) is an important molecule in [[Mammal|mammalian]] cellular signaling.
==AKT family: AKT1, AKT2, AKT3==
In humans, there are three genes in the "Akt family": Akt1, Akt2, and Akt3. These [[enzyme]]s are members of the [[Protein kinase#Serine.2Fthreonine specific protein kinases|serine/threonine-specific protein kinase]] family ({{EC number|2.7.11.1}}).
Akt1 is involved in cellular survival pathways, by inhibiting [[Apoptosis|apoptotic]] processes. Akt1 is also able to induce [[protein synthesis]] pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the [[oncogene]] in the transforming [[retrovirus]], AKT8 by Dr. Philip Tsichlis at Fox Chase Cancer Center in the 1990's.
Akt2 is an important signaling molecule in the Insulin signaling pathway. It's required to induce glucose transport.
These separate roles for Akt1 and Akt2 were demonstrated by studying mice in which either the Akt1 or the Akt2 gene was deleted, or "knocked out". In a mouse which is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice which do not have Akt2, but have normal Akt1, have mild growth deficiency and display a [[diabetes|diabetic]] phenotype ([[insulin resistance]]), again consistent with the idea that Akt2 is more specific for the [[insulin receptor]] signaling pathway {{ref|Garofalo2003}}.
The role of Akt3 is less clear, though it appears to be predominantly expressed in brain. It has been reported that mice lacking Akt3 have small brains {{ref|Yang2004}}.
The name Akt does not refer to its function. Presumably, the "Ak" in Akt was a temporary classification name for a mouse strain developing spontaneous thymic lymphomas. The "t" stands for 'transforming', the letter was added when a transforming retrovirus was isolated from the Ak strain, which was termed "Akt-8". When the oncogene encoded in this virus was discovered, it was termed v-Akt. Thus, the later identified human analogues were named accordingly.
==Regulation: Activation and Inactivation of Akt==
===Binding phospho-lipids in the membrane===
Akt possesses a [[protein domain]] known as a [[PH domain]], or [[Pleckstrin homology domain|Pleckstrin Homology domain]], named after [[Pleckstrin]], the protein in which it was first discovered. This domain binds to [[phosphoinositides]] with high affinity. In the case of the PH domain of Akt, it binds either [[phosphatidylinositol (3,4,5)-trisphosphate]] (PtdIns(3,4,5)''P''<sub>3</sub> aka [[PIP<sub>3</sub>]]) or [[phosphatidylinositol (3,4)-bisphosphate]] (PtdIns(3,4)''P''<sub>2</sub> aka PI(3,4)P<sub>2</sub>). This is useful for control of cellular signaling because the di-phosphorylated phosphoinositide [[PtdIns(4,5)P<sub>2</sub>]] is only phosphorylated by the family of enzymes, PI 3-kinases ([[phosphoinositide 3-kinase]] or PI3K), and only upon receipt of chemical messengers which tell the cell to begin the growth process. For example, PI 3-kinases may be activated by a [[GPCR|G protein coupled receptor]] or [[tyrosine kinase|receptor tyrosine kinase]] such as the [[insulin receptor]]. Once activated, PI 3-kinases phosphorylates [[PtdIns(4,5)P2]] to form [[PtdIns(3,4,5)P3]].
===Phosphorylation by PDK1 and PDK2===
Once correctly positioned in the membrane via binding of [[PIP3]], Akt can then be phosphorylated by its activating kinases, phosphoinositide dependent kinase 1 ([[PDK1]]) and mTORC2. First, the mammalian target of rapamycin complex 2 (mTORC2) phosphorylates Akt; [[mTORC2]] therefore functionally acts as the long-sought PDK2 molecule. Phosphorylation by mTORC2 stimulates the subsequent phosphorylation of Akt by [[PDK1]]. Activated Akt can then go on to activate or deactivate its myriad substrates via its kinase activity. See this link for a more thorough and detailed image of the [http://www.cellsignal.com/pathways/akt-signaling.jsp Akt signaling pathway].
Besides being a downstream effector of PI 3-kinases, Akt may also be activated in a PI 3-kinase-independent manner. Studies have suggested that [[cAMP]]-elevating agents could activate Akt through protein kinase A ([[PKA]]), although these studies are disputed and the mechanism of action is unclear.
===Lipid phosphatases control the amount of PIP3, thereby modulating the ability of Akt to be activated===
PI3K dependent Akt activation can be regulated through the [[tumor suppressor gene|tumor suppressor]] [[PTEN (gene)|PTEN]], which works essentially as the opposite of [[PI3K]] mentioned above ([http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.figgrp.2669 PTEN and PI3K]). PTEN acts as a [[phosphatase]] to dephosphorylate [[PtdIns(3,4,5)P3]] back to [[PtdIns(4,5)P2]]. This removes the membrane-localization factor from the Akt signaling pathway. Without this localization, the rate of Akt activation decreases significantly, as do the all the downstream pathways that depend on Akt for activation.
PIP3 can also be de-phosphorylated at the "5" position by the SHIP family of inositol phosphatases, [[SHIP1]] and [[SHIP2]]. These poly-phosphate inositil phosphatases dephosphorylate [[PtdIns(3,4,5)P3]] to form [[PtdIns(3,4)P2]].
===Protein phosphatases control the amount of phosphorylated Akt===
The phosphatases in the [[PHLPP]] family, [[PHLPP1]] and [[PHLPP2]] have been shown to directly de-phosphorylate, and therefore inactivate, distinct Akt isoforms. PHLPP2 dephosphorylates Akt1 and Akt3, whereas PHLPP1 is specific for Akt 2 and Akt3.
==Functions==
Akt regulate the cellular survival {{ref|Song2005}} and [[metabolism]] by binding and regulating many downstream effectors, e.g. [[NF-kB|Nuclear Factor-κB]], Bcl-2 family proteins and murine double minute 2 (MDM2).
=====Cell survival=====
Akt could promote growth factor-mediated cell survival both directly and indirectly. BAD is a pro-apoptotic protein of the [[Bcl-2]] family. Akt could phosphorylate BAD on Ser136 ([http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.2865 BAD phosphorylation by Akt)], which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function ([http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6902 BAD interaction with Bcl-2]). Akt could also activate [[NF-kB|NF-κB]] via regulating IκB kinase (IKK), thus result in transcription of pro-survival genes ([http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.figgrp.997 regulation of NF-kB]).
=====Metabolism=====
Akt is required for the insulin-induced translocation of glucose transporter 4 ([[GLUT4]]) to the [[plasma membrane]]. Glycogen synthase kinase 3 ([[GSK-3]]) could be inhibited upon phosphorylation by Akt, which results in promotion of glycogen synthesis. It's worthy to note that GSK3 is also involved in [[Wnt signalling pathway|Wnt]] signaling cascade, so Akt might be also implicated in the Wnt pathway.
Still unknown role in HCV induced steatosis.
=====Angiogenesis=====
Akt1 has also been implicated in angiogenesis and tumor development. Deficiency of Akt1 in mice although inhibited physiological angiogenesis, it enhanced pathological angiogenesis and tumor growth associated with matrix abnormalities in skin and blood vessels {{ref|Chen2005}},{{ref|Somanath2006}}
==References==
#{{note|Garofalo2003}}Robert S. Garofalo, Stephen J. Orena, Kristina Rafidi, Anthony J. Torchia, Jeffrey L. Stock, Audrey L. Hildebrandt, Timothy Coskran, Shawn C. Black, Dominique J. Brees, Joan R. Wicks, John D. McNeish, and Kevin G. Coleman (2003) "Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta" ''[[Journal of Clinical Investigation]]'' Volume 112, pages 197-208. [http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=12843127 full text online] {{Entrez Pubmed|12843127}}
#{{note|Yang2004}} Z. Z. Yang, O. Tschopp, A. Baudry, B. Dummler, D. Hynx and B. A. Hemmings. (2004) Physiological functions of protein kinase B/Akt. ''Biochem Soc Trans.'' 32:350-354. Review. [http://www.biochemsoctrans.org/bst/032/0350/bst0320350.htm full text online] {{Entrez Pubmed|15046607}}
#{{note|Song2005}} Gang Song, Gaoliang Ouyang and Shideng Bao. (2005) The activation of Akt/PKB signaling pathway and cell survival. ''J. Cell. Mol. Med.'' 9:59-71. [http://www.jcmm.org/en/pdf/9/1/jcmm009.001.07.pdf Download full text] ([[PDF]] format).
#{{note|Chen2005}} Chen J, Somanath PR, Razorenova O, Chen WS, Hay N, Bornstein P, Byzova TV. Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nat Med. 2005 Nov;11(11):1188-96.
#{{note|Somanath2005}} Somanath PR, Razorenova OV, Chen J, Byzova TV. Akt1 in endothelial cell and angiogenesis. Cell Cycle. 2006 Mar;5(5):512-8.
==External links==
* {{MeshName|Proto-Oncogene+Proteins+c-akt}}
{{Oncogenes}}
{{Serine/threonine-specific protein kinases}}
[[Category:EC 2.7.11]]
[[Category:Protein kinases]]
[[de:Proteinkinase B]]
****** 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_AKT1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1h10.
| PDB = {{PDB2|1h10}}, {{PDB2|1unp}}, {{PDB2|1unq}}, {{PDB2|1unr}}, {{PDB2|2uvm}}
| Name = v-akt murine thymoma viral oncogene homolog 1
| HGNCid = 391
| Symbol = AKT1
| AltSymbols =; AKT; MGC99656; PKB; PRKBA; RAC; RAC-ALPHA
| OMIM = 164730
| ECnumber =
| Homologene = 3785
| MGIid = 87986
| 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:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004672 |text = protein kinase activity}} {{GNF_GO|id=GO:0004674 |text = protein serine/threonine kinase activity}} {{GNF_GO|id=GO:0005351 |text = sugar:hydrogen ion symporter activity}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005819 |text = spindle}} {{GNF_GO|id=GO:0005975 |text = carbohydrate metabolic process}} {{GNF_GO|id=GO:0005978 |text = glycogen biosynthetic process}} {{GNF_GO|id=GO:0006006 |text = glucose metabolic process}} {{GNF_GO|id=GO:0006417 |text = regulation of translation}} {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0006809 |text = nitric oxide biosynthetic process}} {{GNF_GO|id=GO:0006810 |text = transport}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0006954 |text = inflammatory response}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007186 |text = G-protein coupled receptor protein signaling pathway}} {{GNF_GO|id=GO:0007281 |text = germ cell development}} {{GNF_GO|id=GO:0008286 |text = insulin receptor signaling pathway}} {{GNF_GO|id=GO:0008637 |text = apoptotic mitochondrial changes}} {{GNF_GO|id=GO:0009408 |text = response to heat}} {{GNF_GO|id=GO:0009725 |text = response to hormone stimulus}} {{GNF_GO|id=GO:0015758 |text = glucose transport}} {{GNF_GO|id=GO:0016567 |text = protein ubiquitination}} {{GNF_GO|id=GO:0016740 |text = transferase activity}} {{GNF_GO|id=GO:0030027 |text = lamellipodium}} {{GNF_GO|id=GO:0030163 |text = protein catabolic process}} {{GNF_GO|id=GO:0042640 |text = anagen}} {{GNF_GO|id=GO:0042802 |text = identical protein binding}} {{GNF_GO|id=GO:0045884 |text = regulation of survival gene product activity}} {{GNF_GO|id=GO:0046777 |text = protein amino acid autophosphorylation}} {{GNF_GO|id=GO:0048009 |text = insulin-like growth factor receptor signaling pathway}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 207
| Hs_Ensembl = ENSG00000142208
| Hs_RefseqProtein = NP_001014431
| Hs_RefseqmRNA = NM_001014431
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 14
| Hs_GenLoc_start = 104306734
| Hs_GenLoc_end = 104333125
| Hs_Uniprot = P31749
| Mm_EntrezGene = 11651
| Mm_Ensembl = ENSMUSG00000001729
| Mm_RefseqmRNA = NM_009652
| Mm_RefseqProtein = NP_033782
| Mm_GenLoc_db =
| Mm_GenLoc_chr = 12
| Mm_GenLoc_start = 113101636
| Mm_GenLoc_end = 113122084
| 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 serine-threonine protein kinase encoded by the AKT1 gene is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor. The activation is rapid and specific, and it is abrogated by mutations in the pleckstrin homology domain of AKT1. It was shown that the activation occurs through phosphatidylinositol 3-kinase. In the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery. Multiple alternatively spliced transcript variants have been found for this gene.
<!-- BOT: SUMMARY END -->
APOE
- REDIRECT: Protein Redirected to: Apolipoprotein E {August 12, 2007 2:05:30 AM PDT}
- NO JOB: Both updates are turned off with errors. {August 12, 2007 2:05:34 AM PDT}
- BAD FORMAT: There is a problem with the BOT commands for this protein: Apolipoprotein E. Invoking a Mandantory Inspection. {August 12, 2007 2:05:34 AM 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 (biochemistry)|receptor]] on [[hepatocyte|liver cell]]s 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 acid]]s 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]], [[kidney]]s, and [[spleen]]. In the nervous system, non-neuronal cell types, most notably [[Astrocyte|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 (human)|chromosome 19]] in a cluster with [[Apolipoprotein C1]] and [[Apolipoprotein C2]]. ''ApoE'' consists of four [[exons]] and three [[introns]], totaling 3597 [[base pair]]s.
The gene is [[Polymorphism (biology)|polymorphic]], with three major [[allele]]s, ''ApoE2'', ''ApoE3'', ''ApoE4'', which translate into three [[isoforms]] of the protein: normal - ApoE-ε3; dysfunctional - ApoE-ε2 and ApoE-ε4. 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-ε4 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-ε4 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==
<references/>
==External links==
* {{MeshName|Apolipoproteins+E}}
{{Lipoproteins}}
[[Category:Apolipoproteins]]
[[Category:Alzheimer's disease]]
[[ru:�полипопротеин E]]
[[tr:Apolipoprotein E]]
[[zh:载脂蛋白 E]]
****** 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_APOE_image.jpg
| image_source = [[Protein_Data_Bank|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 =
<!-- The Following entry is a time stamp of the last bot update. It is typically hidden data -->
| 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 =
}}
}}
<!-- 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==
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.
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APP
- NO JOB: Both updates are turned off with errors. {August 12, 2007 2:05:39 AM PDT}
- BAD FORMAT: There is a problem with the BOT commands for this protein: Amyloid_precursor_protein. Invoking a Mandantory Inspection. {August 12, 2007 2:05:39 AM PDT}
[[Image:2fjz_app.png|thumb|250px|The metal-binding domain of APP with a bound [[copper]] ion. The [[side chain]]s 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|thumb|250px|The extracellular E2 domain, a dimeric [[coiled coil]] 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]] [[proteoglycan]]s.<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 [[biological tissue|tissues]] and concentrated in the [[synapse]]s of [[neuron]]s. 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 plaque]]s found in the brains of [[Alzheimer's disease]] patients.
==Genetics==
In [[human]]s, the [[gene]] for APP is located on [[chromosome 21]] and contains at least 18 [[exon]]s in 240 [[kilobase]]s.<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> [[Homology (biology)|Homologous]] proteins have been identified in other organisms such as ''[[Drosophila]]'' (fruit flies), ''[[C. elegans]]'' (roundworms), and all [[mammal]]s.<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|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 Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.<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 [[protein folding|folding]] structural [[protein domain|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 [[proteoglycan]]s 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 [[proteolysis|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 [[protease]]s in the [[secretase]] family; [[alpha secretase]] and [[beta secretase]] both remove nearly the entire extracellular domain to release membrane-anchored [[C-terminus|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 raft]]s. 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 [[gene expression|expression]] is [[gene regulation|upregulated]] during neuronal [[cell differentiation|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 [[transmembrane receptor|receptor]] protein [[Notch signaling|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 [[phenotype|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==
{{Reflist|2}}
==External links==
* {{MeshName|Amyloid+Protein+Precursor}}
[[Category:Alzheimer's disease]]
[[Category:Integral membrane proteins]]
[[Category:Neurochemistry]]
[[fr:Protéine précurtrice de l'amyloïde]]
[[es:ProteÃna Precursora AmiloÃdea]]
****** Appended Protein Page ******
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<!-- 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_APP_image.jpg
| image_source = [[Protein_Data_Bank|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 =
<!-- The Following entry is a time stamp of the last bot update. It is typically hidden data -->
| 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 =
}}
}}
<!-- 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 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.
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AR
- AMBIGUITY: More than one potential page found for updating, AR AIS Ais KD Kd SBMA TFM {August 12, 2007 2:06:24 AM PDT}
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<!-- 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 =
| image_source =
| 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 =
<!-- The Following entry is a time stamp of the last bot update. It is typically hidden data -->
| 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 =
}}
}}
<!-- 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 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.
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BCL2
- REDIRECT: Protein Redirected to: Bcl-2 {August 12, 2007 2:06:24 AM PDT}
- NO JOB: Both updates are turned off with errors. {August 12, 2007 2:06:28 AM PDT}
- BAD FORMAT: There is a problem with the BOT commands for this protein: Bcl-2. Invoking a Mandantory Inspection. {August 12, 2007 2:06:28 AM 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 [[gene]]s and the [[protein]]s they produce. They govern [[mitochondria]]l outer membrane permeabilisation (MOMP) and can be either pro-[[apoptosis|apoptotic]] ([[Bax]], [[Bcl-2-associated death promoter|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 [[chromosome]]s 14 and 18 in follicular [[lymphoma]]s.
==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 [[calcium in biology|Ca<sup>2+</sup>]], [[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|left|thumb|300px|Bcl-2 family<ref>Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16:395-419. Review.</ref>]]
The members of the Bcl-2 family share one or more of the four characteristic [[Domain (biology)|domain]]s of [[Homology (biology)|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 [[Hydrophobe|hydrophobic]] helix surrounded by amphipathic helices. Many members of the family have [[Transmembrane_proteins|transmembrane domain]]s. 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 [[caspase]]s. 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 [[cancer]]s, including [[melanoma]], [[breast cancer|breast]], [[prostate cancer|prostate]], and [[lung cancer|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, 47–63). 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, 47–63).
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 [[non-Hodgkin lymphoma|follicular B-cell lymphoma]], a [[chromosomal translocation]] occurs between the fourteenth and the eighteenth [[chromosome]]s - 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]] [[cell (biology)|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 [[Food and Drug Administration|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>.
==See also==
* [[Apoptosis]]
* [[Apoptosome]]
* [[Bcl-2-associated_X_protein]] (BAX)
* [[BH3 interacting domain death agonist]] (BID)
* [[Caspases]]
* [[Cytochrome c]]
* [[Noxa]]
* [[Mitochondrion]]
* [[p53 upregulated modulator of apoptosis]] (PUMA)
==References==
{{Reflist|2}}
==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}}
{{Oncogenes}}
[[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 ******
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{{GNF_Protein_box
| image = PBB_Protein_BCL2_image.jpg
| image_source = [[Protein_Data_Bank|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 =
<!-- 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: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 =
}}
}}
<!-- 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 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.
<!-- BOT: SUMMARY END -->
BRCA1
- AMBIGUITY: More than one potential page found for updating, BRCA1 IRIS Iris PSCP {August 12, 2007 2:06:58 AM PDT}
<!-- BOT: MANUAL_INSPECTION_REQUIRED = NO - change this option to YES to have the protein box bot require an operator inspection before updating occurs. -->
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{{GNF_Protein_box
| image =
| image_source =
| 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 =
<!-- The Following entry is a time stamp of the last bot update. It is typically hidden data -->
| 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 =
}}
}}
<!-- 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 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.
<!-- BOT: SUMMARY END -->
CASP3
- REDIRECT: Protein Redirected to: Caspase 3 {August 12, 2007 2:06:58 AM PDT}
- NO JOB: Both updates are turned off with errors. {August 12, 2007 2:07:02 AM PDT}
- BAD FORMAT: There is a problem with the BOT commands for this protein: Caspase 3. Invoking a Mandantory Inspection. {August 12, 2007 2:07:02 AM 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|thumbnail|center|500px|Signaling pathway of [[Tumor necrosis factor-alpha|TNF]]-R1. Dashed grey lines represent multiple steps]]
{{biochem-stub}}
{{Cysteine proteases}}
****** Appended Protein Page ******
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{{GNF_Protein_box
| image = PBB_Protein_CASP3_image.jpg
| image_source = [[Protein_Data_Bank|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.
<!-- BOT: SUMMARY END -->
CDKN1A
- REDIRECT: Protein Redirected to: p21 {August 12, 2007 2:07:02 AM PDT}
- NO JOB: Both updates are turned off with errors. {August 12, 2007 2:07:06 AM PDT}
- BAD FORMAT: There is a problem with the BOT commands for this protein: p21. Invoking a Mandantory Inspection. {August 12, 2007 2:07:06 AM 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 (medicine)|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 cell]]s 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==
<div class="references-small"><references /></div>
{{Tumor suppressor genes}}
{{Cell cycle proteins}}
[[Category:Genes]]
[[Category:Cell cycle]]
[[de:P21]]
[[pt:P21]]
****** 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 =
| 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 =
<!-- The Following entry is a time stamp of the last bot update. It is typically hidden data -->
| 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 =
}}
}}
<!-- 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 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.
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CDKN2A
- REDIRECT: Protein Redirected to: P16INK4a {August 12, 2007 2:07:06 AM PDT}
- NO JOB: Both updates are turned off with errors. {August 12, 2007 2:07:10 AM PDT}
- BAD FORMAT: There is a problem with the BOT commands for this protein: P16INK4a. Invoking a Mandantory Inspection. {August 12, 2007 2:07:10 AM 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 complex]]es.
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]]
{{genetics-stub}}
{{Cell cycle proteins}}
****** Appended Protein Page ******
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{{GNF_Protein_box
| image = PBB_Protein_CDKN2A_image.jpg
| image_source = [[Protein_Data_Bank|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 =
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| 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 =
}}
}}
<!-- 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 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.
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MMP9
- CREATED: Created new protein page: MMP9 {August 12, 2007 2:07:57 AM PDT}
end log.
