TP63

Tumor protein p63
C-terminal domain of the p63 protein PDB rendering based on 1rg6.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1RG6​, 2RMN​, 2Y9T​, 2Y9U​, 3QYM​, 3QYN​, 3US0​, 3US1​, 3US2​, 3ZY0​, 3ZY1​, 4A9Z​
Identifiers
Symbols	TP63 ; AIS; B(p51A); B(p51B); EEC3; KET; LMS; NBP; OFC8; RHS; SHFM4; TP53CP; TP53L; TP73L; p40; p51; p53CP; p63; p73H; p73L
External IDs	OMIM: 603273 MGI: 1330810 HomoloGene: 31189 GeneCards: TP63 Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription • p53 binding • DNA binding • chromatin binding • damaged DNA binding • double-stranded DNA binding • sequence-specific DNA binding transcription factor activity • protein binding • identical protein binding • sequence-specific DNA binding • transcription regulatory region DNA binding • metal ion binding Cellular component • chromatin • nuclear chromatin • nucleus • nucleoplasm • transcription factor complex • nucleolus • cytoplasm • Golgi apparatus • cytosol • dendrite Biological process • negative regulation of transcription from RNA polymerase II promoter • skeletal system development • establishment of planar polarity • positive regulation of mesenchymal cell proliferation • epithelial cell development • chromatin remodeling • apoptotic process • induction of apoptosis • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator • Notch signaling pathway • ectoderm and mesoderm interaction • cell aging • proximal/distal pattern formation • response to X-ray • multicellular organismal aging • response to gamma radiation • keratinocyte differentiation • embryonic limb morphogenesis • polarized epithelial cell differentiation • hair follicle morphogenesis • mitotic cell cycle G1/S transition DNA damage checkpoint • cellular response to UV • odontogenesis of dentin-containing tooth • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • regulation of neuron apoptotic process • skin morphogenesis • keratinocyte proliferation • negative regulation of keratinocyte differentiation • positive regulation of osteoblast differentiation • positive regulation of Notch signaling pathway • negative regulation of transcription, DNA-dependent • positive regulation of transcription, DNA-dependent • positive regulation of transcription from RNA polymerase II promoter • sympathetic nervous system development • smooth muscle tissue development • female genitalia morphogenesis • protein homotetramerization • neuron apoptotic process • urinary bladder development • cloacal septation • prostatic bud formation • squamous basal epithelial stem cell differentiation involved in prostate gland acinus development Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	8626	22061
Ensembl	ENSG00000073282	ENSMUSG00000022510
UniProt	Q9H3D4	O88898
RefSeq (mRNA)	NM_001114978	NM_001127259
RefSeq (protein)	NP_001108450	NP_001120731
Location (UCSC)	Chr 3: 189.35 – 189.62 Mb	Chr 16: 25.68 – 25.89 Mb
PubMed search

Tumor protein p63 also known as transformation-related protein 63 is a protein that in humans is encoded by the TP63 gene.^[1][2][3][4]

TP63 also known as the p63 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.^[5] 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.^[6]

Function

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.^[7] In contrast, TAp63 has been mostly restricted to its apoptotic function and more recently as the guardian of oocyte integrity.^[8] Recently, two new functions have been attributed to TAp63 in heart development^[9] and premature aging.^[10]

Clinical significance

TP63 mutations underlie several malformation syndromes that include cleft lip and/or palate as a hallmark feature.^[11] Mutations in the TP63 gene are associated with ectrodactyly-ectodermal dysplasia-cleft syndrome in which a midline cleft lip is a common feature,^[11] 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,^[11] 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.^[11] Recently, induced pluripotent stem cells have be produced from patients affected by EEC syndromes by cell reprogramming. The defective epithelial commitment could be partially rescued by a small therapeutic compound.^[12]

Diagnostic utility

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;^[13] normal prostatic glands stain with p63 (as they have basal cells), while the malignant glands in prostatic adenocarcinoma (which lacks these cells) do not.^[14] 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.^[15]

Interactions

TP63 has been shown to interact with HNRPAB.^[16] It also activates IRF6 transcription through the IRF6 enhancer element.^[11]

Regulation

There is some evidence that the expression of p63 is regulated by the microRNA miR-203.^[17][18]

See also

• AMACR - another marker for prostate adenocarcinoma

References

1. Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, Andrews NC, Caput D, McKeon F (Sep 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.
2. Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, Ikawa Y, Nimura Y, Nakagawara A, Obinata M, Ikawa S (Jul 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.
3. Zeng X, Zhu Y, Lu H (Feb 2001). "NBP is the p53 homolog p63". Carcinogenesis 22 (2): 215–9. doi:10.1093/carcin/22.2.215. PMID 11181441.
4. Tan M, Bian J, Guan K, Sun Y (Feb 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.
5. 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 (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.
6. Skipper M (January 2007). "Dedicated protection for the female germline". Nature Reviews Molecular Cell Biology 8 (1): 4–5. doi:10.1038/nrm2091.
7. 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.
8. 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 (Feb 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.
9. 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 (Nov 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. PMID 21898690.
10. Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER (Jul 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.
11. Dixon MJ, Marazita ML, Beaty TH, Murray JC (Mar 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.
12. Shalom Feuerstein R. et al. Impaired epithelial differentiation of induced pluripotent stem cells from EEC patients is rescued by APR-246/PRIMA-1MET. P.N.A.S 2012. http://minus.com/lbmC3TVGDx350s
13. Shiran MS, Tan GC, Sabariah AR, Rampal L, Phang KS (Mar 2007). "p63 as a complimentary 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.
14. Herawi M, Epstein JI (Jun 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.
15. Zhang H, Liu J, Cagle PT, Allen TC, Laga AC, Zander DS (Jan 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.
16. Fomenkov A, Huang YP, Topaloglu O, Brechman A, Osada M, Fomenkova T, Yuriditsky E, Trink B, Sidransky D, Ratovitski E (Jun 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.
17. Yi R, Poy MN, Stoffel M, Fuchs E (Mar 2008). "A skin microRNA promotes differentiation by repressing 'stemness'". Nature 452 (7184): 225–9. doi:10.1038/nature06642. PMID 18311128.
18. Aberdam D, Candi E, Knight RA, Melino G (Dec 2008). "miRNAs, 'stemness' and skin". Trends in Biochemical Sciences 33 (12): 583–91. doi:10.1016/j.tibs.2008.09.002. PMID 18848452.

Further reading

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

External links

• TP73L protein, human at the US 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.