TP63

From Quire, the open reference·Protein-coding gene in the species Homo sapiens·5 min read

TP63
Identifiers
Image: source and license
Aliases	TP63, AIS, B(p51A), B(p51B), EEC3, KET, LMS, NBP, OFC8, RHS, SHFM4, TP53CP, TP53L, TP73L, p40, p51, p53CP, p63, p73H, p73L, tumor protein p63
External IDs	OMIM: 603273; MGI: 1330810; GeneCards: TP63
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4A9Z, 1RG6, 2RMN, 2Y9T, 2Y9U, 3QYM, 3QYN, 3US0, 3US1, 3US2, 3ZY0, 3ZY1
Gene ontology Molecular function DNA-binding transcription activator activity, RNA polymerase II-specific metal ion binding damaged DNA binding protein binding WW domain binding double-stranded DNA binding DNA binding sequence-specific DNA binding identical protein binding chromatin binding p53 binding DNA-binding transcription factor activity MDM2/MDM4 family protein binding DNA-binding transcription factor activity, RNA polymerase II-specific protein domain specific binding Cellular component cytoplasm neuron projection nucleus rough endoplasmic reticulum transcription regulator complex nucleoplasm dendrite mitochondrion Golgi apparatus cytosol protein-containing complex Biological process pattern specification process skeletal system development epithelial cell development negative regulation of keratinocyte differentiation epidermal cell division anatomical structure formation involved in morphogenesis prostate gland development transcription by RNA polymerase II squamous basal epithelial stem cell differentiation involved in prostate gland acinus development ectoderm and mesoderm interaction cellular response to DNA damage stimulus female genitalia morphogenesis odontogenesis of dentin-containing tooth prostatic bud formation positive regulation of cell cycle G1/S phase transition positive regulation of mesenchymal cell proliferation spermatogenesis multicellular organism aging smooth muscle tissue development positive regulation of fibroblast apoptotic process animal organ morphogenesis hair follicle morphogenesis positive regulation of Notch signaling pathway apoptotic process chromatin remodeling regulation of transcription, DNA-templated regulation of neuron apoptotic process positive regulation of apoptotic signaling pathway regulation of cysteine-type endopeptidase activity involved in apoptotic process transcription, DNA-templated embryonic limb morphogenesis negative regulation of mesoderm development epidermis development post-anal tail morphogenesis response to gamma radiation protein homotetramerization Notch signaling pathway hair follicle development neuron apoptotic process polarized epithelial cell differentiation proximal/distal pattern formation cell differentiation positive regulation of keratinocyte proliferation skin morphogenesis epithelial cell differentiation urinary bladder development cellular response to UV establishment of planar polarity negative regulation of apoptotic process negative regulation of transcription by RNA polymerase II protein tetramerization keratinocyte proliferation positive regulation of osteoblast differentiation regulation of epidermal cell division negative regulation of transcription, DNA-templated negative regulation of cellular senescence intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator sympathetic nervous system development establishment of skin barrier morphogenesis of a polarized epithelium keratinocyte differentiation multicellular organism development mitotic G1 DNA damage checkpoint signaling cloacal septation response to X-ray positive regulation of transcription by RNA polymerase II DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway regulation of signal transduction by p53 class mediator regulation of apoptotic process ageing negative regulation of intracellular estrogen receptor signaling pathway positive regulation of transcription, DNA-templated positive regulation of somatic stem cell population maintenance cell population proliferation epidermal cell differentiation embryonic forelimb morphogenesis embryonic hindlimb morphogenesis skin epidermis development cranial skeletal system development developmental process Sources:Amigo / QuickGO
Orthologs Databases NCBI: entry; OMA: entry Species Human Mouse Entrez 8626 22061 Ensembl ENSG00000073282 ENSMUSG00000022510 UniProt Q9H3D4 O88898 RefSeq (mRNA) NM_001114978 NM_001114979 NM_001114980 NM_001114981 NM_001114982 NM_003722 NM_001329144 NM_001329145 NM_001329146 NM_001329148 NM_001329149 NM_001329150 NM_001329964 NM_001127259 NM_001127260 NM_001127261 NM_001127262 NM_001127263 NM_001127264 NM_001127265 NM_011641 RefSeq (protein) NP_001108450 NP_001108451 NP_001108452 NP_001108453 NP_001108454 NP_001316073 NP_001316074 NP_001316075 NP_001316077 NP_001316078 NP_001316079 NP_001316893 NP_003713 NP_001120731 NP_001120732 NP_001120733 NP_001120734 NP_001120735 NP_001120736 NP_001120737 NP_035771 Location (UCSC) Chr 3: 189.63 – 189.9 Mb Chr 16: 25.5 – 25.71 Mb PubMed search ^[1] ^[2]
Wikidata
View/Edit Human View/Edit Mouse

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.^[3]^[4]^[5]^[6]

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.^[7] 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.^[8]

Function#edit

Tumor protein p63 is a member of the p53 family of transcription factors. 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.^[9] In contrast, TAp63 has been mostly restricted to its apoptotic function and more recently as the guardian of oocyte integrity.^[10] Recently, two new functions have been attributed to TAp63 in heart development^[11] and premature aging.^[12]

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.^[13]

Oocyte integrity#edit

In oocytes, a unique quality control system has evolved that eliminates by apoptosis those oocytes in which chromosomes do not align correctly, or in which chromosomes cannot be repaired.^[14] This monitoring system is conserved from fruit flies and nematodes to humans, and central to this system is the p53 protein family and, in vertebrates in particular, the p63 protein.^[14] Oocytes that are unable to repair DNA double-strand breaks produced during meiosis by the process of homologous recombination are eliminated by apoptosis that is linked to p63.^[14]

Clinical significance#edit

At least 42 disease-causing mutations in this gene have been discovered.^[15] TP63 mutations underlie several malformation syndromes that include cleft lip and/or palate as a hallmark feature.^[16] Mutations in the TP63 gene are associated with ectrodactyly-ectodermal dysplasia-cleft syndrome in which a midline cleft lip is a common feature,^[16] 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,^[16] Acro–dermato–ungual–lacrimal–tooth syndrome (ADULT); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8.

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.^[16] 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.^[17]

Molecular mechanism#edit

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.^[18] 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.^[19]

Vulvar cancer#edit

TP63 has been observed overexpressed in Vulvar Squamous Cell Carcinoma samples, in association with hypermethylation-Induced inactivation of the IRF6 tumor suppressor gene.^[20] 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.^[20]

Diagnostic utility#edit

p63 immunostaining has utility for head and neck squamous cell carcinomas, differentiating prostatic adenocarcinoma (the most common type of prostate cancer) and benign prostatic tissue;^[21] the 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.^[22] 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.^[23]

Cytoplasmic staining on immunohistochemistry is seen in cells with muscle differentiation.^[24]

Interactions#edit

TP63 has been shown to interact with HNRPAB.^[25] It also activates IRF6 transcription through the IRF6 enhancer element.^[16]

Regulation#edit

There is some evidence that the expression of p63 is regulated by the microRNA miR-203^[26]^[27] and USP28 at protein level ^[28]^[29]

References#edit

^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, et al. (September 1998). "p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities". Molecular Cell. 2 (3): 305–16. doi:10.1016/S1097-2765(00)80275-0. PMID 9774969.
^ Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, et al. (July 1998). "Cloning and functional analysis of human p51, which structurally and functionally resembles p53". Nature Medicine. 4 (7): 839–43. doi:10.1038/nm0798-839. PMID 9662378. S2CID 21953916.
^ Zeng X, Zhu Y, Lu H (February 2001). "NBP is the p53 homolog p63". Carcinogenesis. 22 (2): 215–9. doi:10.1093/carcin/22.2.215. PMID 11181441.
^ Tan M, Bian J, Guan K, Sun Y (February 2001). "p53CP is p51/p63, the third member of the p53 gene family: partial purification and characterization". Carcinogenesis. 22 (2): 295–300. doi:10.1093/carcin/22.2.295. PMID 11181451.
^ Wu G, Nomoto S, Hoque MO, Dracheva T, Osada M, Lee CC, et al. (May 2003). "DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development". Cancer Research. 63 (10): 2351–7. PMID 12750249.
^ Skipper M (January 2007). "Dedicated protection for the female germline". Nature Reviews Molecular Cell Biology. 8 (1): 4–5. doi:10.1038/nrm2091. S2CID 10702219.
^ Crum CP, McKeon FD (2010). "p63 in epithelial survival, germ cell surveillance, and neoplasia". Annual Review of Pathology. 5: 349–71. doi:10.1146/annurev-pathol-121808-102117. PMID 20078223.
^ Deutsch GB, Zielonka EM, Coutandin D, Weber TA, Schäfer B, Hannewald J, et al. (February 2011). "DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer". Cell. 144 (4): 566–76. doi:10.1016/j.cell.2011.01.013. PMC 3087504. PMID 21335238.
^ Rouleau M, Medawar A, Hamon L, Shivtiel S, Wolchinsky Z, Zhou H, et al. (November 2011). "TAp63 is important for cardiac differentiation of embryonic stem cells and heart development". Stem Cells. 29 (11): 1672–83. doi:10.1002/stem.723. hdl:2066/97162. PMID 21898690. S2CID 40628077. Archived from the original on 2014-08-08.
^ Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, et al. (July 2009). "TAp63 prevents premature aging by promoting adult stem cell maintenance". Cell Stem Cell. 5 (1): 64–75. doi:10.1016/j.stem.2009.04.003. PMC 3418222. PMID 19570515.
^ Roberts O, Paraoan L (Dec 2020). "PERP-ing into diverse mechanisms of cancer pathogenesis: Regulation and role of the p53/p63 effector PERP". Biochim Biophys Acta Rev Cancer. 1874 (1) 188393. doi:10.1016/j.bbcan.2020.188393. PMID 32679166. S2CID 220631324.
^ a b c Gebel J, Tuppi M, Sänger N, Schumacher B, Dötsch V (December 2020). "DNA Damaged Induced Cell Death in Oocytes". Molecules. 25 (23): 5714. doi:10.3390/molecules25235714. PMC 7730327. PMID 33287328.
^ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1) 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
^ a b c d e Dixon MJ, Marazita ML, Beaty TH, Murray JC (March 2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Reviews. Genetics. 12 (3): 167–78. doi:10.1038/nrg2933. PMC 3086810. PMID 21331089.
^ Shalom-Feuerstein R, Serror L, Aberdam E, Müller FJ, van Bokhoven H, Wiman KG, et al. (February 2013). "Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET". Proceedings of the National Academy of Sciences of the United States of America. 110 (6): 2152–6. Bibcode:2013PNAS..110.2152S. doi:10.1073/pnas.1201753109. PMC 3568301. PMID 23355677.
^ Qu J, Tanis SE, Smits JP, Kouwenhoven EN, Oti M, van den Bogaard EH, et al. (December 2018). "Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape". Cell Reports. 25 (12): 3490–503. doi:10.1016/j.celrep.2018.11.039. hdl:2066/200262. PMID 30566872.
^ Qu J, Yi G, Zhou H (June 2019). "p63 cooperates with CTCF to modulate chromatin architecture in skin keratinocytes". Epigenetics & Chromatin. 12 (1) 31. doi:10.1186/s13072-019-0280-y. PMC 6547520. PMID 31164150.
^ a b Rotondo JC, Borghi A, Selvatici R, Magri E, Bianchini E, Montinari E, et al. (August 2016). "Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus". JAMA Dermatology. 152 (8): 928–33. doi:10.1001/jamadermatol.2016.1336. PMID 27223861.
^ Shiran MS, Tan GC, Sabariah AR, Rampal L, Phang KS (March 2007). "p63 as a complementary basal cell specific marker to high molecular weight-cytokeratin in distinguishing prostatic carcinoma from benign prostatic lesions". The Medical Journal of Malaysia. 62 (1): 36–9. PMID 17682568.
^ Herawi M, Epstein JI (June 2007). "Immunohistochemical antibody cocktail staining (p63/HMWCK/AMACR) of ductal adenocarcinoma and Gleason pattern 4 cribriform and noncribriform acinar adenocarcinomas of the prostate". The American Journal of Surgical Pathology. 31 (6): 889–94. doi:10.1097/01.pas.0000213447.16526.7f. PMID 17527076. S2CID 9054387.
^ Zhang H, Liu J, Cagle PT, Allen TC, Laga AC, Zander DS (January 2005). "Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach". Modern Pathology. 18 (1): 111–8. doi:10.1038/modpathol.3800251. PMID 15309021.
^ Martin SE, Temm CJ, Goheen MP, Ulbright TM, Hattab EM (October 2011). "Cytoplasmic p63 immunohistochemistry is a useful marker for muscle differentiation: an immunohistochemical and immunoelectron microscopic study". Modern Pathology. 24 (10): 1320–1326. doi:10.1038/modpathol.2011.89. PMID 21623385.
^ Fomenkov A, Huang YP, Topaloglu O, Brechman A, Osada M, Fomenkova T, et al. (June 2003). "P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome". The Journal of Biological Chemistry. 278 (26): 23906–14. doi:10.1074/jbc.M300746200. PMID 12692135.
^ Yi R, Poy MN, Stoffel M, Fuchs E (March 2008). "A skin microRNA promotes differentiation by repressing 'stemness'". Nature. 452 (7184): 225–9. Bibcode:2008Natur.452..225Y. doi:10.1038/nature06642. PMC 4346711. PMID 18311128.
^ Aberdam D, Candi E, Knight RA, Melino G (December 2008). "miRNAs, 'stemness' and skin". Trends in Biochemical Sciences. 33 (12): 583–91. doi:10.1016/j.tibs.2008.09.002. hdl:2381/4113. PMID 18848452.
^ Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, et al. (2020). "Maintaining protein stability of ∆Np63 via USP 28 is required by squamous cancer cells". EMBO Molecular Medicine. 12 (4) e11101. bioRxiv 10.1101/683508. doi:10.15252/emmm.201911101. PMC 7136964. PMID 32128997.
^ Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, et al. (March 2020). "Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells". EMBO Molecular Medicine. 12 (4) e11101. doi:10.15252/emmm.201911101. PMC 7136964. PMID 32128997.

External links#edit

TP73L+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
GeneReviews/NCBI/NIH/UW entry on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome or AEC Syndrome, Hay-Wells Syndrome. Includes: Rapp–Hodgkin Syndrome
OMIM entries on AEC
TP63 human gene location in the UCSC Genome Browser.
TP63 human gene details in the UCSC Genome Browser.

Categories Genes on human chromosome 3 P53 family proteins

This article is mirrored from “TP63” on English Wikipedia, revision 1382347427, written by Wikipedia's contributors and licensed CC BY-SA 4.0. Editing it here creates a Quire copy with its own history.

Synced with Wikipedia revision 1382347427 · just now