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p63 protein; p53 homolog p63; tumor protein p73-like; p73L; TP63; p51; p40; keratinocyte transcription factor KET; chronic ulcerative stomatitis protein (CUSP, TP73L, KET, p63, P73H)

Function: - sequence specific DNA binding transcriptional activator or transcriptional repressor - the isoforms contain a varying set of transactivation & auto-regulating transactivation inhibiting domains thus showing an isoform specific activity - may be required in conjunction with TP73/p73 for initiation of TP53/p53 dependent apoptosis in response to genotoxic insults & the presence of activated oncogenes - involved in notch signaling by probably inducing JAG1 & JAG2 - role in the regulation of epithelial morphogenesis - the ratio of deltaN-type & TA*-type isoforms may govern the maintenance of epithelial stem cell compartments & regulate the initiation of epithelial stratification from the undifferentiated embryonal ectoderm - required for limb formation from the apical ectodermal ridge - binds DNA as a homotetramer - isoform composition of the tetramer may determine transactivation activity - isoforms alpha & gamma interact with HIPK2 - interacts with SSRP1, leading to stimulate coactivator activity - may be sumoylated (putative) Cofactor: binds 1 Zn+2 per subunit (putative) Structure: - transactivation inhibitory domain (TID) can interact with, & inhibit the activity of the N-terminal transcriptional activation domain of TA*-type isoforms - belongs to the p53 family - at least 3 isforms contain transactivation, DNA binding & oligomerization domains (TAp63-alpha, TAp63-beta & TAp63-gamma) similar to p53 - at least 3 isoforms 3 do not contain the acidic N-terminal domain (Np63-alpha, Np63-beta & Np63-gamma) necessary in p53 for transcriptional activation - contains 1 SAM domain (sterile alpha motif) Compartment: nucleus Alternative splicing: - named isoforms=12 - alternative promoter usage Expression: - TP63 forms detected in heart, testis, kidney, adrenal, thymus, brain, cerebellum. Np63 forms present in kidney, adrenal, spleen, thymus & basal cells in epidermis, cervix, urothelium & prostate, & absent from heart, liver, testis, brain - progenitor cell layers of skin, breast, eye & prostate express high levels of deltaN-type isoforms Pathology: - isoform 10 is predominantly expressed in skin squamous cell carcinomas, but not in normal skin tissues - defects in TP63 are the cause of [4] a) acro-dermato-ungual-acrimal-tooth syndrome (ADULT syndrome) b) ankyloblepharon-ectodermal defects-cleft lip/palate c) ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome type 3 (EEC3) d) split-hand/foot malformation 4 e) limb-mammary syndrome f) ectodermal dysplasia Rapp-Hodgkin type g) non-syndromic orofacial cleft type 8 f) cervical cancer, colon cancer, head & neck cancer, lung cancer & ovarian cancer Comparative biology: - transgenic mice lacking p63 protein show major defects in limb, craniofacial & epithelial development - limbs are absent or truncated due to failure of apical ectodermal ridge to differentiate - the skin remains at an early stage of development - lacking are squamous epithelia & their derivatives, including mammary glands, lacrimal glands, salivary glands, hair follicles & teeth - transgenic mice overexpressing p63 display a phenotype of accelerated aging, characterized by reduced longevity, weight loss, wound healing defects, diminished skin thickiness with loss of subcutaneous tissue, graying & loss of hair - these effects may occur through downregulation of SIRT1 [5]

Related

p63 Ag in tissue p63 gene p63+smooth muscle myosin heavy chain+cytokeratin 8 Ag in tissue TP73L gene mutation; p63 gene mutation

General

p53 family protein

Properties

SIZE: MW = 77 kD entity length = 680 aa COMPARTMENT: cell nucleus MOTIF: transcriptional activation domain SITE: 1-107 DNA-binding motif SITE: 170-362 MOTIF: Zn+2-binding site SITE: 244-244 Zn+2-binding site SITE: 247-247 Zn+2-binding site SITE: 308-308 Zn+2-binding site SITE: 312-312 binding site SITE: 352-388 FOR-BINDING-OF: homeodomain-interacting protein kinase 2 Oligomerization. {394-443} glutamine-rich region {437-444} MOTIF: glutamine residue (SEVERAL) sterile alpha motif NAME: sterile alpha motif SITE: 541-607 silencer element SITE: 610-680

Database Correlations

OMIM correlations MORBIDMAP 603273 UniProt Q9H3D4 PFAM correlations

References

  1. Yang et al. Molecular Cell 2:305-16, 1998
  2. Mills et al. Nature 398:708-13, 1999
  3. Yang et al. Nature 398:714-8, 1999
  4. Celli et al. Cell 99:143-53, 1999
  5. Sommer M, Poliak N, Neiken BD, Sidransky D SIRT1 down regulation through p63 induces accelerated aging in mice Aging: Mechanisms and Prevention 34th Annual Meeting of the American Aging Association June 3-6, 2005, Oakland CA
  6. UniProt :accession Q9H3D4
  7. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=TP63