P53 24762 226012261 2008-07-16T13:01:14Z Boghog2 2428506 added group abbreviation to TF navbox template {{lowercase}}{{PBB|geneid=7157}} '''p53''' (also known as '''protein 53''' or '''tumor protein 53'''), is a [[transcription factor]] encoded by the ''[[TP53]]'' gene. p53 is important in [[multicellular organism]]s, where it regulates the [[cell cycle]] and thus functions as a [[tumor suppressor]] that is involved in preventing [[cancer]]. As such, p53 has been described as "the guardian of the [[genome]]," "the guardian angel gene," and the "master watchman," referring to its role in conserving stability by preventing genome mutation.<ref name="isbn0-471-33061-2">{{cite book | author = Read, A. P.; Strachan, T. | title = Human molecular genetics 2 | publisher = Wiley | location = New York | year = 1999 | pages = | isbn = 0-471-33061-2 | oclc = | doi = | chapter = Chapter 18: Cancer Genetics }}</ref> The name p53 is in reference to its apparent [[molecular mass]]: it runs as a 53 [[kilodalton]] (kDa) protein on [[SDS-PAGE]]. But based on calculations from its [[amino acid]] residues, p53's mass is actually only 43.7kDa. This difference is due to the high number of [[proline]] residues in the protein which slow its migration on [[SDS-PAGE]], thus making it appear larger than it actually is. This effect is observed with p53 from a variety of species, including humans, rodents, frogs and fish. ==Gene== In humans, p53 is encoded by the ''[[TP53]]'' gene located on the short arm of [[chromosome 17 (human)|chromosome 17]] (17p13.1). The gene is on different locations in other animals: *[[Mus musculus|Mouse]] - chromosome 11 *[[Rattus norvegicus|Rat]] - chromosome 10 *[[Dog]] - chromosome 5 *[[Pig]] - chromosome 12 (''Italics'' are used to distinguish the ''TP53'' gene name from the protein it encodes.) ==Structure== Human p53 is 393 [[amino acid]]s long and has seven [[domain (protein)|domains]]: * An [[N-terminal]] transcription-activation domain (TAD), also known as activation domain 1 (AD1) which activates [[transcription factor]]s: residues 1-42. * An activation domain 2 (AD2) important for apoptotic activity: residues 43-63. * A [[Proline]] rich domain important for the apoptotic activity of p53: residues 80-94. * A central [[DNA]]-binding core domain ([[DBD]]). Contains one zinc atom and several [[arginine]] amino acids: residues 100-300. * A nuclear localization signalling domain, residues 316-325. * A homo-oligomerisation domain (OD): residues 307-355. Tetramerization is essential for the activity of p53 ''in vivo''. * A [[C-terminal]] involved in downregulation of DNA binding of the central domain: residues 356-393.<ref name="pmid15713654">{{cite journal | author = Harms KL, Chen X | title = The C terminus of p53 family proteins is a cell fate determinant | journal = Mol. Cell. Biol. | volume = 25 | issue = 5 | pages = 2014–30 | year = 2005 | pmid = 15713654 | doi = 10.1128/MCB.25.5.2014-2030.2005 }}</ref> Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are [[recessive allele|recessive]] [[loss-of-function]] mutations. Molecules of p53 with mutations in the OD dimerise with [[wild-type]] p53, and prevent them from activating transcription. Therefore OD mutations have a dominant negative effect on the function of p53. Wild-type p53 is a [[labile]] [[protein]], comprising folded and [[Intrinsically unstructured proteins|unstructured regions]] which function in a synergistic manner.<ref name="pmid12367518">{{cite journal | author = Bell S, Klein C, Müller L, Hansen S, Buchner J | title = p53 contains large unstructured regions in its native state | journal = J. Mol. Biol. | volume = 322 | issue = 5 | pages = 917–27 | year = 2002 | pmid = 12367518 | doi = 10.1016/S0022-2836(02)00848-3 }}</ref> ==Functional significance== p53 has many anti-cancer mechanisms: * It can activate [[DNA repair]] proteins when DNA has sustained damage. * It can also hold the [[cell cycle]] at the G<sub>1</sub>/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.) * It can initiate [[apoptosis]], the programmed cell death, if the DNA damage proves to be irreparable. [[Image:P53 pathways.jpg|300px|right|thumb|'''p53 pathway:''' In a normal cell p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stress, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will either induce a cell cycle arrest to allow repair and survival of the cell or apoptosis to discard the damage cell. How p53 makes this choice is currently unknown.]] p53 is central to many of the cell's anti-cancer mechanisms. It can induce growth arrest, [[apoptosis]] and cell [[senescence]]. In normal cells p53 is usually inactive, bound to the protein [[Mdm2|MDM2]] (also called HDM2 in humans), which prevents its action and promotes its degradation by acting as [[ubiquitin]] [[ligase]]. Active p53 is induced after the effects of various cancer-causing agents such as [[UV radiation]], [[oncogene]]s and some DNA-damaging drugs. DNA damage is sensed by 'checkpoints' in a cell's cycle, and causes proteins such as [[Ataxia telangiectasia mutated|ATM]], [[Chk1|CHK1]] and [[Chk2|CHK2]] to [[phosphorylate]] p53 at sites that are close to or within the MDM2-binding region and p300-binding region of the protein. Oncogenes also stimulate p53 activation, mediated by the protein [[p14ARF]]. Some oncogenes can also stimulate the transcription of proteins which bind to MDM2 and inhibit its activity. Once activated p53 activates expression of several genes including one encoding for [[p21]]. p21 binds to the [[G1 phase|G1]]-[[S phase|S]]/[[CDK]] and S/CDK complexes (molecules important for the [[G1/S transition]] in the cell cycle) inhibiting their activity. p53 has many anticancer mechanisms, and plays a role in apoptosis, genetic stability, and inhibition of [[angiogenesis]]. The p53 gene has been mapped to chromosome 17. In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is complexed with cdk2 the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the 'stop signal' for cell division. Thus cells divide uncontrollably, and form tumors.<ref name="urlThe p53 tumor suppressor protein">{{cite web | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.107 | title = The p53 tumor suppressor protein | author = National Center for Biotechnology Information | authorlink = | coauthors = | date = | format = | work = Genes and Disease | publisher = United States National Institutes of Health | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-05-28}}</ref> Recent research has also linked the p53 and [[RB1]] pathways, via p14ARF, raising the possibility that the pathways may regulate each other.<ref name="pmid9744267">{{cite journal | author = Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH | title = p14ARF links the tumour suppressors RB and p53 | journal = Nature | volume = 395 | issue = 6698 | pages = 124–5 | year = 1998 | pmid = 9744267 | doi = 10.1038/25867 }}</ref> Research published in 2007 showed when p53 expression is stimulated by [[sunlight]], it begins the chain of events leading to [[sun tanning|tanning]].<ref>{{cite news | title = Genome's guardian gets a tan started | url = http://www.newscientist.com/channel/health/mg19325955.800-genomes-guardian-gets-a-tan-started.html | publisher = New Scientist | date = March 17, 2007 | accessdate = 2007-03-29}}</ref><ref name="pmid17350573">{{cite journal | author = Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE, D'Orazio J, Fung CY, Schanbacher CF, Granter SR, Fisher DE | title = Central role of p53 in the suntan response and pathologic hyperpigmentation | journal = Cell | volume = 128 | issue = 5 | pages = 853–64 | year = 2007 | pmid = 17350573 | doi = 10.1016/j.cell.2006.12.045 }}</ref> ==Regulation of p53 activity== p53 becomes activated in response to a myriad of stress types, which include but is not limited to [[DNA damage]] (induced by either [[UV]], [[Ionizing radiation|IR]] or chemical agents,such as hydrogen peroxide), [[oxidative stress]], [[osmotic shock]], ribonucleotide depletion and deregulated oncogene expression. This activation is marked by two major events. Firstly, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Secondly, a [[conformational change]] forces p53 to take on an active role as a [[Transcriptional regulation|transcription regulator]] in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals. The [[protein kinases]] that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the [[MAPK]] family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc... A second group of protein kinases (ATR, ATM, Chk1, Chk2, DNA-PK, CAK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called [[Mdm2]] binds to p53 and transports it from the [[Cell nucleus|nucleus]] to the [[cytosol]] where it becomes degraded by the [[proteasome]]. Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53 which prevents Mdm2-binding even more. Trancriptional coactivators, like [[P300/CBP|p300]] or [[PCAF]], then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as [[Sirt1]] and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis.<ref name="pmid18239138">{{cite journal | author = Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, Braun T, Bober | title = Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice | journal = Circ. Res. | volume = 102 | issue = 6 | pages = 703–10 | year = 2008 | month = March | pmid = 18239138 | doi = 10.1161/CIRCRESAHA.107.164558 | url = }}</ref> ==Role in disease== If the ''TP53'' gene is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of the ''TP53'' gene will most likely develop tumors in early adulthood, a disease known as [[Li-Fraumeni syndrome]]. The ''TP53'' gene can also be damaged in cells by [[mutagen]]s ([[chemical substance|chemicals]], [[radiation]] or [[virus]]es), increasing the likelihood that the cell will begin uncontrolled division. More than 50 percent of [[human]] [[tumor]]s contain a [[mutation]] or [[genetic deletion|deletion]] of the ''TP53'' gene. Increasing the amount of p53, which may initially seem a good way to treat tumors or prevent them from spreading, is in actuality not a usable method of treatment, since it can cause premature aging.<ref name="pmid11780111">{{cite journal | author = Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Hee Park S, Thompson T, Karsenty G, Bradley A, Donehower LA | title = p53 mutant mice that display early ageing-associated phenotypes | journal = Nature | volume = 415 | issue = 6867 | pages = 45–53 | year = 2002 | pmid = 11780111 | doi = 10.1038/415045a }}</ref> However, restoring [[endogenous]] p53 function holds a lot of promise.<ref name="pmid17251932">{{cite journal | author = Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T | title = Restoration of p53 function leads to tumour regression in vivo | journal = Nature | volume = 445 | issue = 7128 | pages = 661–5 | year = 2007 | pmid = 17251932 | doi = 10.1038/nature05541 }}</ref> Certain pathogens can also affect the p53 protein that the ''TP53'' gene expresses. One such example, the [[Human papillomavirus]] (HPV), encodes a protein, [[E6 - protein|E6]], which binds the p53 protein and inactivates it. This, in synergy with the inactivation of another cell cycle regulator, [[p105RB]], allows for repeated cell division manifestested in the clinical disease of [[wart]]s. In healthy humans, the p53 protein is continually produced and degraded in the cell. The degradation of the p53 protein is, as mentioned, associated with MDM2 binding. In a negative feedback loop MDM2 is itself induced by the p53 protein. However mutant p53 proteins often don't induce MDM2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 protein levels. === Brief History === Originally P53 was thought to be an [[oncogene]] because well over half of all cancer cells tested showed high levels of P53 protein. However, these were all mutated forms of P53.{{fact|date=March 2008}} ==History== p53 was identified in 1979 by [[Arnold Levine]], [[David Lane (Oncology)|David Lane]], and [[Lloyd Old]], working at [[Princeton University]], [[Imperial Cancer Research Fund]] (UK), and [[Sloan-Kettering Memorial Hospital]], respectively. It had been hypothesized to exist before as the target of the [[SV40]] virus, a strain that induced development of tumors. The ''[[TP53]]'' gene from the mouse was first cloned by [[Peter Chumakov]] of the [[Moscow Academy of Sciences]] in 1982,<ref>{{cite journal |author=Chumakov P, Iotsova V, Georgiev G |title=[Isolation of a plasmid clone containing the mRNA sequence for mouse nonviral T-antigen] |journal=Dokl Akad Nauk SSSR |volume=267 |issue=5 |pages=1272–5 |year=1982 |pmid=6295732}}</ref> and independently in 1983 by [[Moshe Oren]] ([[Weizmann Institute]]). It was initially presumed to be an [[oncogene]] due to the use of mutated [[cDNA]] following purification of tumour cell [[mRNA]]. Its character as a [[tumor suppressor gene]] was finally revealed in 1989 by [[Bert Vogelstein]] working at [[Johns Hopkins School of Medicine]]. Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.<ref>{{cite journal |author=Maltzman W, Czyzyk L |title=UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells |journal=Mol Cell Biol |volume=4 |issue=9 |pages=1689–94 |year=1984 |pmid=6092932}}</ref> In a series of publications in 1991-92, Michael Kastan, Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage. In 1993, p53 was voted ''molecule of the year'' by [[Science (journal)|Science]] magazine.<ref name="pmid8266084">{{cite journal | author = Koshland DE | title = Molecule of the year | journal = Science | volume = 262 | issue = 5142 | pages = 1953 | year = 1993 | pmid = 8266084 | doi = 10.1126/science.8266084 }}</ref> ==Other names== *Official protein name: Cellular [[tumor antigen]] p53 *Tumor suppressor p53 *Transformation-related protein 53 (TRP53) *Phosphoprotein p53 *Antigen NY-CO-13 == References == {{reflist|2}} ==Additional images== <gallery> Image:DAXX Pathway.svg|The [[DAXX]] Pathway </gallery> == External links == * {{cite web | url = http://p53.bii.a-star.edu.sg/ | title = p53 Knowledgebase | accessdate = 2008-04-06 | author = | authorlink = | coauthors = | date = | format = | work = | publisher = Lane Group at the Institute of Molecular and Cell Biology (IMCB), Singapore | pages = | language = | archiveurl = | archivedate = | quote = }} * {{cite web | url = http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb31_2.html | title = p53 Tumor Suppressor | accessdate = 2008-04-06 | author = David S. Goodsell | authorlink = | coauthors = | date = 2002-07-01 | format = | work = Molecule of the Month | publisher = RCSB Protein Data Bank | pages = | language = | archiveurl = | archivedate = | quote = }} * {{cite web | url = http://p53.free.fr/ | title = p53 Web Site | accessdate = 2008-04-06 | author = Thierry Soussi | authorlink = | coauthors = | date = | format = | work = | publisher = | pages = | language = | archiveurl = | archivedate = | quote = }} {{Signaling proteins}} {{Transcription factors|g4}} {{Tumor suppressor genes}} [[Category:Programmed cell death]] [[Category:Proteins]] [[Category:Transcription factors]] [[Category:Tumor suppressor genes]] [[Category:Oncology]] [[Category:Apoptosis]] [[de:P53]] [[es:P53]] [[fr:P53]] [[it:P53]] [[he:P53]] [[hu:P53]] [[ja:P53遺伝子]] [[pl:P53]] [[pt:P53]] [[ru:P53]] [[sl:P53]] [[fi:P53]] [[th:P53]] [[vi:P53]] [[tr:P53]] [[uk:P53]] [[ur:P53 (لحمیہ)]] <!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --> {{PBB_Controls | update_page = yes | require_manual_inspection = no | update_protein_box = yes | update_summary = no | update_citations = no }}