Array ( [0] => {{short description|Mammalian protein found in Homo sapiens}} [1] => {{other uses}} [2] => {{Lowercase title}} [3] => {{Infobox_gene}} [4] => {{cs1 config|name-list-style=vanc|display-authors=3}} [5] => '''p53''', also known as '''Tumor protein P53''', '''cellular [[tumor antigen]] p53''' ([[UniProt]] name), or '''transformation-related protein 53 (TRP53)''' is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often spoken of as, a single protein) are crucial in [[vertebrate]]s, where they prevent [[cancer]] formation.{{cite journal |vauthors=Surget S, Khoury MP, Bourdon JC |title=Uncovering the role of p53 splice variants in human malignancy: a clinical perspective |journal=OncoTargets and Therapy |volume=7 |pages=57–68 |date=December 2013 |pmid=24379683 |pmc=3872270 |doi=10.2147/OTT.S53876 |doi-access=free }} As such, p53 has been described as "the guardian of the [[genome]]" because of its role in conserving stability by preventing genome mutation.{{cite journal |vauthors=Toufektchan E, Toledo F |title=The Guardian of the Genome Revisited: p53 Downregulates Genes Required for Telomere Maintenance, DNA Repair, and Centromere Structure |journal=Cancers |volume=10 |issue=5 |pages=135 |date=May 2018 |pmid=29734785 |pmc=5977108 |doi=10.3390/cancers10050135 |doi-access=free}} Hence ''TP53''[[Gene nomenclature#Vertebrate gene and protein symbol conventions|''italics'']] are used to denote the ''TP53'' gene name and distinguish it from the protein it encodes is classified as a [[tumor suppressor gene]].{{cite journal |vauthors=Matlashewski G, Lamb P, Pim D, Peacock J, Crawford L, Benchimol S |title=Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene |journal=The EMBO Journal |volume=3 |issue=13 |pages=3257–62 |date=December 1984 |pmid=6396087 |pmc=557846 |doi=10.1002/j.1460-2075.1984.tb02287.x}}{{cite journal |vauthors=Isobe M, Emanuel BS, Givol D, Oren M, Croce CM | title = Localization of gene for human p53 tumour antigen to band 17p13 |journal=Nature |volume=320 |issue=6057 |pages=84–5 |year=1986 |pmid=3456488 |doi=10.1038/320084a0 |s2cid=4310476 |bibcode=1986Natur.320...84I}}{{cite journal |vauthors=Kern SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B |title=Identification of p53 as a sequence-specific DNA-binding protein |journal=Science |volume=252 |issue=5013 |pages=1708–11 |date=June 1991 |pmid=2047879 |doi=10.1126/science.2047879 |s2cid=19647885 |bibcode=1991Sci...252.1708K}}{{cite journal |vauthors=McBride OW, Merry D, Givol D |title=The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13) |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=83 |issue=1 |pages=130–4 |date=January 1986 |pmid=3001719 |pmc=322805 |doi=10.1073/pnas.83.1.130 |doi-access=free |bibcode=1986PNAS...83..130M}} [6] => [7] => 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.{{cite book |veditors=Levine AJ, Lane DP |title=The p53 family |series=Cold Spring Harbor Perspectives in Biology |date=2010 |publisher=Cold Spring Harbor Laboratory Press |location=Cold Spring Harbor, N.Y. |isbn=978-0-87969-830-0}} In addition to the full-length protein, the human ''TP53'' gene encodes at least 12 protein [[Protein isoform|isoforms]].Khoury MP, Bourdon JC. p53 Isoforms: An Intracellular Microprocessor? Genes Cancer. 2011 Apr;2(4):453-65. doi: 10.1177/1947601911408893. PMID: 21779513; PMCID: PMC3135639. [8] => [9] => == Gene == [10] => In humans, the ''TP53'' gene is located on the short arm of [[chromosome 17 (human)|chromosome 17]] (17p13.1). The gene spans 20 [[Kilo-base pair|kb]], with a non-coding [[exon]] 1 and a very long first intron of 10 kb, overlapping the [[Hp53int1]] gene. 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.{{cite journal | vauthors = May P, May E | title = Twenty years of p53 research: structural and functional aspects of the p53 protein | journal = Oncogene | volume = 18 | issue = 53 | pages = 7621–36 | date = December 1999 | pmid = 10618702 | doi = 10.1038/sj.onc.1203285 | doi-access = free }} ''TP53'' [[orthologs]]{{cite web | title = OrthoMaM phylogenetic marker: TP53 coding sequence | url = http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000141510_TP53.xml | access-date = 2009-12-02 | archive-url = https://web.archive.org/web/20180317110251/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000141510_TP53.xml | archive-date = 2018-03-17 | url-status = dead }} have been identified in most [[mammals]] for which complete genome data are available. [11] => [12] => === Human TP53 gene === [13] => In humans, a common [[polymorphism (biology)|polymorphism]] involves the substitution of an [[arginine]] for a [[proline]] at [[codon]] position 72 of exon 4. 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.{{cite journal | vauthors = Klug SJ, Ressing M, Koenig J, Abba MC, Agorastos T, Brenna SM, Ciotti M, Das BR, Del Mistro A, Dybikowska A, Giuliano AR, Gudleviciene Z, Gyllensten U, Haws AL, Helland A, Herrington CS, Hildesheim A, Humbey O, Jee SH, Kim JW, Madeleine MM, Menczer J, Ngan HY, Nishikawa A, Niwa Y, Pegoraro R, Pillai MR, Ranzani G, Rezza G, Rosenthal AN, Roychoudhury S, Saranath D, Schmitt VM, Sengupta S, Settheetham-Ishida W, Shirasawa H, Snijders PJ, Stoler MH, Suárez-Rincón AE, Szarka K, Tachezy R, Ueda M, van der Zee AG, von Knebel Doeberitz M, Wu MT, Yamashita T, Zehbe I, Blettner M | title = TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies | journal = The Lancet. Oncology | volume = 10 | issue = 8 | pages = 772–84 | date = August 2009 | pmid = 19625214 | doi = 10.1016/S1470-2045(09)70187-1 }} A 2011 study found that the ''TP53'' proline mutation did have a profound effect on pancreatic cancer risk among males.{{cite journal | vauthors = Sonoyama T, Sakai A, Mita Y, Yasuda Y, Kawamoto H, Yagi T, Yoshioka M, Mimura T, Nakachi K, Ouchida M, Yamamoto K, Shimizu K | title = TP53 codon 72 polymorphism is associated with pancreatic cancer risk in males, smokers and drinkers | journal = Molecular Medicine Reports | volume = 4 | issue = 3 | pages = 489–95 | year = 2011 | pmid = 21468597 | doi = 10.3892/mmr.2011.449 | doi-access = free }} A study of Arab women found that proline homozygosity at ''TP53'' codon 72 is associated with a decreased risk for breast cancer.{{cite journal | vauthors = Alawadi S, Ghabreau L, Alsaleh M, Abdulaziz Z, Rafeek M, Akil N, Alkhalaf M | title = P53 gene polymorphisms and breast cancer risk in Arab women | journal = Medical Oncology | volume = 28 | issue = 3 | pages = 709–15 | date = September 2011 | pmid = 20443084 | doi = 10.1007/s12032-010-9505-4 | s2cid = 207372095 }} 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.{{cite journal | vauthors = Yu H, Huang YJ, Liu Z, Wang LE, Li G, Sturgis EM, Johnson DG, Wei Q | title = Effects of MDM2 promoter polymorphisms and p53 codon 72 polymorphism on risk and age at onset of squamous cell carcinoma of the head and neck | journal = Molecular Carcinogenesis | volume = 50 | issue = 9 | pages = 697–706 | date = September 2011 | pmid = 21656578 | pmc = 3142329 | doi = 10.1002/mc.20806 }} A 2011 study found that ''TP53'' codon 72 polymorphism was associated with an increased risk of lung cancer.{{cite journal | vauthors = Piao JM, Kim HN, Song HR, Kweon SS, Choi JS, Yun WJ, Kim YC, Oh IJ, Kim KS, Shin MH | title = p53 codon 72 polymorphism and the risk of lung cancer in a Korean population | journal = Lung Cancer | volume = 73 | issue = 3 | pages = 264–7 | date = September 2011 | pmid = 21316118 | doi = 10.1016/j.lungcan.2010.12.017 }} [14] => [15] => Meta-analyses from 2011 found no significant associations between ''TP53'' codon 72 polymorphisms and both colorectal cancer risk{{cite journal | vauthors = Wang JJ, Zheng Y, Sun L, Wang L, Yu PB, Dong JH, Zhang L, Xu J, Shi W, Ren YC | title = TP53 codon 72 polymorphism and colorectal cancer susceptibility: a meta-analysis | journal = Molecular Biology Reports | volume = 38 | issue = 8 | pages = 4847–53 | date = November 2011 | pmid = 21140221 | doi = 10.1007/s11033-010-0619-8 | s2cid = 11730631 }} and endometrial cancer risk.{{cite journal | vauthors = Jiang DK, Yao L, Ren WH, Wang WZ, Peng B, Yu L | title = TP53 Arg72Pro polymorphism and endometrial cancer risk: a meta-analysis | journal = Medical Oncology | volume = 28 | issue = 4 | pages = 1129–35 | date = December 2011 | pmid = 20552298 | doi = 10.1007/s12032-010-9597-x | s2cid = 32990396 }} 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.{{cite journal | vauthors = Thurow HS, Haack R, Hartwig FP, Oliveira IO, Dellagostin OA, Gigante DP, Horta BL, Collares T, Seixas FK | title = TP53 gene polymorphism: importance to cancer, ethnicity and birth weight in a Brazilian cohort | journal = Journal of Biosciences | volume = 36 | issue = 5 | pages = 823–31 | date = December 2011 | pmid = 22116280 | doi = 10.1007/s12038-011-9147-5 | s2cid = 23027087 }} Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma.{{cite journal | vauthors = Huang CY, Su CT, Chu JS, Huang SP, Pu YS, Yang HY, Chung CJ, Wu CC, Hsueh YM | title = The polymorphisms of P53 codon 72 and MDM2 SNP309 and renal cell carcinoma risk in a low arsenic exposure area | journal = Toxicology and Applied Pharmacology | volume = 257 | issue = 3 | pages = 349–55 | date = December 2011 | pmid = 21982800 | doi = 10.1016/j.taap.2011.09.018 }} [16] => [17] => == Function == [18] => [19] => === DNA damage and repair === [20] => p53 plays a role in regulation or progression through the cell cycle, [[apoptosis]], and [[Genome instability|genomic stability]] by means of several mechanisms: [21] => * It can activate [[DNA repair]] proteins when DNA has sustained damage. Thus, it may be an important factor in [[aging]].{{cite book | vauthors = Gilbert SF |title=Developmental Biology, 10th ed. |publisher=Sinauer Associates, Inc. Publishers |location=Sunderland, MA USA |pages=588}} [22] => * It can arrest growth by holding the [[cell cycle]] at the [[G1/S transition|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. [23] => * It can initiate apoptosis (i.e., [[programmed cell death]]) if DNA damage proves to be irreparable. [24] => * It is essential for the [[Cellular senescence|senescence]] response to short [[telomere]]s. [25] => [26] => [[File: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 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.]] [27] => [28] => WAF1/CIP1 encodes for [[p21]] and hundreds of other down-stream genes. p21 (WAF1) binds to the [[G1 phase|G1]]-[[S phase|S]]/[[Cyclin-dependent kinase|CDK]] ([[CDK4]]/[[CDK6]], [[CDK2]], and [[CDK1]]) complexes (molecules important for the [[G1/S transition]] in the cell cycle) inhibiting their activity. [29] => [30] => When p21(WAF1) is complexed with CDK2, the cell cannot 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.{{cite book | chapter-url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.107 | chapter = Skin and Connective Tissue | title = Genes and Disease |author=National Center for Biotechnology Information |publisher=United States National Institutes of Health |access-date=2008-05-28 |year=1998}} 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 [[microRNA]]s (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs. [31] => [32] => 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. [33] => [34] => The p53 and [[Retinoblastoma protein|RB1]] pathways are linked via p14ARF, raising the possibility that the pathways may regulate each other.{{cite journal |vauthors=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 |date=September 1998 |pmid=9744267 |doi=10.1038/25867 |bibcode=1998Natur.395..124B |s2cid=4355786}} [35] => [36] => p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to [[sun tanning|tanning]].{{cite magazine |title=Genome's guardian gets a tan started |url=https://www.newscientist.com/channel/health/mg19325955.800-genomes-guardian-gets-a-tan-started.html |magazine=New Scientist |date=March 17, 2007 |access-date=2007-03-29}}{{cite journal |vauthors=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 |date=March 2007 |pmid=17350573 |doi=10.1016/j.cell.2006.12.045 |doi-access=free}} [37] => [38] => === Stem cells === [39] => Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life. [40] => [41] => In human [[embryonic stem cell]]s (hESCs)s, p53 is maintained at low inactive levels.{{cite journal |vauthors=Jain AK, Allton K, Iacovino M, Mahen E, Milczarek RJ, Zwaka TP, Kyba M, Barton MC |title=p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells |journal=PLOS Biology |volume=10 |issue=2 |pages= e1001268 |pmid=22389628 |pmc=3289600 |doi=10.1371/journal.pbio.1001268 |year=2012 |doi-access=free }} This is because activation of p53 leads to rapid differentiation of hESCs.{{cite journal |vauthors=Maimets T, Neganova I, Armstrong L, Lako M |title=Activation of p53 by nutlin leads to rapid differentiation of human embryonic stem cells |journal=Oncogene |volume=27 |issue=40 |pages=5277–87 |date=September 2008 |pmid=18521083 |doi=10.1038/onc.2008.166 |doi-access=free}} 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. Work in mouse embryonic stem cells has recently shown however that the expression of P53 does not necessarily lead to differentiation.{{cite journal |vauthors=ter Huurne M, Peng T, Yi G, van Mierlo G, Marks H, Stunnenberg HG |title=Critical role for P53 in regulating the cell cycle of ground state embryonic stem cells |journal=Stem Cell Reports |volume=14 |issue=2 |pages=175–183 |date=February 2020 |pmid=32004494 |doi=10.1016/j.stemcr.2020.01.001 |doi-access=free |pmc=7013234}} p53 also activates [[MIR34A|miR-34a]] and [[Mir-145|miR-145]], which then repress the hESCs pluripotency factors, further instigating differentiation. [42] => [43] => In adult stem cells, p53 regulation is important for maintenance of stemness in [[Stem-cell niche|adult stem cell niches]]. Mechanical signals such as [[hypoxia (medical)|hypoxia]] affect levels of p53 in these niche cells through the [[hypoxia inducible factors]], [[HIF1A|HIF-1α]] and HIF-2α. While HIF-1α stabilizes p53, HIF-2α suppresses it.{{cite journal |vauthors=Das B, Bayat-Mokhtari R, Tsui M, Lotfi S, Tsuchida R, Felsher DW, Yeger H |title=HIF-2α suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells |journal=Stem Cells |volume=30 |issue=8 |pages=1685–95 |date=August 2012 |pmid=22689594 |pmc=3584519 |doi=10.1002/stem.1142}} 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.{{cite journal |vauthors=Lake BB, Fink J, Klemetsaune L, Fu X, Jeffers JR, Zambetti GP, Xu Y |title=Context-dependent enhancement of induced pluripotent stem cell reprogramming by silencing Puma |journal=Stem Cells |volume=30 |issue=5 |pages=888–97 |date=May 2012 |pmid=22311782 |pmc=3531606 |doi=10.1002/stem.1054}}{{cite journal |vauthors=Marión RM, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M, Blasco MA |title=A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity |journal=Nature |volume=460 |issue=7259 |pages=1149–53 |date=August 2009 |pmid=19668189 |pmc=3624089 |doi=10.1038/nature08287 |bibcode=2009Natur.460.1149M}} 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.{{cite journal |vauthors=Yun MH, Gates PB, Brockes JP |title=Regulation of p53 is critical for vertebrate limb regeneration |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=110 |issue=43 |pages=17392–7 |date=October 2013 |pmid=24101460 |pmc=3808590 |doi=10.1073/pnas.1310519110 |bibcode=2013PNAS..11017392Y |doi-access=free}} 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.{{cite journal |vauthors=Aloni-Grinstein R, Shetzer Y, Kaufman T, Rotter V |title=p53: the barrier to cancer stem cell formation |journal=FEBS Letters |volume=588 |issue=16 |pages=2580–9 |date=August 2014 |pmid=24560790 |doi=10.1016/j.febslet.2014.02.011 |s2cid=37901173 |doi-access=free}} [44] => [45] => === Other === [46] => [[File:P53 and angiogenesis.png|thumb|490x490px|An overview of the molecular mechanism of action of p53 on the angiogenesis.{{cite journal | vauthors = Babaei G, Aliarab A, Asghari Vostakolaei M, Hotelchi M, Neisari R, Gholizadeh-Ghaleh Aziz S, Bazl MR | title = Crosslink between p53 and metastasis: focus on epithelial-mesenchymal transition, cancer stem cell, angiogenesis, autophagy, and anoikis | journal = Molecular Biology Reports | volume = 48 | issue = 11 | pages = 7545–7557 | date = November 2021 | pmid = 34519942 | doi = 10.1007/s11033-021-06706-1 | s2cid = 237506513 }}]] [47] => Apart from the cellular and molecular effects above, p53 has a tissue-level anticancer effect that works by inhibiting [[angiogenesis]]. As tumors grow they need to recruit new blood vessels to supply them, and p53 inhibits that by (i) interfering with regulators of [[tumor hypoxia]] that also affect angiogenesis, such as HIF1 and HIF2, (ii) inhibiting the production of angiogenic promoting factors, and (iii) directly increasing the production of angiogenesis inhibitors, such as [[arresten]].{{cite journal | vauthors = Teodoro JG, Evans SK, Green MR | title = Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome | journal = Journal of Molecular Medicine | volume = 85 | issue = 11 | pages = 1175–1186 | date = November 2007 | pmid = 17589818 | doi = 10.1007/s00109-007-0221-2 | type = Review | s2cid = 10094554 }}{{cite journal | vauthors = Assadian S, El-Assaad W, Wang XQ, Gannon PO, Barrès V, Latour M, Mes-Masson AM, Saad F, Sado Y, Dostie J, Teodoro JG | title = p53 inhibits angiogenesis by inducing the production of Arresten | journal = Cancer Research | volume = 72 | issue = 5 | pages = 1270–1279 | date = March 2012 | pmid = 22253229 | doi = 10.1158/0008-5472.CAN-11-2348 | doi-access = free }} [48] => [49] => p53 by regulating [[leukemia inhibitory factor|Leukemia Inhibitory Factor]] has been shown to facilitate [[Implantation (human embryo)|implantation]] in the mouse and possibly humans reproduction.{{cite journal | vauthors = Hu W, Feng Z, Teresky AK, Levine AJ | title = p53 regulates maternal reproduction through LIF | journal = Nature | volume = 450 | issue = 7170 | pages = 721–4 | date = November 2007 | pmid = 18046411 | doi = 10.1038/nature05993 | bibcode = 2007Natur.450..721H | s2cid = 4357527 }} [50] => [51] => The immune response to infection also involves p53 and [[NF-κB]]. Checkpoint control of the [[cell cycle]] and of [[apoptosis]] by p53 is inhibited by some infections such as [[Mycoplasma]] bacteria,{{cite journal | vauthors = Borchsenius SN, Daks A, Fedorova O, Chernova O, Barlev NA | title = Effects of mycoplasma infection on the host organism response via p53/NF-κB signaling | journal = Journal of Cellular Physiology | volume = 234 | issue = 1 | pages = 171–180 | date = January 2018 | pmid = 30146800 | doi = 10.1002/jcp.26781 }} raising the specter of [[carcinogenesis|oncogenic infection]]. [52] => [53] => == Regulation == [54] => p53 acts as a cellular stress sensor. It is normally kept at low levels by being constantly marked for degradation by the [[E3 ubiquitin ligase]] protein [[MDM2]].{{cite journal | vauthors = Bykov VJ, Eriksson SE, Bianchi J, Wiman KG | title = Targeting mutant p53 for efficient cancer therapy | journal = Nature Reviews. Cancer | volume = 18 | issue = 2 | pages = 89–102 | date = February 2018 | pmid = 29242642 | doi = 10.1038/nrc.2017.109 | s2cid = 4552678 }} p53 is activated in response to myriad stressors – including [[DNA damage]] (induced by either [[Ultraviolet|UV]], [[Ionizing radiation|IR]], or chemical agents such as hydrogen peroxide), [[oxidative stress]],{{cite journal | vauthors = Han ES, Muller FL, Pérez VI, Qi W, Liang H, Xi L, Fu C, Doyle E, Hickey M, Cornell J, Epstein CJ, Roberts LJ, Van Remmen H, Richardson A | title = The in vivo gene expression signature of oxidative stress | journal = Physiological Genomics | volume = 34 | issue = 1 | pages = 112–126 | date = June 2008 | pmid = 18445702 | pmc = 2532791 | doi = 10.1152/physiolgenomics.00239.2007 }} [[osmotic shock]], ribonucleotide depletion, [[Viral pneumonia|viral lung infections]]{{cite journal | vauthors = Grajales-Reyes GE, Colonna M | title = Interferon responses in viral pneumonias | journal = Science | volume = 369 | issue = 6504 | pages = 626–627 | date = August 2020 | pmid = 32764056 | doi = 10.1126/science.abd2208 | bibcode = 2020Sci...369..626G }} 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 [[Transcriptional regulation|transcription regulator]] in these cells. The critical event leading to the activation of p53 is the phosphorylation of its [[N-terminus|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. [55] => [56] => 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 ([[Ataxia telangiectasia and Rad3 related|ATR]], [[Ataxia telangiectasia mutated|ATM]], [[Chk1|CHK1]] and [[Chk2|CHK2]], [[DNA-PKcs|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. [[Oncogene]]s also stimulate p53 activation, mediated by the protein [[p14ARF]]. [57] => [58] => 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 [[Cell nucleus|nucleus]] to the [[cytosol]]. Mdm2 also acts as an [[ubiquitin ligase]] and covalently attaches [[ubiquitin]] to p53 and thus marks p53 for degradation by the [[proteasome]]. However, ubiquitylation of p53 is reversible. On activation of p53, Mdm2 is also activated, setting up a [[feedback loop]]. p53 levels can show [[oscillation]]s (or repeated pulses) in response to certain stresses, and these pulses can be important in determining whether the cells survive the stress, or die.{{cite journal | vauthors = Purvis JE, Karhohs KW, Mock C, Batchelor E, Loewer A, Lahav G | title = p53 dynamics control cell fate | journal = Science | volume = 336 | issue = 6087 | pages = 1440–1444 | date = June 2012 | pmid = 22700930 | pmc = 4162876 | doi = 10.1126/science.1218351 | bibcode = 2012Sci...336.1440P }} [59] => [60] => MI-63 binds to MDM2, reactivating p53 in situations where p53's function has become inhibited.{{cite journal | vauthors = Canner JA, Sobo M, Ball S, Hutzen B, DeAngelis S, Willis W, Studebaker AW, Ding K, Wang S, Yang D, Lin J | title = MI-63: a novel small-molecule inhibitor targets MDM2 and induces apoptosis in embryonal and alveolar rhabdomyosarcoma cells with wild-type p53 | journal = British Journal of Cancer | volume = 101 | issue = 5 | pages = 774–81 | date = September 2009 | pmid = 19707204 | pmc = 2736841 | doi = 10.1038/sj.bjc.6605199 }} [61] => [62] => A ubiquitin specific protease, [[USP7]] (or [[USP7|HAUSP]]), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the [[Ubiquitination|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.{{cite journal | vauthors = Hock AK, Vigneron AM, Carter S, Ludwig RL, Vousden KH | title = Regulation of p53 stability and function by the deubiquitinating enzyme USP42 | journal = The EMBO Journal | volume = 30 | issue = 24 | pages = 4921–30 | date = November 2011 | pmid = 22085928 | pmc = 3243628 | doi = 10.1038/emboj.2011.419 }} [63] => [64] => 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 in 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. [65] => [66] => [[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. [67] => [68] => 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 [[EP300|p300]] and [[PCAF]], which then acetylate the [[C-terminus|C-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.{{cite journal | vauthors = Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, Braun T, Bober E | title = Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice | journal = Circulation Research | volume = 102 | issue = 6 | pages = 703–10 | date = March 2008 | pmid = 18239138 | doi = 10.1161/CIRCRESAHA.107.164558 | doi-access = free }} Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity. [69] => [70] => == Role in disease == [71] => [[File:Signal transduction pathways.svg|300px|thumb|right|Overview of signal transduction pathways involved in [[apoptosis]]]] [72] => [[File:Anaplastic astrocytoma - p53 - very high mag.jpg|thumb|A [[micrograph]] showing cells with abnormal p53 expression (brown) in a brain tumor. [[immunostain|p53 immunostain]].]] [73] => 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]]. [74] => [75] => The ''TP53'' gene can also be modified by [[mutagen]]s ([[chemical substance|chemicals]], [[radiation]], or [[virus]]es), increasing the likelihood for uncontrolled cell division. More than 50 percent of human [[tumor]]s contain a [[mutation]] or [[genetic deletion|deletion]] of the ''TP53'' gene.{{cite journal | vauthors = Hollstein M, Sidransky D, Vogelstein B, Harris CC | title = p53 mutations in human cancers | journal = Science | volume = 253 | issue = 5015 | pages = 49–53 | date = July 1991 | pmid = 1905840 | doi = 10.1126/science.1905840 | bibcode = 1991Sci...253...49H | s2cid = 38527914 | url = https://zenodo.org/record/1230948 }} Loss of p53 creates genomic instability that most often results in an [[aneuploidy]] phenotype.{{cite journal | vauthors = Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM, Lowe SW | title = Dissecting p53 tumor suppressor functions in vivo | journal = Cancer Cell | volume = 1 | issue = 3 | pages = 289–98 | date = April 2002 | pmid = 12086865 | doi = 10.1016/S1535-6108(02)00047-8 | doi-access = free }} [76] => [77] => 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.{{cite journal | vauthors = Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Park SH, 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 | date = January 2002 | pmid = 11780111 | doi = 10.1038/415045a | bibcode = 2002Natur.415...45T | s2cid = 749047 }} 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.{{cite journal | vauthors = 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 | date = February 2007 | pmid = 17251932 | doi = 10.1038/nature05541 | s2cid = 4373520 }}{{cite journal | vauthors = Herce HD, Deng W, Helma J, Leonhardt H, Cardoso MC | title = Visualization and targeted disruption of protein interactions in living cells | journal = Nature Communications | volume = 4 | pages = 2660 | year = 2013 | pmid = 24154492 | pmc = 3826628 | doi = 10.1038/ncomms3660 | bibcode = 2013NatCo...4.2660H }} The first commercial gene therapy, [[Gendicine]], was approved in China in 2003 for the treatment of [[head and neck cancer|head and neck squamous cell carcinoma]]. It delivers a functional copy of the p53 gene using an engineered [[adenovirus]].{{cite journal | vauthors = Pearson S, Jia H, Kandachi K | title = China approves first gene therapy | journal = Nature Biotechnology | volume = 22 | issue = 1 | pages = 3–4 | date = January 2004 | pmid = 14704685 | doi = 10.1038/nbt0104-3 | pmc = 7097065 }} [78] => [79] => 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 [[wart]]s. 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.{{cite book | vauthors = Angeletti PC, Zhang L, Wood C | chapter = The Viral Etiology of AIDS-Associated Malignancies | title = HIV-1: Molecular Biology and Pathogenesis | series = Advances in Pharmacology | volume = 56 | pages = 509–57 | year = 2008 | pmid = 18086422 | pmc = 2149907 | doi = 10.1016/S1054-3589(07)56016-3 | isbn = 978-0-12-373601-7 }} [80] => [81] => The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation (see a stochastic model of this process in {{cite journal | vauthors = Ribeiro AS, Charlebois DA, Lloyd-Price J | title = CellLine, a stochastic cell lineage simulator | journal = Bioinformatics | volume = 23 | issue = 24 | pages = 3409–3411 | date = December 2007 | pmid = 17928303 | doi = 10.1093/bioinformatics/btm491 | doi-access = free }}). 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.{{cite journal | vauthors = Bullock AN, Henckel J, DeDecker BS, Johnson CM, Nikolova PV, Proctor MR, Lane DP, Fersht AR | title = Thermodynamic stability of wild-type and mutant p53 core domain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 26 | pages = 14338–42 | date = December 1997 | pmid = 9405613 | pmc = 24967 | doi = 10.1073/pnas.94.26.14338 | bibcode = 1997PNAS...9414338B | doi-access = free }} [82] => [83] => {| class="wikitable" [84] => | [85] => [[File:Patterns of p53 expression.png|right|340px]] [86] => This image shows different patterns of p53 expression in endometrial cancers on chromogenic [[immunohistochemistry]], whereof all except wild-type are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying TP53 mutation:{{cite journal | vauthors = Köbel M, Ronnett BM, Singh N, Soslow RA, Gilks CB, McCluggage WG | title = Interpretation of P53 Immunohistochemistry in Endometrial Carcinomas: Toward Increased Reproducibility | journal = International Journal of Gynecological Pathology | volume = 38 | issue = Suppl 1 | pages = S123–S131 | date = January 2019 | pmid = 29517499 | pmc = 6127005 | doi = 10.1097/PGP.0000000000000488 }} {{CC-notice|cc=by4}} [87] => * '''Wild-type''', upper left: Endometrial endometrioid carcinoma showing normal wild-type pattern of p53 expression with variable proportion of tumor cell nuclei staining with variable intensity. Note, this wild-type pattern should not be reported as "positive," because this is ambiguous reporting language. [88] => * '''Overexpression''', upper right: Endometrial endometrioid carcinoma, grade 3, with overexpression, showing strong staining in virtually all tumor cell nuclei, much stronger compared with the internal control of fibroblasts in the center. Note, there is some cytoplasmic background indicating that this staining is quite strong but this should not be interpreted as abnormal cytoplasmic pattern. [89] => * '''Complete absence''', lower left: Endometrial serous carcinoma showing complete absence of p53 expression with internal control showing moderate to strong but variable staining. Note, wild-type pattern in normal atrophic glands at 12 and 6 o'clock. [90] => * '''Both cytoplasmic and nuclear''', lower right: Endometrial endometrioid carcinoma showing cytoplasmic p53 expression with internal control (stroma and normal endometrial glands) showing nuclear wild-type pattern. The cytoplasmic pattern is accompanied by nuclear staining of similar intensity. [91] => |} [92] => [[File:Expression of p53 in urothelial neoplasms.png|thumb|[[Immunohistochemistry]] for p53 can help distinguish a [[papillary urothelial neoplasm of low malignant potential]] (PUNLMP) from a low grade [[urothelial carcinoma]]. Overexpression is seen in 75% of low-grade urothelial carcinomas and only 10% of PUNLMP.Image is taken from following source, with some modification by Mikael Häggström, MD:
- {{cite journal| vauthors =Schallenberg S, Plage H, Hofbauer S, Furlano K, Weinberger S, Bruch PG | title=Altered p53/p16 expression is linked to urothelial carcinoma progression but largely unrelated to prognosis in muscle-invasive tumors. | journal=Acta Oncol | year= 2023 | volume= 62| issue= 12| pages= 1880–1889 | pmid=37938166 | doi=10.1080/0284186X.2023.2277344 | pmc= | doi-access=free }} Source for role in distinguishing PUNLMP from low-grade carcinoma:
- {{cite journal| author=Kalantari MR, Ahmadnia H| title=P53 overexpression in bladder urothelial neoplasms: new aspect of World Health Organization/International Society of Urological Pathology classification. | journal=Urol J | year= 2007 | volume= 4 | issue= 4 | pages= 230–3 | pmid=18270948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18270948 }} ]] [93] => 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]].{{cite journal | vauthors = Mitkin NA, Hook CD, Schwartz AM, Biswas S, Kochetkov DV, Muratova AM, Afanasyeva MA, Kravchenko JE, Bhattacharyya A, Kuprash DV | title = p53-dependent expression of CXCR5 chemokine receptor in MCF-7 breast cancer cells | journal = Scientific Reports | volume = 5 | issue = 5 | pages = 9330 | date = March 2015 | pmid = 25786345 | pmc = 4365401 | doi = 10.1038/srep09330 | bibcode = 2015NatSR...5E9330M }} [94] => [95] => One study found that p53 and [[Myc]] proteins were key to the survival of [[Chronic myeloid leukaemia|Chronic Myeloid Leukaemia]] (CML) cells. Targeting p53 and Myc proteins with drugs gave positive results on mice with CML.{{cite journal | vauthors = Abraham SA, Hopcroft LE, Carrick E, Drotar ME, Dunn K, Williamson AJ, Korfi K, Baquero P, Park LE, Scott MT, Pellicano F, Pierce A, Copland M, Nourse C, Grimmond SM, Vetrie D, Whetton AD, Holyoake TL | title = Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells | journal = Nature | volume = 534 | issue = 7607 | pages = 341–6 | date = June 2016 | pmid = 27281222 | pmc = 4913876 | doi = 10.1038/nature18288 | bibcode = 2016Natur.534..341A }}{{Cite web |url=https://www.myscience.uk/news/2016/cientists_identify_drugs_to_target_achilles_heel_of_chronic_myeloid_leukaemia_cells-2016-glasgow |title=Scientists identify drugs to target 'Achilles heel' of Chronic Myeloid Leukaemia cells |date=2016-06-08 |website=myScience |access-date=2016-06-09}} [96] => [97] => == Experimental analysis of p53 mutations == [98] => 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 effects. [99] => [100] => The large spectrum of cancer phenotypes due to mutations in the ''TP53'' gene is also supported by the fact that different [[protein isoform|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. Recent studies show that p53 isoforms are differentially expressed in different human tissues, and the [[mutation|loss-of-function or gain-of-function mutations]] within the isoforms can cause tissue-specific cancer or provide cancer [[stem cell]] [[cell potency|potential]] in different tissues.{{cite journal | vauthors = Khoury MP, Bourdon JC | title = p53 Isoforms: An Intracellular Microprocessor? | journal = Genes & Cancer | volume = 2 | issue = 4 | pages = 453–65 | date = April 2011 | pmid = 21779513 | pmc = 3135639 | doi = 10.1177/1947601911408893 }}{{cite journal | vauthors = Avery-Kiejda KA, Morten B, Wong-Brown MW, Mathe A, Scott RJ | title = The relative mRNA expression of p53 isoforms in breast cancer is associated with clinical features and outcome | journal = Carcinogenesis | volume = 35 | issue = 3 | pages = 586–96 | date = March 2014 | pmid = 24336193 | doi = 10.1093/carcin/bgt411 | doi-access = free }}{{cite journal | vauthors = Arsic N, Gadea G, Lagerqvist EL, Busson M, Cahuzac N, Brock C, Hollande F, Gire V, Pannequin J, Roux P | title = The p53 isoform Δ133p53β promotes cancer stem cell potential | journal = Stem Cell Reports | volume = 4 | issue = 4 | pages = 531–40 | date = April 2015 | pmid = 25754205 | pmc = 4400643 | doi = 10.1016/j.stemcr.2015.02.001 }} TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells.{{cite journal | vauthors = Harami-Papp H, Pongor LS, Munkácsy G, Horváth G, Nagy ÁM, Ambrus A, Hauser P, Szabó A, Tretter L, Győrffy B | title = TP53 mutation hits energy metabolism and increases glycolysis in breast cancer | journal = Oncotarget | volume = 7 | issue = 41 | pages = 67183–67195 | date = October 2016 | pmid = 27582538 | pmc = 5341867 | doi = 10.18632/oncotarget.11594 }} [101] => [102] => The dynamics of p53 proteins, along with its antagonist [[Mdm2]], indicate that the levels of p53, in units of concentration, [[oscillation|oscillate]] as a function of time. This "[[Damping ratio|damped]]" oscillation is both clinically documented {{cite journal | vauthors = Geva-Zatorsky N, Rosenfeld N, Itzkovitz S, Milo R, Sigal A, Dekel E, Yarnitzky T, Liron Y, Polak P, Lahav G, Alon U | title = Oscillations and variability in the p53 system | journal = Molecular Systems Biology | volume = 2 | pages = 2006.0033 | date = June 2006 | pmid = 16773083 | pmc = 1681500 | doi = 10.1038/msb4100068 }} and [[Mathematical modelling|mathematically modelled]].{{cite journal | vauthors = Proctor CJ, Gray DA | title = Explaining oscillations and variability in the p53-Mdm2 system | journal = BMC Systems Biology | volume = 2 | issue = 75 | pages = 75 | date = August 2008 | pmid = 18706112 | pmc = 2553322 | doi = 10.1186/1752-0509-2-75 | doi-access = free }}{{cite journal | vauthors = Chong KH, Samarasinghe S, Kulasiri D | title = Mathematical modelling of p53 basal dynamics and DNA damage response | journal = C-fACS | issue = 20th International Congress on Mathematical Modelling and Simulation | pages = 670–6 | date = December 2013| volume = 259 | doi = 10.1016/j.mbs.2014.10.010 | pmid = 25433195 }} Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as [[DNA repair|double-stranded breaks (DSB) or UV radiation]], are introduced to the [[Systems biology|system]]. This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation (see [[#Regulation|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]]. [103] => [104] => == Discovery == [105] => p53 was identified in 1979 by [[Lionel Crawford]], [[David P. Lane]], [[Arnold J. Levine|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 name '''p53''' was given in 1979 describing the apparent [[molecular mass]]. [106] => [107] => The ''TP53'' gene from the mouse was first cloned by [[Peter Chumakov]] of [[The Academy of Sciences of the USSR]] in 1982,{{cite journal | vauthors = Chumakov PM, Iotsova VS, Georgiev GP | title = [Isolation of a plasmid clone containing the mRNA sequence for mouse nonviral T-antigen] | language = ru | journal = Doklady Akademii Nauk SSSR | volume = 267 | issue = 5 | pages = 1272–5 | year = 1982 | pmid = 6295732 }} and independently in 1983 by [[Moshe Oren]] in collaboration with [[David Givol]] ([[Weizmann Institute of Science]]).{{cite journal | vauthors = Oren M, Levine AJ | title = Molecular cloning of a cDNA specific for the murine p53 cellular tumor antigen | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 80 | issue = 1 | pages = 56–9 | date = January 1983 | pmid = 6296874 | pmc = 393308 | doi = 10.1073/pnas.80.1.56 | bibcode = 1983PNAS...80...56O | doi-access = free }}{{cite journal | vauthors = Zakut-Houri R, Oren M, Bienz B, Lavie V, Hazum S, Givol D | title = A single gene and a pseudogene for the cellular tumour antigen p53 | journal = Nature | volume = 306 | issue = 5943 | pages = 594–7 | year = 1983 | pmid = 6646235 | doi = 10.1038/306594a0 | bibcode = 1983Natur.306..594Z | s2cid = 4325094 }} The human ''TP53'' gene was cloned in 1984 and the full length clone in 1985.{{cite journal | vauthors = Zakut-Houri R, Bienz-Tadmor B, Givol D, Oren M | title = Human p53 cellular tumor antigen: cDNA sequence and expression in COS cells | journal = The EMBO Journal | volume = 4 | issue = 5 | pages = 1251–5 | date = May 1985 | pmid = 4006916 | pmc = 554332 | doi = 10.1002/j.1460-2075.1985.tb03768.x}} [108] => [109] => 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 J. Levine|Arnold Levine]] at Princeton University.{{cite journal | vauthors = Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, White R, Vogelstein B | title = Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas | journal = Science | volume = 244 | issue = 4901 | pages = 217–21 | date = April 1989 | pmid = 2649981 | doi = 10.1126/science.2649981 | bibcode = 1989Sci...244..217B }}{{cite journal | vauthors = Finlay CA, Hinds PW, Levine AJ | title = The p53 proto-oncogene can act as a suppressor of transformation | journal = Cell | volume = 57 | issue = 7 | pages = 1083–93 | date = June 1989 | pmid = 2525423 | doi = 10.1016/0092-8674(89)90045-7 | doi-access = free }} p53 went on to be identified as a transcription factor by [[Guillermina Lozano]] working at [[MD Anderson Cancer Center]].{{cite journal | vauthors = Raycroft L, Wu HY, Lozano G | title = Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene | journal = Science | volume = 249 | issue = 4972 | pages = 1049–1051 | date = August 1990 | pmid = 2144364 | doi = 10.1126/science.2144364 | pmc = 2935288 | bibcode = 1990Sci...249.1049R }} [110] => [111] => Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.{{cite journal | vauthors = Maltzman W, Czyzyk L | title = UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells | journal = Molecular and Cellular Biology | volume = 4 | issue = 9 | pages = 1689–94 | date = September 1984 | pmid = 6092932 | pmc = 368974 | doi = 10.1128/mcb.4.9.1689 }} 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.{{cite journal | vauthors = Kastan MB, Kuerbitz SJ | title = Control of G1 arrest after DNA damage | journal = Environmental Health Perspectives | volume = 101 | issue = Suppl 5 | pages = 55–8 | date = December 1993 | pmid = 8013425 | pmc = 1519427 | doi = 10.2307/3431842 | jstor = 3431842 }} [112] => [113] => In 1993, p53 was voted ''molecule of the year'' by [[Science (journal)|Science]] magazine.{{cite journal | vauthors = Koshland DE | title = Molecule of the year | journal = Science | volume = 262 | issue = 5142 | pages = 1953 | date = December 1993 | pmid = 8266084 | doi = 10.1126/science.8266084 | doi-access = | bibcode = 1993Sci...262.1953K }} [114] => [115] => == Structure == [116] => [[File:P53 Schematic.tif|thumb|right|A schematic of the known protein domains in p53. (NLS = Nuclear Localization Signal).|360x360px]] [117] => [[File:3KMD p53 DNABindingDomian.png|thumb|Crystal structure of four p53 DNA binding domains (as found in the bioactive homo-tetramer)]]p53 has seven [[domain (protein)|domains]]: [118] => # an acidic [[N-terminus]] transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates [[transcription factor]]s. 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.{{cite journal |vauthors=Venot C, Maratrat M, Dureuil C, Conseiller E, Bracco L, Debussche L |date=August 1998 |title=The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression |journal=The EMBO Journal |volume=17 |issue=16 |pages=4668–79 |doi=10.1093/emboj/17.16.4668 |pmc=1170796 |pmid=9707426}} [119] => # activation domain 2 (AD2) important for [[Apoptosis|apoptotic]] activity: residues 43–63. [120] => # [[proline]] rich domain important for the apoptotic activity of p53 by nuclear exportation via [[MAPK]]: residues 64–92. [121] => # central [[DNA]]-binding core domain ([[DNA-binding 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]].{{cite journal |vauthors=Larsen S, Yokochi T, Isogai E, Nakamura Y, Ozaki T, Nakagawara A |date=February 2010 |title=LMO3 interacts with p53 and inhibits its transcriptional activity |journal=Biochemical and Biophysical Research Communications |volume=392 |issue=3 |pages=252–7 |doi=10.1016/j.bbrc.2009.12.010 |pmid=19995558}} [122] => # [[Nuclear localization sequence|Nuclear Localization Signaling]] (NLS) domain, residues 316–325. [123] => # homo-oligomerisation domain (OD): residues 307–355. Tetramerization is essential for the activity of p53 ''in vivo''. [124] => # [[C-terminal]] involved in downregulation of DNA binding of the central domain: residues 356–393.{{cite journal |vauthors=Harms KL, Chen X |date=March 2005 |title=The C terminus of p53 family proteins is a cell fate determinant |journal=Molecular and Cellular Biology |volume=25 |issue=5 |pages=2014–30 |doi=10.1128/MCB.25.5.2014-2030.2005 |pmc=549381 |pmid=15713654}} [125] => [126] => 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. [127] => [128] => Wild-type p53 is a [[labile]] [[protein]], comprising folded and [[Intrinsically unstructured proteins|unstructured regions]] that function in a synergistic manner.{{cite journal |vauthors=Bell S, Klein C, Müller L, Hansen S, Buchner J |date=October 2002 |title=p53 contains large unstructured regions in its native state |journal=Journal of Molecular Biology |volume=322 |issue=5 |pages=917–27 |doi=10.1016/S0022-2836(02)00848-3 |pmid=12367518}} [129] => [130] => [[SDS-PAGE]] analysis indicates that p53 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.{{cite journal |vauthors=Ziemer MA, Mason A, Carlson DM |date=September 1982 |title=Cell-free translations of proline-rich protein mRNAs |journal=The Journal of Biological Chemistry |volume=257 |issue=18 |pages=11176–80 |doi=10.1016/S0021-9258(18)33948-6 |pmid=7107651 |doi-access=free}} [131] => [132] => == Isoforms == [133] => [134] => As with 95% of human genes, TP53 encodes more than one protein. All these p53 proteins are called the '''p53 isoforms'''. These proteins range in size from 3.5 to 43.7 kDa. Several [[protein isoform|isoforms]] were discovered in 2005, and so far 12 human p53 isoforms have been 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.{{cite journal | vauthors = Bourdon JC, Fernandes K, Murray-Zmijewski F, Liu G, Diot A, Xirodimas DP, Saville MK, Lane DP | title = p53 isoforms can regulate p53 transcriptional activity | journal = Genes & Development | volume = 19 | issue = 18 | pages = 2122–37 | date = September 2005 | pmid = 16131611 | pmc = 1221884 | doi = 10.1101/gad.1339905 }} [135] => [136] => The full length p53 isoform proteins can be subdivided into different [[protein domain]]s. Starting from the [[N-terminus]], there are first the amino-terminal transcription-activation 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]].{{cite journal | vauthors = Zhu J, Zhang S, Jiang J, Chen X | title = Definition of the p53 functional domains necessary for inducing apoptosis | journal = The Journal of Biological Chemistry | volume = 275 | issue = 51 | pages = 39927–34 | date = December 2000 | pmid = 10982799 | doi = 10.1074/jbc.M005676200 | doi-access = free }} 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 [[C-terminus]] 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. [137] => [138] => 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. [139] => [140] => Due to the [[isoform]]ic 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|Experimental analysis of p53 mutations]] for more details). [141] => [142] => == Interactions == [143] => p53 has been shown to [[Protein-protein interaction|interact]] with: [144] => {{div col|colwidth=20em}} [145] => * [[Multisynthetase complex auxiliary component p38|AIMP2]],{{cite journal | vauthors = Han JM, Park BJ, Park SG, Oh YS, Choi SJ, Lee SW, Hwang SK, Chang SH, Cho MH, Kim S | title = AIMP2/p38, the scaffold for the multi-tRNA synthetase complex, responds to genotoxic stresses via p53 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 32 | pages = 11206–11 | date = August 2008 | pmid = 18695251 | pmc = 2516205 | doi = 10.1073/pnas.0800297105 | bibcode = 2008PNAS..10511206H | doi-access = free }} [146] => * [[ANKRD2]], [147] => * [[Aprataxin|APTX]], [148] => * [[Ataxia telangiectasia mutated|ATM]],{{cite journal | vauthors = Fabbro M, Savage K, Hobson K, Deans AJ, Powell SN, McArthur GA, Khanna KK | title = BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage | journal = The Journal of Biological Chemistry | volume = 279 | issue = 30 | pages = 31251–8 | date = July 2004 | pmid = 15159397 | doi = 10.1074/jbc.M405372200 | doi-access = free }}{{cite journal | vauthors = Kang J, Ferguson D, Song H, Bassing C, Eckersdorff M, Alt FW, Xu Y | title = Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression | journal = Molecular and Cellular Biology | volume = 25 | issue = 2 | pages = 661–70 | date = January 2005 | pmid = 15632067 | pmc = 543410 | doi = 10.1128/MCB.25.2.661-670.2005 }}{{cite journal | vauthors = Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K, Taya Y, Gabrielli B, Chan D, Lees-Miller SP, Lavin MF | title = ATM associates with and phosphorylates p53: mapping the region of interaction | journal = Nature Genetics | volume = 20 | issue = 4 | pages = 398–400 | date = December 1998 | pmid = 9843217 | doi = 10.1038/3882 | s2cid = 23994762 }}{{cite journal | vauthors = Westphal CH, Schmaltz C, Rowan S, Elson A, Fisher DE, Leder P | title = Genetic interactions between atm and p53 influence cellular proliferation and irradiation-induced cell cycle checkpoints | journal = Cancer Research | volume = 57 | issue = 9 | pages = 1664–7 | date = May 1997 | pmid = 9135004 }} [149] => * [[Ataxia telangiectasia and Rad3 related|ATR]],{{cite journal | vauthors = Kim ST, Lim DS, Canman CE, Kastan MB | title = Substrate specificities and identification of putative substrates of ATM kinase family members | journal = The Journal of Biological Chemistry | volume = 274 | issue = 53 | pages = 37538–43 | date = December 1999 | pmid = 10608806 | doi = 10.1074/jbc.274.53.37538 | doi-access = free }} [150] => * [[ATF3]],{{cite journal | vauthors = Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE | title = A human protein-protein interaction network: a resource for annotating the proteome | journal = Cell | volume = 122 | issue = 6 | pages = 957–68 | date = September 2005 | pmid = 16169070 | doi = 10.1016/j.cell.2005.08.029 | doi-access = free | hdl = 11858/00-001M-0000-0010-8592-0 | hdl-access = free }}{{cite journal | vauthors = Yan C, Wang H, Boyd DD | title = ATF3 represses 72-kDa type IV collagenase (MMP-2) expression by antagonizing p53-dependent trans-activation of the collagenase promoter | journal = The Journal of Biological Chemistry | volume = 277 | issue = 13 | pages = 10804–12 | date = March 2002 | pmid = 11792711 | doi = 10.1074/jbc.M112069200 | doi-access = free }} [151] => * [[Aurora A kinase|AURKA]],{{cite journal | vauthors = Chen SS, Chang PC, Cheng YW, Tang FM, Lin YS | title = Suppression of the STK15 oncogenic activity requires a transactivation-independent p53 function | journal = The EMBO Journal | volume = 21 | issue = 17 | pages = 4491–9 | date = September 2002 | pmid = 12198151 | pmc = 126178 | doi = 10.1093/emboj/cdf409 }} [152] => * [[BAK1]],{{cite journal | vauthors = Leu JI, Dumont P, Hafey M, Murphy ME, George DL | title = Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex | journal = Nature Cell Biology | volume = 6 | issue = 5 | pages = 443–50 | date = May 2004 | pmid = 15077116 | doi = 10.1038/ncb1123 | s2cid = 43063712 }} [153] => * [[BARD1]], [154] => * [[Bloom syndrome protein|BLM]],{{cite journal | vauthors = Wang XW, Tseng A, Ellis NA, Spillare EA, Linke SP, Robles AI, Seker H, Yang Q, Hu P, Beresten S, Bemmels NA, Garfield S, Harris CC | title = Functional interaction of p53 and BLM DNA helicase in apoptosis | journal = The Journal of Biological Chemistry | volume = 276 | issue = 35 | pages = 32948–55 | date = August 2001 | pmid = 11399766 | doi = 10.1074/jbc.M103298200 | doi-access = free }}{{cite journal | vauthors = Garkavtsev IV, Kley N, Grigorian IA, Gudkov AV | title = The Bloom syndrome protein interacts and cooperates with p53 in regulation of transcription and cell growth control | journal = Oncogene | volume = 20 | issue = 57 | pages = 8276–80 | date = December 2001 | pmid = 11781842 | doi = 10.1038/sj.onc.1205120 | s2cid = 13084911 | doi-access = }} [155] => * [[BRCA1]],{{cite journal | vauthors = Abramovitch S, Werner H | title = Functional and physical interactions between BRCA1 and p53 in transcriptional regulation of the IGF-IR gene | journal = Hormone and Metabolic Research | volume = 35 | issue = 11–12 | pages = 758–62 | year = 2003 | pmid = 14710355 | doi = 10.1055/s-2004-814154 | s2cid = 20898175 }}{{cite journal | vauthors = Ouchi T, Monteiro AN, August A, Aaronson SA, Hanafusa H | title = BRCA1 regulates p53-dependent gene expression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 5 | pages = 2302–6 | date = March 1998 | pmid = 9482880 | pmc = 19327 | doi = 10.1073/pnas.95.5.2302 | bibcode = 1998PNAS...95.2302O | doi-access = free }}{{cite journal | vauthors = Chai YL, Cui J, Shao N, Shyam E, Reddy P, Rao VN | title = The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoter | journal = Oncogene | volume = 18 | issue = 1 | pages = 263–8 | date = January 1999 | pmid = 9926942 | doi = 10.1038/sj.onc.1202323 | s2cid = 7462625 | doi-access = }}{{cite journal | vauthors = Zhang H, Somasundaram K, Peng Y, Tian H, Zhang H, Bi D, Weber BL, El-Deiry WS | title = BRCA1 physically associates with p53 and stimulates its transcriptional activity | journal = Oncogene | volume = 16 | issue = 13 | pages = 1713–21 | date = April 1998 | pmid = 9582019 | doi = 10.1038/sj.onc.1201932 | s2cid = 24616900 | doi-access = }} [156] => * [[BRCA2]],{{cite journal | vauthors = Marmorstein LY, Ouchi T, Aaronson SA | title = The BRCA2 gene product functionally interacts with p53 and RAD51 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 23 | pages = 13869–74 | date = November 1998 | pmid = 9811893 | pmc = 24938 | doi = 10.1073/pnas.95.23.13869 | bibcode = 1998PNAS...9513869M | doi-access = free }} [157] => * [[BRCC3]], [158] => * [[BRE (gene)|BRE]],{{cite journal | vauthors = Dong Y, Hakimi MA, Chen X, Kumaraswamy E, Cooch NS, Godwin AK, Shiekhattar R | title = Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair | journal = Molecular Cell | volume = 12 | issue = 5 | pages = 1087–99 | date = November 2003 | pmid = 14636569 | doi = 10.1016/S1097-2765(03)00424-6 | doi-access = free }} [159] => * [[CCAAT/enhancer binding protein zeta|CEBPZ]],{{cite journal | vauthors = Uramoto H, Izumi H, Nagatani G, Ohmori H, Nagasue N, Ise T, Yoshida T, Yasumoto K, Kohno K | title = Physical interaction of tumour suppressor p53/p73 with CCAAT-binding transcription factor 2 (CTF2) and differential regulation of human high-mobility group 1 (HMG1) gene expression | journal = The Biochemical Journal | volume = 371 | issue = Pt 2 | pages = 301–10 | date = April 2003 | pmid = 12534345 | pmc = 1223307 | doi = 10.1042/BJ20021646 }} [160] => * [[CDC14A]], [161] => * [[Cdk1]],{{cite journal | vauthors = Luciani MG, Hutchins JR, Zheleva D, Hupp TR | title = The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A | journal = Journal of Molecular Biology | volume = 300 | issue = 3 | pages = 503–18 | date = July 2000 | pmid = 10884347 | doi = 10.1006/jmbi.2000.3830 }}{{cite journal | vauthors = Ababneh M, Götz C, Montenarh M | title = Downregulation of the cdc2/cyclin B protein kinase activity by binding of p53 to p34(cdc2) | journal = Biochemical and Biophysical Research Communications | volume = 283 | issue = 2 | pages = 507–12 | date = May 2001 | pmid = 11327730 | doi = 10.1006/bbrc.2001.4792 }} [162] => * [[CFLAR]],{{cite journal | vauthors = Abedini MR, Muller EJ, Brun J, Bergeron R, Gray DA, Tsang BK | title = Cisplatin induces p53-dependent FLICE-like inhibitory protein ubiquitination in ovarian cancer cells | journal = Cancer Research | volume = 68 | issue = 12 | pages = 4511–7 | date = June 2008 | pmid = 18559494 | doi = 10.1158/0008-5472.CAN-08-0673 | doi-access = free }} [163] => * [[CHEK1]],{{cite journal | vauthors = Sengupta S, Robles AI, Linke SP, Sinogeeva NI, Zhang R, Pedeux R, Ward IM, Celeste A, Nussenzweig A, Chen J, Halazonetis TD, Harris CC | title = Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest | journal = The Journal of Cell Biology | volume = 166 | issue = 6 | pages = 801–13 | date = September 2004 | pmid = 15364958 | pmc = 2172115 | doi = 10.1083/jcb.200405128 }}{{cite journal | vauthors = Tian H, Faje AT, Lee SL, Jorgensen TJ | title = Radiation-induced phosphorylation of Chk1 at S345 is associated with p53-dependent cell cycle arrest pathways | journal = Neoplasia | volume = 4 | issue = 2 | pages = 171–80 | year = 2002 | pmid = 11896572 | pmc = 1550321 | doi = 10.1038/sj.neo.7900219 }} [164] => * [[CCNG1]],{{cite journal | vauthors = Zhao L, Samuels T, Winckler S, Korgaonkar C, Tompkins V, Horne MC, Quelle DE | title = Cyclin G1 has growth inhibitory activity linked to the ARF-Mdm2-p53 and pRb tumor suppressor pathways | journal = Molecular Cancer Research | volume = 1 | issue = 3 | pages = 195–206 | date = January 2003 | pmid = 12556559 }} [165] => * [[CREB-binding protein|CREBBP]],{{cite journal | vauthors = Ito A, Kawaguchi Y, Lai CH, Kovacs JJ, Higashimoto Y, Appella E, Yao TP | title = MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation | journal = The EMBO Journal | volume = 21 | issue = 22 | pages = 6236–45 | date = November 2002 | pmid = 12426395 | pmc = 137207 | doi = 10.1093/emboj/cdf616 }} [166] => * [[CREB1]],{{cite journal | vauthors = Giebler HA, Lemasson I, Nyborg JK | title = p53 recruitment of CREB binding protein mediated through phosphorylated CREB: a novel pathway of tumor suppressor regulation | journal = Molecular and Cellular Biology | volume = 20 | issue = 13 | pages = 4849–58 | date = July 2000 | pmid = 10848610 | pmc = 85936 | doi = 10.1128/MCB.20.13.4849-4858.2000 }} [167] => * [[Cyclin H]],{{cite journal | vauthors = Schneider E, Montenarh M, Wagner P | title = Regulation of CAK kinase activity by p53 | journal = Oncogene | volume = 17 | issue = 21 | pages = 2733–41 | date = November 1998 | pmid = 9840937 | doi = 10.1038/sj.onc.1202504 | s2cid = 6281777 | doi-access = }} [168] => * [[Cyclin-dependent kinase 7|CDK7]],{{cite journal | vauthors = Ko LJ, Shieh SY, Chen X, Jayaraman L, Tamai K, Taya Y, Prives C, Pan ZQ | title = p53 is phosphorylated by CDK7-cyclin H in a p36MAT1-dependent manner | journal = Molecular and Cellular Biology | volume = 17 | issue = 12 | pages = 7220–9 | date = December 1997 | pmid = 9372954 | pmc = 232579 | doi = 10.1128/mcb.17.12.7220 }} [169] => * [[DNA-PKcs]],{{cite journal | vauthors = Goudelock DM, Jiang K, Pereira E, Russell B, Sanchez Y | title = Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex | journal = The Journal of Biological Chemistry | volume = 278 | issue = 32 | pages = 29940–7 | date = August 2003 | pmid = 12756247 | doi = 10.1074/jbc.M301765200 | doi-access = free }}{{cite journal | vauthors = Yavuzer U, Smith GC, Bliss T, Werner D, Jackson SP | title = DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D | journal = Genes & Development | volume = 12 | issue = 14 | pages = 2188–99 | date = July 1998 | pmid = 9679063 | pmc = 317006 | doi = 10.1101/gad.12.14.2188 }} [170] => * [[E4F1]],{{cite journal | vauthors = Rizos H, Diefenbach E, Badhwar P, Woodruff S, Becker TM, Rooney RJ, Kefford RF | title = Association of p14ARF with the p120E4F transcriptional repressor enhances cell cycle inhibition | journal = The Journal of Biological Chemistry | volume = 278 | issue = 7 | pages = 4981–9 | date = February 2003 | pmid = 12446718 | doi = 10.1074/jbc.M210978200 | doi-access = free }}{{cite journal | vauthors = Sandy P, Gostissa M, Fogal V, Cecco LD, Szalay K, Rooney RJ, Schneider C, Del Sal G | title = p53 is involved in the p120E4F-mediated growth arrest | journal = Oncogene | volume = 19 | issue = 2 | pages = 188–99 | date = January 2000 | pmid = 10644996 | doi = 10.1038/sj.onc.1203250 | doi-access = free }} [171] => * [[EFEMP2]],{{cite journal | vauthors = Gallagher WM, Argentini M, Sierra V, Bracco L, Debussche L, Conseiller E | title = MBP1: a novel mutant p53-specific protein partner with oncogenic properties | journal = Oncogene | volume = 18 | issue = 24 | pages = 3608–16 | date = June 1999 | pmid = 10380882 | doi = 10.1038/sj.onc.1202937 | doi-access = free }} [172] => * [[Protein kinase R|EIF2AK2]],{{cite journal | vauthors = Cuddihy AR, Wong AH, Tam NW, Li S, Koromilas AE | title = The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro | journal = Oncogene | volume = 18 | issue = 17 | pages = 2690–702 | date = April 1999 | pmid = 10348343 | doi = 10.1038/sj.onc.1202620 | s2cid = 22467088 | doi-access = }} [173] => * [[ELL (gene)|ELL]],{{cite journal | vauthors = Shinobu N, Maeda T, Aso T, Ito T, Kondo T, Koike K, Hatakeyama M | title = Physical interaction and functional antagonism between the RNA polymerase II elongation factor ELL and p53 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 24 | pages = 17003–10 | date = June 1999 | pmid = 10358050 | doi = 10.1074/jbc.274.24.17003 | doi-access = free }} [174] => * [[EP300]],{{cite journal | vauthors = Livengood JA, Scoggin KE, Van Orden K, McBryant SJ, Edayathumangalam RS, Laybourn PJ, Nyborg JK | title = p53 Transcriptional activity is mediated through the SRC1-interacting domain of CBP/p300 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 11 | pages = 9054–61 | date = March 2002 | pmid = 11782467 | doi = 10.1074/jbc.M108870200 | doi-access = free }}{{cite journal | vauthors = Grossman SR, Perez M, Kung AL, Joseph M, Mansur C, Xiao ZX, Kumar S, Howley PM, Livingston DM | title = p300/MDM2 complexes participate in MDM2-mediated p53 degradation | journal = Molecular Cell | volume = 2 | issue = 4 | pages = 405–15 | date = October 1998 | pmid = 9809062 | doi = 10.1016/S1097-2765(00)80140-9 | doi-access = free }}{{cite journal | vauthors = An W, Kim J, Roeder RG | title = Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53 | journal = Cell | volume = 117 | issue = 6 | pages = 735–48 | date = June 2004 | pmid = 15186775 | doi = 10.1016/j.cell.2004.05.009 | doi-access = free }}{{cite journal | vauthors = Pastorcic M, Das HK | title = Regulation of transcription of the human presenilin-1 gene by ets transcription factors and the p53 protooncogene | journal = The Journal of Biological Chemistry | volume = 275 | issue = 45 | pages = 34938–45 | date = November 2000 | pmid = 10942770 | doi = 10.1074/jbc.M005411200 | doi-access = free }} [175] => * [[ERCC6]],{{cite journal | vauthors = Wang XW, Yeh H, Schaeffer L, Roy R, Moncollin V, Egly JM, Wang Z, Freidberg EC, Evans MK, Taffe BG | title = p53 modulation of TFIIH-associated nucleotide excision repair activity | journal = Nature Genetics | volume = 10 | issue = 2 | pages = 188–95 | date = June 1995 | pmid = 7663514 | doi = 10.1038/ng0695-188 | hdl = 1765/54884 | s2cid = 38325851 | url = http://repub.eur.nl/pub/54884 | hdl-access = free }}{{cite journal | vauthors = Yu A, Fan HY, Liao D, Bailey AD, Weiner AM | title = Activation of p53 or loss of the Cockayne syndrome group B repair protein causes metaphase fragility of human U1, U2, and 5S genes | journal = Molecular Cell | volume = 5 | issue = 5 | pages = 801–10 | date = May 2000 | pmid = 10882116 | doi = 10.1016/S1097-2765(00)80320-2 | doi-access = free }} [176] => * [[GNL3]],{{cite journal | vauthors = Tsai RY, McKay RD | title = A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells | journal = Genes & Development | volume = 16 | issue = 23 | pages = 2991–3003 | date = December 2002 | pmid = 12464630 | pmc = 187487 | doi = 10.1101/gad.55671 }} [177] => * [[GPS2 (gene)|GPS2]],{{cite journal | vauthors = Peng YC, Kuo F, Breiding DE, Wang YF, Mansur CP, Androphy EJ | title = AMF1 (GPS2) modulates p53 transactivation | journal = Molecular and Cellular Biology | volume = 21 | issue = 17 | pages = 5913–24 | date = September 2001 | pmid = 11486030 | pmc = 87310 | doi = 10.1128/MCB.21.17.5913-5924.2001 }} [178] => * [[GSK3B]],{{cite journal | vauthors = Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GV, Jope RS | title = Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 12 | pages = 7951–5 | date = June 2002 | pmid = 12048243 | pmc = 123001 | doi = 10.1073/pnas.122062299 | bibcode = 2002PNAS...99.7951W | doi-access = free }} [179] => * [[Heat shock protein 90kDa alpha (cytosolic), member A1|HSP90AA1]],{{cite journal | vauthors = Wang C, Chen J | title = Phosphorylation and hsp90 binding mediate heat shock stabilization of p53 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 3 | pages = 2066–71 | date = January 2003 | pmid = 12427754 | doi = 10.1074/jbc.M206697200 | doi-access = free }}{{cite journal | vauthors = Peng Y, Chen L, Li C, Lu W, Chen J | title = Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization | journal = 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of the United States of America | volume = 96 | issue = 18 | pages = 10355–60 | date = August 1999 | pmid = 10468612 | pmc = 17892 | doi = 10.1073/pnas.96.18.10355 | bibcode = 1999PNAS...9610355G | doi-access = free }}{{cite journal | vauthors = Mao Y, Mehl IR, Muller MT | title = Subnuclear distribution of topoisomerase I is linked to ongoing transcription and p53 status | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 3 | pages = 1235–40 | date = February 2002 | pmid = 11805286 | pmc = 122173 | doi = 10.1073/pnas.022631899 | bibcode = 2002PNAS...99.1235M | doi-access = free }} [233] => * [[TOP2A]], [234] => * [[TP53BP1]],{{cite journal | vauthors = Derbyshire DJ, Basu BP, Serpell LC, Joo WS, Date T, Iwabuchi K, Doherty AJ | title = Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor | journal = The EMBO Journal | volume = 21 | issue = 14 | pages = 3863–72 | date = July 2002 | pmid = 12110597 | pmc = 126127 | doi = 10.1093/emboj/cdf383 }}{{cite journal | vauthors = Ekblad CM, Friedler A, Veprintsev D, Weinberg RL, Itzhaki LS | title = Comparison of BRCT domains of BRCA1 and 53BP1: a biophysical analysis | journal = Protein Science | volume = 13 | issue = 3 | pages = 617–25 | date = March 2004 | pmid = 14978302 | pmc = 2286730 | doi = 10.1110/ps.03461404 }}{{cite journal | vauthors = Lo KW, Kan HM, Chan LN, Xu WG, Wang KP, Wu Z, Sheng M, Zhang M | title = The 8-kDa dynein light chain binds to p53-binding protein 1 and mediates DNA damage-induced p53 nuclear accumulation | journal = The Journal of Biological Chemistry | volume = 280 | issue = 9 | pages = 8172–9 | date = March 2005 | pmid = 15611139 | doi = 10.1074/jbc.M411408200 | doi-access = free }}{{cite journal | vauthors = Joo WS, Jeffrey PD, Cantor SB, Finnin MS, Livingston DM, Pavletich NP | title = Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure | journal = Genes & Development | volume = 16 | issue = 5 | pages = 583–93 | date = March 2002 | pmid = 11877378 | pmc = 155350 | doi = 10.1101/gad.959202 }}{{cite journal | vauthors = Derbyshire DJ, Basu BP, Date T, Iwabuchi K, Doherty AJ | title = Purification, crystallization and preliminary X-ray analysis of the BRCT domains of human 53BP1 bound to the p53 tumour suppressor | journal = Acta Crystallographica D | volume = 58 | issue = Pt 10 Pt 2 | pages = 1826–9 | date = October 2002 | pmid = 12351827 | doi = 10.1107/S0907444902010910 | bibcode = 2002AcCrD..58.1826D }} [235] => * [[TP53BP2]],{{cite journal | vauthors = Iwabuchi K, Bartel PL, Li B, Marraccino R, Fields S | title = Two cellular proteins that bind to wild-type but not mutant p53 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 13 | pages = 6098–102 | date = June 1994 | pmid = 8016121 | pmc = 44145 | doi = 10.1073/pnas.91.13.6098 | bibcode = 1994PNAS...91.6098I | doi-access = free }}{{cite journal | vauthors = Naumovski L, Cleary ML | title = The p53-binding protein 53BP2 also interacts with Bc12 and impedes cell cycle progression at G2/M | journal = Molecular and Cellular Biology | volume = 16 | issue = 7 | pages = 3884–92 | date = July 1996 | pmid = 8668206 | pmc = 231385 | doi = 10.1128/MCB.16.7.3884}} [236] => * [[TOP2B]],{{cite journal | vauthors = Cowell IG, Okorokov AL, Cutts SA, Padget K, Bell M, Milner J, Austin CA | title = Human topoisomerase IIalpha and IIbeta interact with the C-terminal region of p53 | journal = Experimental Cell Research | volume = 255 | issue = 1 | pages = 86–94 | date = February 2000 | pmid = 10666337 | doi = 10.1006/excr.1999.4772 }} [237] => * [[TP53INP1]],{{cite journal | vauthors = Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B, Soddu S, Malissen B, Dagorn JC, Iovanna JL, Dusetti NJ | title = TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 39 | pages = 37722–9 | date = September 2003 | pmid = 12851404 | doi = 10.1074/jbc.M301979200 | doi-access = free }}{{cite journal | vauthors = Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M, Nakamura Y | title = p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis | journal = Molecular Cell | volume = 8 | issue = 1 | pages = 85–94 | date = July 2001 | pmid = 11511362 | doi = 10.1016/S1097-2765(01)00284-2 | doi-access = free }} [238] => * [[TSG101]],{{cite journal | vauthors = Li L, Liao J, Ruland J, Mak TW, Cohen SN | title = A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 4 | pages = 1619–24 | date = February 2001 | pmid = 11172000 | pmc = 29306 | doi = 10.1073/pnas.98.4.1619 | bibcode = 2001PNAS...98.1619L | doi-access = free }} [239] => * [[UBE2A]],{{cite journal | vauthors = Lyakhovich A, Shekhar MP | title = Supramolecular complex formation between Rad6 and proteins of the p53 pathway during DNA damage-induced response | journal = Molecular and Cellular Biology | volume = 23 | issue = 7 | pages = 2463–75 | date = April 2003 | pmid = 12640129 | pmc = 150718 | doi = 10.1128/MCB.23.7.2463-2475.2003 }} [240] => * [[UBE2I]],{{cite journal | vauthors = Shen Z, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJ | title = Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system | journal = Genomics | volume = 37 | issue = 2 | pages = 183–6 | date = October 1996 | pmid = 8921390 | doi = 10.1006/geno.1996.0540 | url = https://zenodo.org/record/1229705 }}{{cite journal | vauthors = Bernier-Villamor V, Sampson DA, Matunis MJ, Lima CD | title = Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1 | journal = Cell | volume = 108 | issue = 3 | pages = 345–56 | date = February 2002 | pmid = 11853669 | doi = 10.1016/S0092-8674(02)00630-X | doi-access = free }} [241] => * [[Ubiquitin C|UBC]],{{cite journal | vauthors = Sehat B, Andersson S, Girnita L, Larsson O | title = Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis | journal = Cancer Research | volume = 68 | issue = 14 | pages = 5669–77 | date = July 2008 | pmid = 18632619 | doi = 10.1158/0008-5472.CAN-07-6364 | doi-access = }}{{cite journal | vauthors = Song MS, Song SJ, Kim SY, Oh HJ, Lim DS | title = The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex | journal = The EMBO Journal | volume = 27 | issue = 13 | pages = 1863–74 | date = July 2008 | pmid = 18566590 | pmc = 2486425 | doi = 10.1038/emboj.2008.115 }}{{cite journal | vauthors = Yang W, Dicker DT, Chen J, El-Deiry WS | title = CARPs enhance p53 turnover by degrading 14-3-3sigma and stabilizing MDM2 | journal = Cell Cycle | volume = 7 | issue = 5 | pages = 670–82 | date = March 2008 | pmid = 18382127 | doi = 10.4161/cc.7.5.5701 | doi-access = free }}{{cite journal | vauthors = Abe Y, Oda-Sato E, Tobiume K, Kawauchi K, Taya Y, Okamoto K, Oren M, Tanaka N | title = Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 12 | pages = 4838–43 | date = March 2008 | pmid = 18359851 | pmc = 2290789 | doi = 10.1073/pnas.0712216105 | bibcode = 2008PNAS..105.4838A | doi-access = free }}{{cite journal | vauthors = Dohmesen C, Koeppel M, Dobbelstein M | title = Specific inhibition of Mdm2-mediated neddylation by Tip60 | journal = Cell Cycle | volume = 7 | issue = 2 | pages = 222–31 | date = January 2008 | pmid = 18264029 | doi = 10.4161/cc.7.2.5185 | s2cid = 8023403 | doi-access = }} [242] => * [[USP7]],{{cite journal | vauthors = Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W | title = Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization | journal = Nature | volume = 416 | issue = 6881 | pages = 648–53 | date = April 2002 | pmid = 11923872 | doi = 10.1038/nature737 | bibcode = 2002Natur.416..648L | s2cid = 4389394 }} [243] => * [[USP10]],{{cite journal | vauthors = Yuan J, Luo K, Zhang L, Cheville JC, Lou Z| title = USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 | journal = Cell | volume = 140 | issue = 3 | pages = 384–396 | date = February 2010 | pmid = 20096447 | doi = 10.1016/j.cell.2009.12.032 | pmc = 2820153 | doi-access = free }} [244] => * [[Werner syndrome ATP-dependent helicase|WRN]],{{cite journal | vauthors = Yang Q, Zhang R, Wang XW, Spillare EA, Linke SP, Subramanian D, Griffith JD, Li JL, Hickson ID, Shen JC, Loeb LA, Mazur SJ, Appella E, Brosh RM, Karmakar P, Bohr VA, Harris CC | title = The processing of Holliday junctions by BLM and WRN helicases is regulated by p53 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 35 | pages = 31980–7 | date = August 2002 | pmid = 12080066 | doi = 10.1074/jbc.M204111200 | doi-access = free | hdl = 10026.1/10341 | hdl-access = free }}{{cite journal | vauthors = Brosh RM, Karmakar P, Sommers JA, Yang Q, Wang XW, Spillare EA, Harris CC, Bohr VA | title = p53 Modulates the exonuclease activity of Werner syndrome protein | journal = The Journal of Biological Chemistry | volume = 276 | issue = 37 | pages = 35093–102 | date = September 2001 | pmid = 11427532 | doi = 10.1074/jbc.M103332200 | doi-access = free }} [245] => * [[WWOX]],{{cite journal | vauthors = Chang NS, Pratt N, Heath J, Schultz L, Sleve D, Carey GB, Zevotek N | title = Hyaluronidase induction of a WW domain-containing oxidoreductase that enhances tumor necrosis factor cytotoxicity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 5 | pages = 3361–70 | date = February 2001 | pmid = 11058590 | doi = 10.1074/jbc.M007140200 | doi-access = free }} [246] => * [[XPB]], [247] => * [[Y box binding protein 1|YBX1]],{{cite journal | vauthors = Kojic S, Medeot E, Guccione E, Krmac H, Zara I, Martinelli V, Valle G, Faulkner G | title = The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle | journal = Journal of Molecular Biology | volume = 339 | issue = 2 | pages = 313–25 | date = May 2004 | pmid = 15136035 | doi = 10.1016/j.jmb.2004.03.071 }}{{cite journal | vauthors = Okamoto T, Izumi H, Imamura T, Takano H, Ise T, Uchiumi T, Kuwano M, Kohno K | title = Direct interaction of p53 with the Y-box binding protein, YB-1: a mechanism for regulation of human gene expression | journal = Oncogene | volume = 19 | issue = 54 | pages = 6194–202 | date = December 2000 | pmid = 11175333 | doi = 10.1038/sj.onc.1204029 | s2cid = 19222684 | doi-access = }} [248] => * [[YPEL3]],{{cite journal | vauthors = Kelley KD, Miller KR, Todd A, Kelley AR, Tuttle R, Berberich SJ | title = YPEL3, a p53-regulated gene that induces cellular senescence | journal = Cancer Research | volume = 70 | issue = 9 | pages = 3566–75 | date = May 2010 | pmid = 20388804 | pmc = 2862112 | doi = 10.1158/0008-5472.CAN-09-3219 }} [249] => * [[YWHAZ]],{{cite journal | vauthors = Waterman MJ, Stavridi ES, Waterman JL, Halazonetis TD | title = ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins | journal = Nature Genetics | volume = 19 | issue = 2 | pages = 175–8 | date = June 1998 | pmid = 9620776 | doi = 10.1038/542 | s2cid = 26600934 }} [250] => * [[Zif268]],{{cite journal | vauthors = Liu J, Grogan L, Nau MM, Allegra CJ, Chu E, Wright JJ | title = Physical interaction between p53 and primary response gene Egr-1 | journal = International Journal of Oncology | volume = 18 | issue = 4 | pages = 863–70 | date = April 2001 | pmid = 11251186 | doi = 10.3892/ijo.18.4.863 }} [251] => * [[ZNF148]],{{cite journal | vauthors = Bai L, Merchant JL | title = ZBP-89 promotes growth arrest through stabilization of p53 | journal = Molecular and Cellular Biology | volume = 21 | issue = 14 | pages = 4670–83 | date = July 2001 | pmid = 11416144 | pmc = 87140 | doi = 10.1128/MCB.21.14.4670-4683.2001 }} [252] => * [[SIRT1]],{{cite journal | vauthors = Yamakuchi M, Lowenstein CJ | title = MiR-34, SIRT1 and p53: the feedback loop | journal = Cell Cycle | volume = 8 | issue = 5 | pages = 712–5 | date = March 2009 | pmid = 19221490 | doi = 10.4161/cc.8.5.7753 | doi-access = free }} [253] => * circRNA_014511.{{cite journal | vauthors = Wang Y, Zhang J, Li J, Gui R, Nie X, Huang R | title = CircRNA_014511 affects the radiosensitivity of bone marrow mesenchymal stem cells by binding to miR-29b-2-5p | journal = Bosnian Journal of Basic Medical Sciences | volume = 19 | issue = 2 | pages = 155–163 | date = May 2019 | pmid = 30640591 | pmc = 6535393 | doi = 10.17305/bjbms.2019.3935 }} [254] => {{div col end}} [255] => [256] => ==See also== [257] => * [[Pifithrin]], an inhibitor of P53 [258] => [259] => == Notes == [260] => {{reflist|group=note}} [261] => [262] => == References == [263] => {{reflist}} [264] => [265] => == External links == [266] => {{Commons category|Tumor suppressor protein p53}} [267] => * {{cite web|url=http://p53.bii.a-star.edu.sg/|title=p53 Knowledgebase|access-date=2008-04-06 | publisher=Lane Group at the Institute of Molecular and Cell Biology (IMCB), Singapore| archive-url=https://web.archive.org/web/20060103170051/http://p53.bii.a-star.edu.sg/| archive-date=2006-01-03|url-status=dead}} [268] => * [https://www.ncbi.nlm.nih.gov/books/NBK1311/ GeneReviews/NCBI/NIH/UW entry on Li-Fraumeni Syndrome] [269] => * [https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 TUMOR PROTEIN p53] @ [[OMIM]] [270] => * [http://www.news-medical.net/news/20130708/p53-restoration-of-function-drug-candidate-an-interview-with-Dr-Wayne-Danter-MD-FRCPC-President-and-CEO-of-Critical-Outcome-Technologies.aspx p53 restoration of function] [271] => * [http://atlasgeneticsoncology.org/Genes/P53ID88.html p53] @ The Atlas of Genetics and Cytogenetics in Oncology and Haematology [272] => * [https://www.genecards.org/cgi-bin/carddisp.pl?gene=tp53 TP53 Gene] @ GeneCards [273] => * [https://web.archive.org/web/20101124135159/http://insciences.org/articles.php?tag=p53 p53 News] provided by insciences organisation [274] => * {{cite web|url=http://pdb101.rcsb.org/motm/31|title= p53 Tumor Suppressor|access-date=2008-04-06| vauthors = Goodsel DS |date=2002-07-01| work=Molecule of the Month|publisher=RCSB Protein Data Bank}} [275] => * {{cite web|url=http://p53.free.fr/|title=p53 Web Site|access-date=2008-04-06| vauthors = Soussi T }} [276] => * [https://livinglfs.org/ Living LFS] A non-profit Li-Fraumeni Syndrome patient support organization [277] => * [http://www.tp53.co.uk/ The George Pantziarka TP53 Trust] A support group from the UK for people with Li-Fraumeni Syndrome or other TP53-related disorders [278] => * [http://www-p53.iarc.fr/ IARC TP53 Somatic Mutations database] maintained at IARC, Lyon, by Magali Olivier [279] => * [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P04637 PDBe-KB] provides an overview of all the structure information available in the PDB for Human P53. [280] => * [https://www.youtube.com/watch?v=gY1p-xdHbQg|title= scientific animation] conformational changes of p53 upon binding to DNA [281] => [282] => {{PDB Gallery|geneid=7157}} [283] => {{Transcription factors|g4}} [284] => {{Tumor suppressor genes and oncogenes}} [285] => {{Cell cycle proteins}} [286] => [287] => [[Category:Programmed cell death]] [288] => [[Category:Proteins]] [289] => [[Category:Transcription factors]] [290] => [[Category:Tumor suppressor genes]] [291] => [[Category:Apoptosis]] [292] => [[Category:Genes mutated in mice]] [293] => [[Category:Aging-related proteins]] [] => )
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P53

P53 is a protein that plays a crucial role in the regulation of cell division and the prevention of tumor formation. It is encoded by the TP53 gene, located on chromosome 17 in humans.

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It is encoded by the TP53 gene, located on chromosome 17 in humans. P53 is a transcription factor and acts as a tumor suppressor by activating or repressing the expression of various target genes involved in cell-cycle arrest, DNA repair, apoptosis, and senescence. Mutations in the TP53 gene are found in a wide range of cancers, making it one of the most frequently mutated genes in human malignancies. These mutations can lead to a loss or reduction of P53 function, allowing damaged cells to continue dividing and potentially develop into tumors. In addition to mutations, certain viral proteins can also interfere with P53 function and promote tumor growth. P53 is regulated by a complex network of regulatory pathways, including post-translational modifications, protein-protein interactions, and regulatory proteins. Its activity is tightly controlled, and activation occurs in response to various types of cellular stress, such as DNA damage, hypoxia, and oncogene activation. Research on P53 has provided valuable insights into how cancer develops and progresses. Experimental models and studies on patients with TP53 mutations have shown that loss of P53 function not only promotes tumor growth but also affects treatment response and patient prognosis. As a result, P53 has become an important target for cancer therapies, and various strategies are being developed to reactivate or stabilize its function. Overall, the Wikipedia page on P53 provides comprehensive information about the protein's structure, function, regulation, and role in cancer. It covers the historical context, research findings, and clinical implications of P53, making it a valuable resource for scientists, clinicians, and anyone interested in understanding the molecular basis of cancer.

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