p63

p63 is a transcription factor of the p53 family, encoded by the TP63 gene on chromosome 3q28. It shares the DNA-binding and oligomerization domains with p53 and p73 but differs in its N- and C-terminal regions. The TP63 gene uses two promoters to generate N-terminal isoforms: TAp63, which contains an N-terminal transactivation domain, and ΔNp63, which lacks this domain. Alternative splicing at the C-terminus yields α, β, and γ variants, producing a spectrum of p63 proteins with distinct regulatory activities.

p63 plays a critical role in the development and maintenance of stratified epithelia, including the skin, as well as in limb and craniofacial formation. It regulates epidermal proliferation, stem cell maintenance, and differentiation. In mice, loss of p63 results in severe ectodermal defects and perinatal lethality, underscoring its essential developmental function. In humans, TP63 mutations cause ectodermal dysplasia syndromes such as AEC (ankyloblepharon-ectodermal dysplasia-clefting), EEC (ectrodactyly-ectodermal dysplasia-clefting), Hay-Wells syndrome, and limb-mammary syndrome.

p63 functions through DNA binding to p53-like response elements and modulates transcription in a context-dependent manner. TA isoforms can activate p53-responsive genes, promoting cell cycle arrest or apoptosis, while ΔNp63 can antagonize p53 and TAp63 and, in some contexts, act as a transcriptional activator with specific partners. The repertoire of isoforms and C-terminal variants shapes networks that control proliferation, differentiation, adhesion, and cytoskeletal organization in epithelial lineages.

In cancer, p63 serves as a diagnostic marker for squamous differentiation and is frequently overexpressed in squamous cell carcinomas. TP63 mutations are uncommon in cancers; the oncogenic impact of p63 is largely isoform- and context-dependent, with ΔNp63 often associated with proliferative, less-differentiated tumor phenotypes.