P53 - wikipedia P53 For other uses, see P53 ( disambiguation ). TP53 Available structures PDB Ortholog search : PDBe RCSB show List of PDB id codes 4QO1, 1A1U, 1AIE, 1C26, 1DT7, 1GZH, 1H26, 1HS5, 1KZY, 1MA3, 1OLG, 1OLH, 1PES, 1PET, 1SAE, 1SAF, 1SAK, 1SAL, 1TSR, 1TUP, 1UOL, 1XQH, 1YC5, 1YCQ, 1YCR, 1YCS, 2AC0, 2ADY, 2AHI, 2ATA, 2B3G, 2BIM, 2BIN, 2BIO, 2BIP, 2BIQ, 2FEJ, 2FOJ, 2FOO, 2GS0, 2H1L, 2H2D, 2H2F, 2H4F, 2H4H, 2H4J, 2H59, 2J0Z, 2J10, 2J11, 2J1W, 2J1X, 2J1Y, 2J1Z, 2J20, 2J21, 2K8F, 2L14, 2LY4, 2MEJ, 2MWO, 2MWP, 2MZD, 2OCJ, 2PCX, 2RUK, 2VUK, 2WGX, 2X0U, 2X0V, 2X0W, 2XWR, 2YBG, 2YDR, 2Z5S, 2Z5T, 3D05, 3D06, 3D07, 3D08, 3D09, 3D0A, 3DAB, 3DAC, 3IGK, 3IGL, 3KMD, 3KZ8, 3LW1, 3OQ5, 3PDH, 3Q01, 3Q05, 3Q06, 3SAK, 3TG5, 3TS8, 3ZME, 4AGL, 4AGM, 4AGN, 4AGO, 4AGP, 4AGQ, 4BUZ, 4BV2, 4HFZ, 4HJE, 4IBQ, 4IBS, 4IBT, 4IBU, 4IBV, 4IBW, 4IBY, 4IBZ, 4IJT, 4KVP, 4LO9, 4LOE, 4LOF, 4MZI, 4MZR, 4X34, 4ZZJ, 5AOL, 5ABA, 5AOK, 2MWY, 5A7B, 5AOJ, 5AOI, 5ECG, 5AB9, 4FZ3, 4RP6, 4XR8, 5AOM, 4RP7, 5HOU, 5HP0, 5HPD, 5LGY, 5G4M, 5G4O, 5G4N, 5BUA Identifiers Aliases TP53, BCC7, LFS1, P53, TRP53, tumor protein p53 External IDs OMIM : 191170 MGI : 98834 HomoloGene : 460 GeneCards : TP53 hide Gene location ( Human ) Chr. Chromosome 17 ( human ) Band 17p13. 1 Start 7,661,779 bp End 7,687,550 bp show Gene location ( Mouse ) Chr. Chromosome 11 ( mouse ) Band 11 B3 11 42.83 cM Start 69,580,359 bp End 69,591,873 bp hide RNA expression pattern More reference expression data show Gene ontology Molecular function protein N - terminus binding transcription factor activity, sequence - specific DNA binding protein self - association core promoter sequence - specific DNA binding transcription regulatory region DNA binding RNA polymerase II transcription factor activity, sequence - specific DNA binding protein phosphatase binding ATP binding transcription factor binding metal ion binding protein phosphatase 2A binding enzyme binding RNA polymerase II transcription factor binding zinc ion binding chromatin binding protease binding damaged DNA binding protein binding histone acetyltransferase binding copper ion binding protein kinase binding chaperone binding transcriptional activator activity, RNA polymerase II transcription regulatory region sequence - specific binding receptor tyrosine kinase binding p53 binding identical protein binding protein heterodimerization activity ubiquitin protein ligase binding RNA polymerase II regulatory region sequence - specific DNA binding DNA binding Cellular component cytoplasm mitochondrion cell nucleus nuclear body transcription factor TFIID complex nuclear matrix replication fork nucleolus endoplasmic reticulum nuclear chromatin nucleoplasm protein complex mitochondrial matrix PML body cytosol Biological process positive regulation of histone deacetylation chromatin assembly DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest rhythmic process replicative senescence negative regulation of telomerase activity oligodendrocyte apoptotic process cellular response to DNA damage stimulus cell aging intrinsic apoptotic signaling pathway positive regulation of neuron apoptotic process cellular response to drug regulation of mitochondrial membrane permeability positive regulation of reactive oxygen species metabolic process cellular response to ionizing radiation positive regulation of thymocyte apoptotic process negative regulation of helicase activity cell cycle Ras protein signal transduction cell proliferation cellular response to hypoxia negative regulation of cell proliferation nucleotide - excision repair cellular response to glucose starvation regulation of transcription, DNA - templated response to antibiotic transcription, DNA - templated ER overload response positive regulation of transcription, DNA - templated negative regulation of cell growth intrinsic apoptotic signaling pathway by p53 class mediator positive regulation of peptidyl - tyrosine phosphorylation viral process response to gamma radiation negative regulation of fibroblast proliferation positive regulation of intrinsic apoptotic signaling pathway cell differentiation determination of adult lifespan positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress cellular response to UV DNA damage response, signal transduction by p53 class mediator negative regulation of apoptotic process protein tetramerization oxidative stress - induced premature senescence positive regulation of release of cytochrome c from mitochondria circadian behavior negative regulation of transcription, DNA - templated protein localization intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator positive regulation of execution phase of apoptosis protein complex assembly DNA strand renaturation multicellular organism development cellular protein localization positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway positive regulation of gene expression mitotic G1 DNA damage checkpoint cell cycle arrest positive regulation of protein oligomerization positive regulation of apoptotic process entrainment of circadian clock by photoperiod response to X-ray positive regulation of transcription from RNA polymerase II promoter base - excision repair DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator positive regulation of cell cycle arrest regulation of cell cycle G2 / M phase transition proteasome - mediated ubiquitin - dependent protein catabolic process regulation of signal transduction by p53 class mediator apoptotic process transcription from RNA polymerase II promoter positive regulation of protein export from nucleus programmed cell death regulation of apoptotic process protein deubiquitination phosphatidylinositol - mediated signaling negative regulation of transcription from RNA polymerase II promoter Sources : Amigo / QuickGO Orthologs Species Human Mouse Entrez 7157 22059 Ensembl ENSG00000141510 ENSMUSG00000059552 UniProt P04637 P02340 RefSeq ( mRNA ) show NM_001276761 NM_000546 NM_001126112 NM_001126113 NM_001126114 NM_001126115 NM_001126116 NM_001126117 NM_001126118 NM_001276695 NM_001276696 NM_001276697 NM_001276698 NM_001276699 NM_001276760 NM_001127233 NM_011640 RefSeq ( protein ) show NP_000537 NP_001119584 NP_001119585 NP_001119586 NP_001119587 NP_001119588 NP_001119589 NP_001119590 NP_001263624 NP_001263625 NP_001263626 NP_001263627 NP_001263628 NP_001263689 NP_001263690 NP_001120705 NP_035770 Location ( UCSC ) Chr 17 : 7.66 -- 7.69 Mb Chr 11 : 69.58 -- 69.59 Mb PubMed search Wikidata View / Edit Human View / Edit Mouse Tumor protein p53, also known as p53, cellular tumor antigen p53 ( UniProt name ), phosphoprotein p53, tumor suppressor p53, antigen NY - CO-13, or transformation - related protein 53 ( TRP53 ), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 ( humans ) and Trp53 ( mice ). This homolog ( originally thought to be, and often spoken of as, a single protein ) is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor. As such, p53 has been described as `` the guardian of the genome '' because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene. ( Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes. ) The name p53 was given in 1979 describing the apparent molecular mass ; SDS - PAGE analysis indicates that it is a 53 - kilodalton ( kDa ) protein. However, the actual mass of the full - length p53 protein ( p53α ) based on the sum of masses of the amino acid residues is only 43.7 kDa. 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 heavier than it actually is. In addition to the full - length protein, the human TP53 gene encodes at least 15 protein isoforms, ranging in size from 3.5 to 43.7 kDa. All these p53 proteins are called the p53 isoforms. The TP53 gene is the most frequently mutated gene ( > 50 % ) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation. TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome. Contents 1 Gene 2 Structure 3 Function 3.1 Stem cells 3.1. 1 Embryonic stem cells 3.1. 2 Adult stem cells 4 Regulation 5 Role in disease 6 Experimental analysis of p53 mutations 7 Discovery 8 Isoforms 9 Interactions 10 Peto 's paradox 11 References 12 External links Gene In humans, the TP53 gene is located on the short arm of chromosome 17 ( 17p13. 1 ). The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53. TP53 orthologs have been identified in most mammals for which complete genome data are available. In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this variation and cancer susceptibility ; however, the results have been controversial. For instance, a meta - analysis from 2009 failed to show a link for cervical cancer. A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males. A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer. One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women. A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer. Meta - analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk and endometrial cancer risk. A 2011 study of a Brazilian birth cohort found an association between the non mutant arginine TP53 and individuals without a family history of cancer. Another 2011 study found that the p53 homozygous ( Pro / Pro ) genotype was associated with a significantly increased risk for renal cell carcinoma. Structure A schematic of the known protein domains in p53. ( NLS = Nuclear Localization Signal ). Crystal structure of four p53 DNA binding domains ( as found in the bioactive homo - tetramer ) and has seven domains : an acidic N - terminus transcription - activation domain ( TAD ), also known as activation domain 1 ( AD1 ), which activates transcription factors. The N - terminus contains two complementary transcriptional activation domains, with a major one at residues 1 -- 42 and a minor one at residues 55 -- 75, specifically involved in the regulation of several pro-apoptotic genes. activation domain 2 ( AD2 ) important for apoptotic activity : residues 43 - 63. proline rich domain important for the apoptotic activity of p53 by nuclear exportation via MAPK : residues 64 - 92. central DNA - binding core domain ( DBD ). Contains one zinc atom and several arginine amino acids : residues 102 - 292. This region is responsible for binding the p53 co-repressor LMO3. Nuclear Localization Signaling ( NLS ) domain, residues 316 - 325. homo - oligomerisation domain ( OD ) : residues 307 - 355. Tetramerization is essential for the activity of p53 in vivo. C - terminal involved in downregulation of DNA binding of the central domain : residues 356 - 393. A tandem of nine - amino - acid transactivation domains ( 9aaTAD ) was identified in the AD1 and AD2 regions of transcription factor p53. KO mutations and position for p53 interaction with TFIID are listed below : The competence of the p53 transactivation domains 9aaTAD to activate transcription as small peptides was reported. 9aaTADs mediate p53 interaction with general coactivators -- TAF9, CBP / p300 ( all four domains KIX, TAZ1, TAZ2 and IBiD ), GCN5 and PC4, regulatory protein MDM2 and replication protein A ( RPA ). 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 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 unstructured regions that function in a synergistic manner. Function p53 has many mechanisms of anticancer function and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms : It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging. It can arrest growth by holding the cell cycle at the G1 / 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 ( i.e., programmed cell death ) if DNA damage proves to be irreparable. It is essential for the senescence response to short telomeres. p53 pathway : In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown. Activated p53 binds DNA and activates expression of several genes including microRNA miR - 34a, WAF1 / CIP1 encoding for p21 and hundreds of other down - stream genes. p21 ( WAF1 ) binds to the G1 - S / CDK ( CDK4 / CDK6, CDK2, and CDK1 ) complexes ( molecules important for the G1 / S transition in the cell cycle ) inhibiting their activity. When p21 ( WAF1 ) is complexed with CDK2, the cell can not continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the `` stop signal '' for cell division. Studies of human embryonic stem cells ( hESCs ) commonly describe the nonfunctional p53 - p21 axis of the G1 / S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response ( DDR ). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs ( like miR - 302a, miR - 302b, miR - 302c, and miR - 302d ) that directly inhibit the p21 expression in hESCs. Research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other. p53 by regulating LIF has been shown to facilitate implantation in the mouse model and possibly in humans. p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning. The p21 protein binds directly to cyclin - CDK complexes that drive forward the cell cycle and inhibits their kinase activity thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein. Stem cells Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life. Embryonic stem cells p53 is maintained at low inactive levels in human embryonic stem cells ( hESCs ). This is because activation of p53 leads to rapid differentiation of hESCs. Studies have shown that knocking out p53 delays differentiation and that adding p53 causes spontaneous differentiation, showing how p53 promotes differentiation of hESCs and plays a key role in cell cycle as a differentiation regulator. When p53 becomes stabilized and activated in hESCs, it increases p21 to establish a longer G1. This typically leads to abolition of S - phase entry, which stops the cell cycle in G1, leading to differentiation. p53 also activates miR - 34a and miR - 145, which then repress the hESCs pluripotency factors, further instigating differentiation. Studies of human embryonic stem cells ( hESCs ) commonly describe the nonfunctional p53 - p21 axis of the G1 / S checkpoint pathway. This has subsequent relevance for cell cycle regulation and the DNA damage response ( DDR ). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs ( like miR - 302a, miR - 302b, miR - 302c, and miR - 302d ) that directly inhibit the p21 expression in hESCs. Adult stem cells In adult stem cells, p53 regulation is important for maintenance of stemness in adult stem cell niches. Mechanical signals such as hypoxia affect levels of p53 in these niche cells through the hypoxia inducible factors, HIF - 1α and HIF - 2α. While HIF - 1α stabilizes p53, HIF - 2α suppresses it. Suppression of p53 plays important roles in cancer stem cell phenotype, induced pluripotent stem cells and other stem cell roles and behaviors, such as blastema formation. Cells with decreased levels of p53 have been shown to reprogram into stem cells with a much greater efficiency than normal cells. Papers suggest that the lack of cell cycle arrest and apoptosis gives more cells the chance to be reprogrammed. Decreased levels of p53 were also shown to be a crucial aspect of blastema formation in the legs of salamanders. p53 regulation is very important in acting as a barrier between stem cells and a differentiated stem cell state, as well as a barrier between stem cells being functional and being cancerous. Regulation p53 becomes activated in response to myriad stressors, including but not limited to DNA damage ( induced by either UV, 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. First, the half - life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a 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 and CHK2, DNA - PK, CAK, TP53RK ) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF. In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 ( also called HDM2 in humans ), binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible. MI - 63 binds to MDM2 making the action of p53 again possible in situations were p53 's function has become inhibited. A ubiquitin specific protease, USP7 ( or HAUSP ), can cleave ubiquitin off p53, thereby protecting it from proteasome - dependent degradation via the ubiquitin ligase pathway. This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress. Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result to a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells. USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cytoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2. 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. Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF, which 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. Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity. Role in disease Overview of signal transduction pathways involved in apoptosis. A micrograph showing cells with abnormal p53 expression ( brown ) in a brain tumor. p53 immunostain. If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li - Fraumeni syndrome. The TP53 gene can also be modified by mutagens ( chemicals, radiation, or viruses ), increasing the likelihood for uncontrolled cell division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene. Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype. Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging. Restoring endogenous normal p53 function holds some promise. Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways by which tumor regression occurs depends mainly on the tumor type. For example, restoration of endogenous p53 function in lymphomas may induce apoptosis, while cell growth may be reduced to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option. The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma. It delivers a functional copy of the p53 gene using an engineered adenovirus. Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus ( HPV ), encodes a protein, E6, which binds to the p53 protein and inactivates it. This mechanism, in synergy with the inactivation of the cell cycle regulator pRb by the HPV protein E7, allows for repeated cell division manifested clinically as warts. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high - grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome. The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation. The degradation of the p53 protein is associated with binding of MDM2. In a negative feedback loop, MDM2 itself is induced by the p53 protein. Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels. Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function. Suppression of p53 in human breast cancer cells is shown to lead to increased CXCR5 chemokine receptor gene expression and activated cell migration in response to chemokine CXCL13. One study found that p53 and Myc proteins were key to the survival of Chronic Myeloid Leukaemia ( CML ) cells. Targeting p53 and Myc proteins with drugs gave positive results on mice with CML. Experimental analysis of p53 mutations Most p53 mutations are detected by DNA sequencing. However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional affects. The large spectrum of cancer phenotypes due to mutations in the TP53 gene is also supported by the fact that different isoforms of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations in TP53 can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending the cancer phenotype from mild to severe. Recents studies show that p53 isoforms are differentially expressed in different human tissues, and the loss - of - function or gain - of - function mutations within the isoforms can cause tissue - specific cancer or provides cancer stem cell potential in different tissues. TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells. The dynamics of p53 proteins, along with its antagonist Mdm2, indicate that the levels of p53, in units of concentration, oscillate as a function of time. This `` damped '' oscillation is both clinically documented and mathematically modelled. Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as double - stranded breaks ( DSB ) or UV radiation, are introduced to the system. This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation ( see p53 regulation for more information ). Current models can also be useful for modelling the mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue - specific pharmacological drug discovery. Discovery p53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old, working at Imperial Cancer Research Fund ( UK ) Princeton University / UMDNJ ( Cancer Institute of New Jersey ), and Memorial Sloan - Kettering Cancer Center, 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 Russian Academy of Sciences in 1982, and independently in 1983 by Moshe Oren in collaboration with David Givol ( Weizmann Institute of Science ). The human TP53 gene was cloned in 1984 and the full length clone in 1985. It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumor cell mRNA. Its role as a tumor suppressor gene was revealed in 1989 by Bert Vogelstein at the Johns Hopkins School of Medicine and Arnold Levine at Princeton University. Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation. In a series of publications in 1991 -- 92, Michael Kastan of 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 magazine. Isoforms As with 95 % of human genes, TP53 encodes more than one protein. In 2005 several isoforms were discovered and until now, 12 human p53 isoforms were identified ( p53α, p53β, p53γ, ∆ 40p53α, ∆ 40p53β, ∆ 40p53γ, ∆ 133p53α, ∆ 133p53β, ∆ 133p53γ, ∆ 160p53α, ∆ 160p53β, ∆ 160p53γ ). Furthermore, p53 isoforms are expressed in a tissue dependent manner and p53α is never expressed alone. The full length p53 isoform proteins can be subdivided into different protein domains. Starting from the N - terminus, there are first the amino - terminal transactivation domains ( TAD 1, TAD 2 ), which are needed to induce a subset of p53 target genes. This domain is followed by the Proline rich domain ( PXXP ), whereby the motif PXXP is repeated ( P is a Proline and X can be any amino acid ). It is required among others for p53 mediated apoptosis. Some isoforms lack the Proline rich domain, such as Δ133p53β, γ and Δ160p53α, β, γ ; hence some isoforms of p53 are not mediating apoptosis, emphasizing the diversifying roles of the TP53 gene. Afterwards there is the DNA binding domain ( DBD ), which enables the proteins to sequence specific binding. The carboxyl terminal domain completes the protein. It includes the nuclear localization signal ( NLS ), the nuclear export signal ( NES ) and the oligomerisation domain ( OD ). The NLS and NES are responsible for the subcellular regulation of p53. Through the OD, p53 can form a tetramer and then bind to DNA. Among the isoforms, some domains can be missing, but all of them share most of the highly conserved DNA - binding domain. The isoforms are formed by different mechanisms. The beta and the gamma isoforms are generated by multiple splicing of intron 9, which leads to a different C - terminus. Furthermore, the usage of an internal promoter in intron 4 causes the ∆ 133 and ∆ 160 isoforms, which lack the TAD domain and a part of the DBD. Moreover, alternative initiation of translation at codon 40 or 160 bear the ∆ 40p53 and ∆ 160p53 isoforms. Due to the isoformic nature of p53 proteins, there have been several sources of evidence showing that mutations within the TP53 gene giving rise to mutated isoforms are causative agents of various cancer phenotypes, from mild to severe, due to single mutation in the TP53 gene ( refer to section Experimental analysis of p53 mutations for more details ). Interactions p53 has been shown to interact with : AIMP2, ANKRD2, APTX, ATM, ATR, ATF3, AURKA, BAK1, BARD1, BLM, BRCA1, BRCA2, BRCC3, BRE, CEBPZ, CDC14A, Cdk1, CFLAR, CHEK1, CCNG1, CREBBP, CREB1, Cyclin H, CDK7, DNA - PKcs, E4F1, EFEMP2, EIF2AK2, ELL, EP300, ERCC6, GNL3, GPS2, GSK3B, HSP90AA1, HIF1A, HIPK1, HIPK2, HMGB1, HSPA9, Huntingtin, ING1, ING4, ING5, IκBα, KPNB1, LMO3, Mdm2, MDM4, MED1, MAPK9, MNAT1, NDN, NCL, NUMB, NF - κB, P16, PARC, PARP1, PIAS1, CDC14B, PIN1, PLAGL1, PLK3, PRKRA, PHB, PML, PSME3, PTEN, PTK2, PTTG1, RAD51, RCHY1, RELA, Reprimo RPA1, RPL11, S100B, SUMO1, SMARCA4, SMARCB1, SMN1, STAT3, TBP, TFAP2A, TFDP1, TIGAR, TOP1, TOP2A, TP53BP1, TP53BP2, TOP2B, TP53INP1, TSG101, UBE2A, UBE2I, UBC, USP7, WRN, WWOX, XPB, YBX1, YPEL3, YWHAZ, Zif268, ZNF148. SIRT1. Peto 's paradox Peto 's paradox is the observation, due to Richard Peto, that at the species level, the incidence of cancer does not appear to correlate with the number of cells in an organism. 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External links Wikimedia Commons has media related to Tumor suppressor protein p53. Lane Group at the Institute of Molecular and Cell Biology ( IMCB ), Singapore. p53 Knowledgebase ( archived 2006 - 01 - 03 ; Retrieved 2008 - 04 - 06 ). GeneReviews / NCBI / NIH / UW entry on Li - Fraumeni Syndrome TUMOR PROTEIN p53 @ OMIM p53 restoration of function p53 @ The Atlas of Genetics and Cytogenetics in Oncology and Haematology TP53 Gene @ GeneCards p53 News provided by insciences organisation David S. Goodsel l date = 2002 - 07 - 01. RCSB Protein Data Bank. p53 Tumor Suppressor ( Retrieved 2008 - 04 - 06 ). Thierry Soussi. p53 Web Site ( Retrieved 2008 - 04 - 06 ). The George Pantziarka TP53 Trust A support group from the UK for sufferers of Li - Fraumeni Syndrome or other TP53 - related disorders IARC TP53 Somatic Mutations database maintained at IARC, Lyon, by Magali Olivier PDB gallery 1a1u : SOLUTION STRUCTURE DETERMINATION OF A P53 MUTANT DIMERIZATION DOMAIN, NMR, MINIMIZED AVERAGE STRUCTURE 1aie : P53 TETRAMERIZATION DOMAIN CRYSTAL STRUCTURE 1c26 : CRYSTAL STRUCTURE OF P53 TETRAMERIZATION DOMAIN 1gzh : CRYSTAL STRUCTURE OF THE BRCT DOMAINS OF HUMAN 53BP1 BOUND TO THE P53 TUMOR SUPPRESSOR 1hs5 : NMR SOLUTION STRUCTURE OF DESIGNED P53 DIMER 1kzy : Crystal Structure of the 53bp1 BRCT Region Complexed to Tumor Suppressor P53 1olg : HIGH - RESOLUTION SOLUTION STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR 1olh : HIGH - RESOLUTION SOLUTION STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR 1pes : NMR SOLUTION STRUCTURE OF THE TETRAMERIC MINIMUM TRANSFORMING DOMAIN OF P53 1pet : NMR SOLUTION STRUCTURE OF THE TETRAMERIC MINIMUM TRANSFORMING DOMAIN OF P53 1sae : HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR ( SAC STRUCTURES ) 1saf : HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR ( SAD STRUCTURES ) 1sag : 1sah : HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR ( SAD STRUCTURES ) 1sai : 1saj : HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR ( SAD STRUCTURES ) 1sak : HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR ( SAC STRUCTURES ) 1sal : HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR ( SAD STRUCTURES ) 1tsr : P53 CORE DOMAIN IN COMPLEX WITH DNA 1tup : TUMOR SUPPRESSOR P53 COMPLEXED WITH DNA 1uol : CRYSTAL STRUCTURE OF THE HUMAN P53 CORE DOMAIN MUTANT M133L / V203A / N239Y / N268D AT 1.9 A RESOLUTION. 1ycs : P53 - 53BP2 COMPLEX 2ac0 : Structural Basis of DNA Recognition by p53 Tetramers ( complex I ) 2ady : Structural Basis of DNA Recognition by p53 Tetramers ( complex IV ) 2ahi : Structural Basis of DNA Recognition by p53 Tetramers ( complex III ) 2ata : Structural Basis of DNA Recognition by p53 Tetramers ( complex II ) 2b3g : p53N ( fragment 33 - 60 ) bound to RPA70N 2bim : HUMAN P53 CORE DOMAIN MUTANT M133L - V203A - N239Y - N268D - R273H 2bin : HUMAN P53 CORE DOMAIN MUTANT M133L - H168R - V203A - N239Y - N268D 2bio : HUMAN P53 CORE DOMAIN MUTANT M133L - V203A - N239Y - R249S - N268D 2bip : HUMAN P53 CORE DOMAIN MUTANT M133L - H168R - V203A - N239Y - R249S - N268D 2biq : HUMAN P53 CORE DOMAIN MUTANT T123A - M133L - H168R - V203A - N239Y - R249S - N268D 2fej : Solution structure of human p53 DNA binding domain. 2gs0 : NMR structure of the complex between the PH domain of the Tfb1 subunit from TFIIH and the activation domain of p53 2h1l : The Structure of the Oncoprotein SV40 Large T Antigen and p53 Tumor Suppressor Complex 2j1w : HUMAN P53 CORE DOMAIN MUTANT M133L - V143A - V203A - N239Y - N268D 2j1x : HUMAN P53 CORE DOMAIN MUTANT M133L - V203A - Y220C - N239Y - N268D 2j1y : HUMAN P53 CORE DOMAIN MUTANT M133L - V203A - N239Y - G245S - N268D 2j1z : HUMAN P53 CORE DOMAIN MUTANT M133L - V203A - N239Y - N268D - F270L 2j20 : HUMAN P53 CORE DOMAIN MUTANT M133L - V203A - N239Y - N268D - R273C 2j21 : HUMAN P53 CORE DOMAIN MUTANT M133L - V203A - N239Y - N268D - R282W 2ocj : Human p53 core domain in the absence of DNA 3sak : HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR ( SAC STRUCTURES ) Transcription factors and intracellular receptors ( 1 ) Basic domains ( 1.1 ) Basic leucine zipper ( bZIP ) Activating transcription factor AATF 5 6 7 AP - 1 c - Fos FOSB FOSL1 FOSL2 JDP2 c - Jun JUNB JunD BACH BATF BLZF1 C / EBP α β γ δ ε ζ CREB L1 CREM DBP DDIT3 GABPA GCN4 HLF MAF NFE L1 L2 L3 NFIL3 NRL NRF XBP1 ( 1.2 ) Basic helix - loop - helix ( bHLH ) ATOH1 AhR AHRR ARNT ASCL1 BHLH 9 ARNTL ARNTL ARNTL2 CLOCK EPAS1 FIGLA HAND HES 5 6 HEY HES1 HIF 1A 3A ID LYL1 MESP2 MXD4 MYCL1 MYCN Myogenic regulatory factors MyoD Myogenin MYF5 MYF6 Neurogenins NeuroD NPAS OLIG Pho4 Scleraxis SIM TAL Twist USF1 ( 1.3 ) bHLH - ZIP AP - 4 MAX MXD3 MITF MNT MLX MXI1 Myc SREBP ( 1.4 ) NF - 1 NFI X SMAD R - SMAD 5 9 I - SMAD 6 7 4 ) ( 1.5 ) RF - X RFX 5 6 ANK ( 1.6 ) Basic helix - span - helix ( bHSH ) AP - 2 α β γ δ ε ( 2 ) Zinc finger DNA - binding domains ( 2.1 ) Nuclear receptor ( Cys ) subfamily 1 Thyroid hormone α β CAR FXR LXR α β PPAR α β / δ γ PXR RAR α β γ ROR α β γ Rev - ErbA α β VDR subfamily 2 COUP - TF ( I II Ear - 2 HNF4 α γ PNR RXR α β γ Testicular receptor TLX subfamily 3 Steroid hormone Androgen Estrogen α β Glucocorticoid Mineralocorticoid Progesterone Estrogen related α β γ subfamily 4 NUR NGFIB NOR1 NURR1 subfamily 5 LRH - 1 SF1 subfamily 6 GCNF subfamily 0 DAX1 SHP ( 2.2 ) Other Cys GATA 5 6 MTA TRPS1 ( 2.3 ) Cys His General transcription factors TFIIA TFIIB TFIID TFIIE TFIIF TFIIH 2I 3A 3C1 3C2 ATBF1 BCL 6 11A 11B CTCF E4F1 EGR ERV3 GFI1 GLI - Krüppel family REST S1 S2 YY1 HIC HIVEP IKZF ILF KLF 5 6 7 8 9 10 11 12 13 14 15 17 MTF1 MYT1 OSR1 PRDM9 SALL SP 7 8 TSHZ3 WT1 Zbtb7 7A 7B ZBTB 11 16 17 20 32 33 40 zinc finger 7 9 10 19 22 24 33B 34 35 41 43 44 51 74 143 146 148 165 202 217 219 238 239 259 267 268 281 295 300 318 330 346 350 365 366 384 423 451 452 471 593 638 644 649 655 ( 2.4 ) Cys HIVEP1 ( 2.5 ) Alternating composition AIRE DIDO1 GRLF1 ING JARID 1A 1B 1C 1D JMJD1B ( 2.6 ) WRKY WRKY ( 3 ) Helix - turn - helix domains ( 3.1 ) Homeodomain ARX CDX CRX CUTL1 DBX DLX 5 6 EMX EN FHL HESX1 HHEX HLX Homeobox A1 A2 A3 A4 A5 A7 A9 A10 A11 A13 B1 B2 B3 B4 B5 B6 B7 B8 B9 B13 C4 C5 C6 C8 C9 C10 C11 C12 C13 D1 D3 D4 D8 D9 D10 D11 D12 D13 HOPX IRX 5 6 MKX LMX 1A 1B MEIS MEOX2 MNX1 MSX NANOG NKX 2 - 1 2 - 2 2 - 3 2 - 5 3 - 1 3 - 2 6 - 1 6 - 2 NOBOX PBX PHF 6 8 10 16 17 20 21A PHOX 2A 2B PITX POU domain PIT - 1 BRN - 3 : A Octamer transcription factor : 1 3 / 4 6 7 11 OTX PDX1 SATB2 SHOX2 SIX 5 VAX1 ZEB ( 3.2 ) Paired box PAX 5 6 7 8 9 PRRX RAX ( 3.3 ) Fork head / winged helix E2F 5 FOX proteins A1 A2 A3 C1 C2 D3 D4 E1 E3 F1 G1 H1 I1 J1 J2 K1 K2 L2 M1 N1 N3 O1 O3 O4 P1 P2 P3 P4 ( 3.4 ) Heat shock factors HSF ( 3.5 ) Tryptophan clusters ELF 5 EGF ELK ERF ETS ERG SPIB ETV 5 6 FLI1 Interferon regulatory factors 5 6 7 8 MYB MYBL2 ( 3.6 ) TEA domain transcriptional enhancer factor hide ( 4 ) β - Scaffold factors with minor groove contacts ( 4.1 ) Rel homology region NF - κB NFKB1 NFKB2 REL RELA RELB NFAT C1 C2 C3 C4 5 ( 4.2 ) STAT STAT 5 6 ( 4.3 ) p53 p53 TBX 5 19 21 22 TBR1 TBR2 TFT MYRF TP63 ( 4.4 ) MADS box Mef2 SRF ( 4.6 ) TATA - binding proteins TBP TBPL1 ( 4.7 ) High - mobility group BBX HMGB HMGN HNF 1A 1B LEF1 SOX 5 6 8 9 10 11 12 13 14 15 18 21 SRY SSRP1 TCF TOX ( 4.9 ) Grainyhead TFCP2 ( 4.10 ) Cold - shock domain CSDA YBX1 ( 4.11 ) Runt CBF CBFA2T2 CBFA2T3 RUNX1 RUNX2 RUNX3 RUNX1T1 ( 0 ) Other transcription factors ( 0.2 ) HMGI ( Y ) HMGA HBP1 ( 0.3 ) Pocket domain Rb RBL1 RBL2 ( 0.5 ) AP - 2 / EREBP - related factors Apetala 2 EREBP B3 ( 0.6 ) Miscellaneous ARID 1A 1B 3A 3B 4A CAP IFI 16 35 MLL T1 MNDA NFY Rho / Sigma see also transcription factor / coregulator deficiencies Neoplasm : Tumor suppressor genes / proteins and Oncogenes / Proto - oncogenes Ligand Growth factors ONCO c - Sis / PDGF HGF Receptor Wnt signaling pathway TSP CDH1 Hedgehog signaling pathway TSP PTCH1 TGF beta signaling pathway TSP TGF beta receptor 2 Receptor tyrosine kinase ONCO ErbB / c - ErbB HER2 / neu Her 3 c - Met c - Ret JAK - STAT signaling pathway ONCO c - Kit Flt3 Intracellular signaling P + Ps Wnt signaling pathway ONCO Beta - catenin TSP APC TGF beta signaling pathway TSP SMAD2 SMAD4 Akt / PKB signaling pathway ONCO c - Akt TSP PTEN Hippo signaling pathway TSP Neurofibromin 2 / Merlin MAPK / ERK pathway ONCO c - Ras HRAS c - Raf TSP Neurofibromin 1 Other / unknown ONCO c - Src TSP Maspin Nucleus Cell cycle ONCO CDK4 Cyclin D Cyclin E TSP p53 pRb WT1 p16 / p14arf DNA repair / Fanconi TSP BRCA1 BRCA2 Ubiquitin ligase ONCO CBL MDM2 TSP VHL Transcription factor ONCO AP - 1 c - Fos c - Jun c - Myc TSP KLF6 Mitochondrion Apoptosis inhibitor SDHB SDHD Other / ungrouped c - Bcl - 2 Notch Stathmin Cell cycle proteins Cyclin A ( A1, A2 ) B ( B1, B2, B3 ) D ( D1, D2, D3 ) E ( E1, E2 ) CDK 5 6 7 8 9 10 CDK - activating kinase CDK inhibitor INK4a / ARF ( p14arf / p16, p15, p18, p19 ) cip / kip ( p21, p27, p57 ) P53 p63 p73 family p53 p63 p73 Other Cdc2 Cdc25 Cdc42 Cellular apoptosis susceptibility protein E2F Maturation promoting factor Wee Cullin ( CUL7 ) Phases and checkpoints Interphase G phase S phase G phase M phase Mitosis ( Preprophase Prophase Prometaphase Metaphase Anaphase Telophase ) Cytokinesis Cell cycle checkpoints Restriction point Spindle checkpoint Postreplication checkpoint Other cellular phases Apoptosis G phase Meiosis Retrieved from `` https://en.wikipedia.org/w/index.php?title=P53&oldid=846577623 '' Categories : Genes on human chromosome 17 Programmed cell death Proteins Transcription factors Tumor suppressor genes Apoptosis Genes mutated in mice Aging - related proteins Hidden categories : CS1 maint : Extra text : authors list CS1 Russian - language sources ( ru ) Talk Contents About Wikipedia Afrikaans Català Čeština Cymraeg Deutsch Eesti Español فارسی Français 한국어 Bahasa Indonesia Italiano עברית Lietuvių Magyar 日本 語 Polski Português Русский Simple English Slovenščina Suomi ไทย Türkçe Українська اردو Tiếng Việt 中文 20 more Edit links This page was last edited on 19 June 2018, at 16 : 39 ( UTC ). 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Question: what is the function of the p53 protein
Answer: prevents cancer formation