TAp63

TAp63 is an isoform of the TP63 gene, a member of the p53 family of transcription factors. It contains an N-terminal transactivation domain (TA), which enables it to function as a transcriptional activator. TAp63 is distinguished from other TP63 isoforms by the presence of this TA domain, whereas other isoforms such as ΔNp63 lack it. Like other p53 family proteins, TAp63 can regulate gene expression involved in cell cycle control, apoptosis, and development.

The TP63 gene generates multiple isoforms through alternative promoter usage and alternative splicing. The main grouping is into TAp63, which includes the transactivation domain, and ΔNp63, which lacks this domain. Each group can be further diversified by C-terminal splicing to produce α, β, and γ variants. This combinatorial diversity allows tissue-specific and context-dependent roles in development and homeostasis.

Biological roles of TAp63 include regulation of epidermal differentiation, limb and craniofacial development, and maintenance of genomic integrity in germ cells. A notable function is in female oocytes, where the TAp63α isoform acts as a guardian of the germline: after DNA damage, it becomes activated and promotes transcription of pro-apoptotic genes to eliminate damaged oocytes, helping preserve genome quality. Activation typically involves phosphorylation by DNA-damage signaling kinases, leading to structural changes that enable transcriptional activity.

Clinical relevance: TP63 mutations are linked to a spectrum of ectodermal dysplasia syndromes and orofacial clefting disorders, reflecting critical roles in epithelial development. In cancer, abnormal expression of TP63 isoforms, particularly ΔNp63, is observed in various carcinomas, highlighting the importance of isoform balance in disease.