TP63

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
Identifiers
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 HomoloGene: 31189 GeneCards: TP63
Gene location (Human)
Chr.	Chromosome 3 (human)[1]
End	189,897,279 bp[1]
Gene location (Mouse)
Chr.	Chromosome 16 (mouse)[2]
End	25,892,102 bp[2]
RNA expression pattern
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	• transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding; • transcription regulatory region DNA binding; • metal ion binding; • damaged DNA binding; • protein binding; • WW domain binding; • double-stranded DNA binding; • DNA binding; • sequence-specific DNA binding; • transcription factor activity, transcription factor binding; • identical protein binding; • chromatin binding; • p53 binding; • transcription factor activity, sequence-specific DNA binding; • MDM2/MDM4 family protein binding; • RNA polymerase II transcription factor activity, sequence-specific DNA binding; • protein domain specific binding;
Cellular component	• cytoplasm; • neuron projection; • cell nucleus; • rough endoplasmic reticulum; • nuclear chromatin; • transcription factor complex; • nucleoplasm; • dendrite; • mitochondrion; • Golgi apparatus; • cytosol; • macromolecular 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 from RNA polymerase II promoter; • 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; • cell aging; • 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 from RNA polymerase II promoter; • protein tetramerization; • replicative cell aging; • 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; • cloacal septation; • response to X-ray; • positive regulation of transcription from RNA polymerase II promoter; • 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; • aging; • negative regulation of intracellular estrogen receptor signaling pathway; • positive regulation of transcription, DNA-templated; • positive regulation of somatic stem cell population maintenance; • cell proliferation; • epidermal cell differentiation; • embryonic forelimb morphogenesis; • embryonic hindlimb morphogenesis; • skin epidermis development; • cranial skeletal system development; • developmental process;
	Sources:Amigo / QuickGO
Orthologs
	8626
	22061
	ENSG00000073282
	ENSMUSG00000022510
	Q9H3D4
	O88898
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
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
	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.^[5]^[6]^[7]^[8]

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.^[9] 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.^[10]

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.^[11] In contrast, TAp63 has been mostly restricted to its apoptotic function and more recently as the guardian of oocyte integrity.^[12] Recently, two new functions have been attributed to TAp63 in heart development^[13] and premature aging.^[14]

Clinical significance

TP63 mutations underlie several malformation syndromes that include cleft lip and/or palate as a hallmark feature.^[15] Mutations in the TP63 gene are associated with ectrodactyly-ectodermal dysplasia-cleft syndrome in which a midline cleft lip is a common feature,^[15] 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,^[15] 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.^[15] 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.^[16]

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;^[17] normal prostatic glands stain with p63 (as they have basal cells), while the malignant glands in prostatic adenocarcinoma (which lacks these cells) do not.^[18] 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.^[19]

Interactions

TP63 has been shown to interact with HNRPAB.^[20] It also activates IRF6 transcription through the IRF6 enhancer element.^[15]

Regulation

There is some evidence that the expression of p63 is regulated by the microRNA miR-203.^[21]^[22]

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000073282 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022510 - Ensembl, May 2017
↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ Skipper M (January 2007). "Dedicated protection for the female germline". Nature Reviews Molecular Cell Biology. 8 (1): 4–5. doi:10.1038/nrm2091.
↑ 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, 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.
↑ 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. Archived from the original on 2014-08-08.
↑ 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.
1 2 3 4 5 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.
↑ 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. "Archived copy". Archived from the original on 2014-12-14. Retrieved 2014-12-13.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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. PMC 4346711. PMID 18311128.
↑ 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. Archived from the original on 2013-04-21.

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.

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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000073282 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022510 - Ensembl, May 2017

[3] "Human PubMed Reference:".

[4] "Mouse PubMed Reference:".

[pmid9774969-5] 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.

[pmid9662378-6] 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.

[pmid11181441-7] 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.

[pmid11181451-8] 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.

[pmid12750249-9] 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.

[Skipper_2007-10] Skipper M (January 2007). "Dedicated protection for the female germline". Nature Reviews Molecular Cell Biology. 8 (1): 4–5. doi:10.1038/nrm2091.

[pmid20078223-11] 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.

[pmid21335238-12] 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.

[pmid21898690-13] 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. Archived from the original on 2014-08-08.

[pmid19570515-14] 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.

[Dixon_2011-15] 1 2 3 4 5 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.

[16] 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. "Archived copy". Archived from the original on 2014-12-14. Retrieved 2014-12-13.

[17] 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.

[18] 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.

[pmid15309021-19] 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.

[pmid12692135-20] 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.

[pmid18311128-21] 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. PMC 4346711. PMID 18311128.

[pmid18848452-22] 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. Archived from the original on 2013-04-21.