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
  • acro-dermato-ungual-acrimal-tooth syndrome (ADULT syndrome)
  • ankyloblepharon-ectodermal defects-cleft lip/palate
  • ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome type 3 (EEC3)
  • split-hand/foot malformation 4
  • limb-mammary syndrome
  • ectodermal dysplasia Rapp-Hodgkin type
  • non-syndromic orofacial cleft type 8
  • 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

More general terms

• p53 family protein

Database

• OMIM: https://mirror.omim.org/entry/603273
• OMIM: https://mirror.omim.org/entry/103285
• OMIM: https://mirror.omim.org/entry/106260
• OMIM: https://mirror.omim.org/entry/604292
• OMIM: https://mirror.omim.org/entry/605289
• UniProt: http://www.uniprot.org/uniprot/Q9H3D4.html