View source for TP63

{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox_gene}}
'''Tumor protein p63,''' typically referred to as '''p63''', also known as '''transformation-related protein 63''', is a [[protein]] that in humans is encoded by the '''''TP63''''' (also known as the ''''' p63''''') [[gene]].<ref name="pmid9774969">{{cite journal | vauthors = Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, Andrews NC, Caput D, McKeon F | title = p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities | journal = Molecular Cell | volume = 2 | issue = 3 | pages = 305–16 | date = September 1998 | pmid = 9774969 | doi = 10.1016/S1097-2765(00)80275-0 | doi-access = free }}</ref><ref name="pmid9662378">{{cite journal | vauthors = Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, Ikawa Y, Nimura Y, Nakagawara A, Obinata M, Ikawa S | title = Cloning and functional analysis of human p51, which structurally and functionally resembles p53 | journal = Nature Medicine | volume = 4 | issue = 7 | pages = 839–43 | date = July 1998 | pmid = 9662378 | doi = 10.1038/nm0798-839 | s2cid = 21953916 }}</ref><ref name="pmid11181441">{{cite journal | vauthors = Zeng X, Zhu Y, Lu H | title = NBP is the p53 homolog p63 | journal = Carcinogenesis | volume = 22 | issue = 2 | pages = 215–9 | date = February 2001 | pmid = 11181441 | doi = 10.1093/carcin/22.2.215 | doi-access = free }}</ref><ref name="pmid11181451">{{cite journal | vauthors = Tan M, Bian J, Guan K, Sun Y | title = p53CP is p51/p63, the third member of the p53 gene family: partial purification and characterization | journal = Carcinogenesis | volume = 22 | issue = 2 | pages = 295–300 | date = February 2001 | pmid = 11181451 | doi = 10.1093/carcin/22.2.295 | doi-access = free }}</ref>

The ''TP63'' gene was discovered 20 years after the discovery of the ''[[p53]]'' tumor suppressor gene and along with ''[[p73]]'' constitutes the ''p53'' gene family based on their structural similarity.<ref name="pmid12750249">{{cite journal | vauthors = Wu G, Nomoto S, Hoque MO, Dracheva T, Osada M, Lee CC, Dong SM, Guo Z, Benoit N, Cohen Y, Rechthand P, Califano J, Moon CS, Ratovitski E, Jen J, Sidransky D, Trink B | title = DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development | journal = Cancer Research | volume = 63 | issue = 10 | pages = 2351–7 | date = May 2003 | pmid = 12750249 }}</ref>  Despite being discovered significantly later than ''p53'', phylogenetic analysis of ''p53'', ''p63'' and ''p73'', suggest that ''p63'' was the original member of the family from which ''p53'' and ''p73'' evolved.<ref name="Skipper_2007">{{cite journal | vauthors = Skipper M | title = Dedicated protection for the female germline | journal=Nature Reviews Molecular Cell Biology |date=January 2007 | volume = 8 | pages = 4–5 | doi = 10.1038/nrm2091 | issue=1| s2cid = 10702219 }}</ref>

== Function ==
Tumor protein p63 is a member of the p53 family of [[transcription factor]]s. p63 -/- mice have several developmental defects which include the lack of limbs and other tissues, such as teeth and mammary glands, which develop as a result of interactions between [[mesenchyme]] and [[epithelium]]. TP63 encodes for two main isoforms by alternative promoters (TAp63 and ΔNp63). ΔNp63 is involved in multiple functions during skin development and in adult stem/progenitor cell regulation.<ref name="pmid20078223">{{cite journal | vauthors = Crum CP, McKeon FD | title = p63 in epithelial survival, germ cell surveillance, and neoplasia | journal = Annual Review of Pathology | volume = 5 | pages = 349–71 | year = 2010 | pmid = 20078223 | doi = 10.1146/annurev-pathol-121808-102117 }}</ref> In contrast, TAp63 has been mostly restricted to its apoptotic function and more recently as the guardian of oocyte integrity.<ref name="pmid21335238">{{cite journal | vauthors = Deutsch GB, Zielonka EM, Coutandin D, Weber TA, Schäfer B, Hannewald J, Luh LM, Durst FG, Ibrahim M, Hoffmann J, Niesen FH, Sentürk A, Kunkel H, Brutschy B, Schleiff E, Knapp S, Acker-Palmer A, Grez M, McKeon F, Dötsch V | title = DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer | journal = Cell | volume = 144 | issue = 4 | pages = 566–76 | date = February 2011 | pmid = 21335238 | pmc = 3087504 | doi = 10.1016/j.cell.2011.01.013 }}</ref> Recently, two new functions have been attributed to TAp63 in heart development<ref name="pmid21898690">{{cite journal | vauthors = Rouleau M, Medawar A, Hamon L, Shivtiel S, Wolchinsky Z, Zhou H, De Rosa L, Candi E, de la Forest Divonne S, Mikkola ML, van Bokhoven H, Missero C, Melino G, Pucéat M, Aberdam D | title = TAp63 is important for cardiac differentiation of embryonic stem cells and heart development | journal = Stem Cells | volume = 29 | issue = 11 | pages = 1672–83 | date = November 2011 | pmid = 21898690 | doi = 10.1002/stem.723 | s2cid = 40628077 | url = http://minus.com/lNWTY9g2q5yYG | url-status = dead | archive-url = https://web.archive.org/web/20140808060204/http://minus.com/lNWTY9g2q5yYG | archive-date = 2014-08-08 | hdl = 2066/97162 | hdl-access = free }}</ref> and premature aging.<ref name="pmid19570515">{{cite journal | vauthors = Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER | title = TAp63 prevents premature aging by promoting adult stem cell maintenance | journal = Cell Stem Cell | volume = 5 | issue = 1 | pages = 64–75 | date = July 2009 | pmid = 19570515 | pmc = 3418222 | doi = 10.1016/j.stem.2009.04.003 }}</ref>

In mice, p63 is required for normal skin development via direct transcription of the membrane protein [[PERP]].  TP63 can also regulate PERP expression with TP53 in human [[cancer]].<ref name="pmid32679166">{{cite journal | vauthors = Roberts O, Paraoan L | title = PERP-ing into diverse mechanisms of cancer pathogenesis: Regulation and role of the p53/p63 effector PERP | journal =  Biochim Biophys Acta Rev Cancer | volume = 1874 | issue = 1 |date=Dec 2020 | page = 188393 | pmid = 32679166 | doi = 10.1016/j.bbcan.2020.188393| s2cid = 220631324 }}</ref>

===Oocyte integrity===

In [[oocyte]]s, a unique quality control system has evolved that eliminates by [[apoptosis]] those oocytes in which [[chromosome]]s do not align correctly, or in which chromosomes cannot be repaired.<ref name = Gebel2020>{{cite journal |vauthors=Gebel J, Tuppi M, Sänger N, Schumacher B, Dötsch V |title=DNA Damaged Induced Cell Death in Oocytes |journal=Molecules |volume=25 |issue=23 |pages= |date=December 2020 |pmid=33287328 |pmc=7730327 |doi=10.3390/molecules25235714 |doi-access=free}}</ref>  This monitoring system is conserved from [[Drosophilidae|fruit flies]] and [[nematode]]s to humans, and central to this system is the [[p53]] protein family and, in [[vertebrate]]s in particular, the p63 protein.<ref name = Gebel2020/>   Oocytes that are unable to repair [[DNA damage (naturally occurring)|DNA double-strand breaks]] produced during [[meiosis]] by the process of [[homologous recombination]] are eliminated by apoptosis that is linked to p63.<ref name = Gebel2020/>

== Clinical significance ==

At least 42 disease-causing mutations in this gene have been discovered.<ref name = "Šimčíková_2019 - supplementary table S7">{{cite journal | vauthors = Šimčíková D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4| bibcode = 2019NatSR...918577S }}</ref> ''TP63'' mutations underlie several malformation syndromes that include cleft lip and/or palate as a hallmark feature.<ref name="Dixon_2011"/> Mutations in the ''TP63'' gene are associated with [[ectrodactyly-ectodermal dysplasia-cleft syndrome]] in which a midline cleft lip is a common feature,<ref name="Dixon_2011">{{cite journal | vauthors = Dixon MJ, Marazita ML, Beaty TH, Murray JC | title = Cleft lip and palate: understanding genetic and environmental influences | journal = Nature Reviews. Genetics | volume = 12 | issue = 3 | pages = 167–78 | date = March 2011 | pmid = 21331089 | pmc = 3086810 | doi = 10.1038/nrg2933 }}</ref> [[cleft lip/palate syndrome 3]] (EEC3); [[ectrodactyly]] (also known as split-hand/foot malformation 4 (SHFM4)); ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) or [[Hay–Wells syndrome]] in which a midline cleft lip is also a common feature,<ref name="Dixon_2011" /> [[Acro–dermato–ungual–lacrimal–tooth syndrome]] (ADULT); [[limb-mammary syndrome]]; [[Rap-Hodgkin syndrome]] (RHS); and [[orofacial cleft]] 8. 

[[File:P63 staining on prostate cancer tissue using antibody clone IHC063.jpg|thumb|p63 staining on prostate cancer tissue using antibody clone IHC063]]

Both cleft lip with or without a cleft palate and cleft palate only features have been seen to segregate within the same family with a ''TP63'' mutation.<ref name="Dixon_2011" /> Recently, induced pluripotent stem cells have been produced from patients affected by EEC syndromes by cell reprogramming. The defective epithelial commitment could be partially rescued by a small therapeutic compound.<ref name="pmid23355677">{{cite journal | vauthors = Shalom-Feuerstein R, Serror L, Aberdam E, Müller FJ, van Bokhoven H, Wiman KG, Zhou H, Aberdam D, Petit I | title = Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 6 | pages = 2152–6 | date = February 2013 | pmid = 23355677 | pmc = 3568301 | doi = 10.1073/pnas.1201753109 | bibcode = 2013PNAS..110.2152S | doi-access = free }}</ref> 

== Molecular mechanism ==
Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. In a recent study, researchers used EEC-patient-derived skin keratinocytes carrying heterozygous p63 DNA-binding domain mutations as the cellular model to characterize the global gene regulatory alteration. The epidermal cell identity was compromised in p63 mutant keratinocytes. Besides, p63-binding loss and loss of active enhancers occurs at a genome-wide scale in patient keratinocytes carrying heterozygous EEC mutations. <ref name="PMID30566872">{{cite journal | vauthors = Qu J, Tanis SE, Smits JP, Kouwenhoven EN, Oti M, van den Bogaard EH, Logie C, Stunnenberg HG, van Bokhoven H, Mulder KW, Zhou H | title = Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape | journal = Cell Reports | volume = 25 | issue = 12 | pages = 3490–503 | date = December 2018 | pmid = 30566872 | doi = 10.1016/j.celrep.2018.11.039 | doi-access = free | hdl = 2066/200262 | hdl-access = free }}</ref> Besides, using a multi-omics approach, the deregulated function of DNA loops mediated by p63 and CTCF represents an additional layer to the disease mechanism. It seems that a number of loci nearby epidermal genes were organized into a ‘regulatory chromatin hub’ within the chromatin interactions, mediated by CTCF in epidermal keratinocytes. Such hubs contain multiple connecting DNA loops that require not only CTCF binding that is rather static but also binding of cell type-specific TFs, like p63, for the transcriptional activity. In this model, p63 may be essential to make the DNA loops active in transcription. <ref name="PMID31164150">{{cite journal | vauthors = Qu J, Yi G, Zhou H | title = p63 cooperates with CTCF to modulate chromatin architecture in skin keratinocytes | journal = Epigenetics & Chromatin | date = June 2019 | volume = 12 | issue = 1 | page = 31 | pmid= 31164150 | doi = 10.1186/s13072-019-0280-y | pmc = 6547520 | doi-access = free }}</ref>

=== Vulvar cancer ===
TP63 has been observed overexpressed in [[Vulvar cancer|Vulvar Squamous Cell Carcinoma]] samples, in association with hypermethylation-Induced inactivation of the [[IRF6]] tumor suppressor gene. <ref name = "Rotondo_2016">{{cite journal | vauthors = Rotondo JC, Borghi A, Selvatici R, Magri E, Bianchini E, Montinari E, Corazza M, Virgili A, Tognon M, Martini F | title = Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus | journal = JAMA Dermatology | volume = 152 | issue = 8 | pages = 928–33 | date = August 2016 | pmid = 27223861 | doi = 10.1001/jamadermatol.2016.1336 }}</ref> Indeed, mRNA levels of TP63 tested higher in [[Vulvar cancer]] samples when compared with those of normal skin and preneoplastic vulvar lesions, thus underscoring an epigenetic cross-link between [[IRF6]] gene and the oncogene TP63. <ref name = "Rotondo_2016" />

== Diagnostic utility ==
[[File:Main staining patterns on immunohistochemistry.jpg|thumb|230px|Main staining patterns on chromogenic immunohistochemistry.]]
p63 [[immunostaining]] has utility for head and neck squamous cell carcinomas, differentiating prostatic [[adenocarcinoma]] (the most common type of [[prostate cancer]]) and benign [[prostate|prostatic]] tissue;<ref>{{cite journal | vauthors = Shiran MS, Tan GC, Sabariah AR, Rampal L, Phang KS | title = p63 as a complementary basal cell specific marker to high molecular weight-cytokeratin in distinguishing prostatic carcinoma from benign prostatic lesions | journal = The Medical Journal of Malaysia | volume = 62 | issue = 1 | pages = 36–9 | date = March 2007 | pmid = 17682568 }}</ref> the [[cell nucleus|nuclei]] of the basal cells of normal prostatic glands stain with p63, while the [[malignant]] glands in prostatic adenocarcinoma (which lacks these cells) do not.<ref>{{cite journal | vauthors = Herawi M, Epstein JI | title = Immunohistochemical antibody cocktail staining (p63/HMWCK/AMACR) of ductal adenocarcinoma and Gleason pattern 4 cribriform and noncribriform acinar adenocarcinomas of the prostate | journal = The American Journal of Surgical Pathology | volume = 31 | issue = 6 | pages = 889–94 | date = June 2007 | pmid = 17527076 | doi = 10.1097/01.pas.0000213447.16526.7f | s2cid = 9054387 }}</ref>
P63 is also helpful in distinguishing poorly differentiated squamous cell carcinoma from small cell carcinoma or adenocarcinoma. P63 should be strongly stained in poorly differentiated squamous cell, but negative in small cell or adenocarcinoma.<ref name="pmid15309021">{{cite journal | vauthors = Zhang H, Liu J, Cagle PT, Allen TC, Laga AC, Zander DS | title = Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach | journal = Modern Pathology | volume = 18 | issue = 1 | pages = 111–8 | date = January 2005 | pmid = 15309021 | doi = 10.1038/modpathol.3800251 | doi-access = free }}</ref>

Cytoplasmic staining on immunohistochemistry is seen in cells with muscle differentiation.<ref name="pmid21623385">{{cite journal | vauthors = Martin SE, Temm CJ, Goheen MP, Ulbright TM, Hattab EM | title = Cytoplasmic p63 immunohistochemistry is a useful marker for muscle differentiation: an immunohistochemical and immunoelectron microscopic study | journal = Modern Pathology | volume = 24 | issue = 10 | pages = 1320–1326 | date = October 2011 | pmid = 21623385 | pmc =  | doi = 10.1038/modpathol.2011.89 | doi-access = free }} </ref>

== Interactions ==
TP63 has been shown to [[Protein-protein interaction|interact]] with [[HNRPAB]].<ref name="pmid12692135">{{cite journal | vauthors = Fomenkov A, Huang YP, Topaloglu O, Brechman A, Osada M, Fomenkova T, Yuriditsky E, Trink B, Sidransky D, Ratovitski E | title = P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome | journal = The Journal of Biological Chemistry | volume = 278 | issue = 26 | pages = 23906–14 | date = June 2003 | pmid = 12692135 | doi = 10.1074/jbc.M300746200 | doi-access = free }}</ref>
It also activates [[IRF6]] transcription through the IRF6 enhancer element.<ref name="Dixon_2011"/>

==Regulation==

There is some evidence that the expression of p63 is regulated by the microRNA [[Mir-203 microRNA|miR-203]]<ref name="pmid18311128">{{cite journal | vauthors = Yi R, Poy MN, Stoffel M, Fuchs E | title = A skin microRNA promotes differentiation by repressing 'stemness' | journal = Nature | volume = 452 | issue = 7184 | pages = 225–9 | date = March 2008 | pmid = 18311128 | pmc = 4346711 | doi = 10.1038/nature06642 | bibcode = 2008Natur.452..225Y }}</ref><ref name="pmid18848452">{{cite journal | vauthors = Aberdam D, Candi E, Knight RA, Melino G | title = miRNAs, 'stemness' and skin | journal = Trends in Biochemical Sciences | volume = 33 | issue = 12 | pages = 583–91 | date = December 2008 | pmid = 18848452 | doi = 10.1016/j.tibs.2008.09.002 | url = http://min.us/lGvvAc29SY8ux | url-status = dead | archive-url = https://archive.today/20130421181244/http://min.us/lGvvAc29SY8ux | archive-date = 2013-04-21 | url-access = subscription | hdl = 2381/4113 | hdl-access = free }}</ref> and [[USP28]] at protein level <ref>{{Cite journal| vauthors = Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, Fischer A, Calzado MA, Orian A, Rosenfeldt M, Eilers M |date=Jun 2019 |title=The USP28-∆Np63 axis is a vulnerability of squamous tumours |url=https://www.biorxiv.org/content/10.1101/683508v1|journal=bioRxiv|language=en|pages=683508|doi=10.1101/683508 |s2cid=198263967 |doi-access=free }}</ref><ref name="PMID32128997">{{cite journal | vauthors = Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, Schülein-Völk C, Eilers U, Ade CP, Calzado MA, Orian A, Maric HM, Münch C, Rosenfeldt M, Eilers M, Diefenbacher ME | title = Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells | journal = EMBO Molecular Medicine | pages = e11101 | date = March 2020 | volume = 12 | issue = 4 | pmid = 32128997 | doi = 10.15252/emmm.201911101 | pmc = 7136964 | doi-access = free }}</ref>

== See also ==
*[[AMACR]] - another marker for prostate adenocarcinoma
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== References ==
{{reflist|2}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Little NA, Jochemsen AG | title = p63 | journal = The International Journal of Biochemistry & Cell Biology | volume = 34 | issue = 1 | pages = 6–9 | date = January 2002 | pmid = 11733180 | doi = 10.1016/S1357-2725(01)00086-3 }}
* {{cite journal | vauthors = van Bokhoven H, McKeon F | title = Mutations in the p53 homolog p63: allele-specific developmental syndromes in humans | journal = Trends in Molecular Medicine | volume = 8 | issue = 3 | pages = 133–9 | date = March 2002 | pmid = 11879774 | doi = 10.1016/S1471-4914(01)02260-2 }}
* {{cite journal | vauthors = van Bokhoven H, Brunner HG | title = Splitting p63 | journal = American Journal of Human Genetics | volume = 71 | issue = 1 | pages = 1–13 | date = July 2002 | pmid = 12037717 | pmc = 384966 | doi = 10.1086/341450 }}
* {{cite journal | vauthors = Brunner HG, Hamel BC, van Bokhoven H | title = P63 gene mutations and human developmental syndromes | journal = American Journal of Medical Genetics | volume = 112 | issue = 3 | pages = 284–90 | date = October 2002 | pmid = 12357472 | doi = 10.1002/ajmg.10778 }}
* {{cite journal | vauthors = Jacobs WB, Walsh GS, Miller FD | title = Neuronal survival and p73/p63/p53: a family affair | journal = The Neuroscientist | volume = 10 | issue = 5 | pages = 443–55 | date = October 2004 | pmid = 15359011 | doi = 10.1177/1073858404263456 | s2cid = 39702742 }}
* {{cite journal | vauthors = Zusman I | title = The soluble p51 protein in cancer diagnosis, prevention and therapy | journal = In Vivo | volume = 19 | issue = 3 | pages = 591–8 | year = 2005 | pmid = 15875781 }}
* {{cite journal | vauthors = Morasso MI, Radoja N | title = Dlx genes, p63, and ectodermal dysplasias | journal = Birth Defects Research. Part C, Embryo Today | volume = 75 | issue = 3 | pages = 163–71 | date = September 2005 | pmid = 16187309 | pmc = 1317295 | doi = 10.1002/bdrc.20047 }}
* {{cite journal | vauthors = Barbieri CE, Pietenpol JA | title = p63 and epithelial biology | journal = Experimental Cell Research | volume = 312 | issue = 6 | pages = 695–706 | date = April 2006 | pmid = 16406339 | doi = 10.1016/j.yexcr.2005.11.028 }}
* {{cite journal | vauthors = Shalom-Feuerstein R, Lena AM, Zhou H, De La Forest Divonne S, Van Bokhoven H, Candi E, Melino G, Aberdam D | title = ΔNp63 is an ectodermal gatekeeper of epidermal morphogenesis | journal = Cell Death and Differentiation | volume = 18 | issue = 5 | pages = 887–96 | date = May 2011 | pmid = 21127502 | pmc = 3131930 | doi = 10.1038/cdd.2010.159 }}
{{refend}}

== External links ==
* {{MeshName|TP73L+protein,+human}}
* [https://www.ncbi.nlm.nih.gov/books/NBK43797/  GeneReviews/NCBI/NIH/UW entry on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome or AEC Syndrome, Hay-Wells Syndrome. Includes: Rapp–Hodgkin Syndrome]
* [https://www.ncbi.nlm.nih.gov/omim/106260,603273,106260,603273 OMIM entries on AEC]
* {{UCSC genome browser|TP63}}
* {{UCSC gene details|TP63}}

{{PDB Gallery|geneid=8626}}
{{Tumor suppressor genes}}
{{Transcription factors and intracellular receptors|g4}}
{{Cell cycle proteins}}