The foggy world(s) of p63 isoform regulation in normal cells and cancer

The p53 family member p63 exists as two major protein variants (TAp63 and Delta Np63) with distinct expression patterns and functional properties. Whilst downstream target genes of p63 have been studied intensively, how p63 variants are themselves controlled has been relatively neglected. Here, we review advances in understanding Delta Np63 and TAp63 regulation, highlighting their distinct pathways. TAp63 has roles in senescence and metabolism, and in germ cell genome maintenance, where it is activated post-transcriptionally by phosphorylation cascades after DNA damage. The function and regulation of TAp63 in mesenchymal and haematopoietic cells is less clear but may involve epigenetic control through DNA methylation. Delta Np63 functions to maintain stem/progenitor cells in various epithelia and is overexpressed in squamous and certain other cancers. Delta Np63 is transcriptionally regulated through multiple enhancers in concert with chromatin modifying proteins. Many signalling pathways including growth factors, morphogens, inflammation, and the extracellular matrix influence Delta Np63 levels, with inconsistent results reported. There is also evidence for reciprocal regulation, including Delta Np63 activating its own transcription. Delta Np63 is downregulated during cell differentiation through transcriptional regulation, while post-transcriptional events cause proteasomal degradation. Throughout the review, we identify knowledge gaps and highlight discordances, providing potential explanations including cell-context and cell-matrix interactions. Identifying individual p63 variants has roles in differential diagnosis and prognosis, and understanding their regulation suggests clinically approved agents for targeting p63 that may be useful combination therapies for selected cancer patients. (c) 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Automated summary

This review summarizes the regulation of two major protein variants of the p53 family member p63, TAp63 and Delta Np63, highlighting their different functions and pathways in cellular biology. TAp63 is mainly involved in senescence, metabolism, and germ cell genome maintenance, while Delta Np63 primarily maintains stem/progenitor cells in various epithelia.