Editing P53 (section)

== Role in disease ==
[[File:Signal transduction pathways.svg|300px|thumb|right|Overview of signal transduction pathways involved in [[apoptosis]]]]
[[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]].]]
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]]. {{cn|date=November 2024}}

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.<ref name="pmid1905840">{{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 }}</ref> Loss of p53 creates genomic instability that most often results in an [[aneuploidy]] phenotype.<ref>{{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 }}</ref>

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.<ref name="pmid11780111">{{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 }}</ref> 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.<ref name="pmid17251932">{{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 }}</ref><ref name="pmid24154492">{{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 }}</ref> 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]].<ref name="Gend">{{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 }}</ref>

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.<ref name="pmid18086422">{{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 }}</ref>

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 <ref name="Ribeiro_2007">{{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 }}</ref>). 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.<ref name="Bullock_1997">{{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 }}</ref>

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[[File:Patterns of p53 expression.png|right|340px]]
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:<ref>{{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}}</ref>
* '''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.
* '''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.
* '''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.
* '''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.
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[[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.<ref>Image is taken from following source, with some modification by Mikael Häggström, MD:<br>- {{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 }} </ref><ref>Source for role in distinguishing PUNLMP from low-grade carcinoma:<br>- {{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  }} </ref>]]
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]].<ref name="pmid25786345">{{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...5.9330M }}</ref>

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.<ref>{{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 }}</ref><ref>{{Cite news |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}}</ref>