The carboxy-terminus of p63 links cell cycle control and the proliferative potential of epidermal progenitor cells

Abstract

The transcription factor p63 (Trp63) plays a key role in homeostasis and regeneration of the skin. The p63 gene is transcribed from dual promoters, generating TAp63 isoforms with growth suppressive functions and dominant-negative ΔNp63 isoforms with opposing properties. p63 also encodes multiple carboxy (C)-terminal variants. Although mutations of C-terminal variants have been linked to the pathogenesis of p63-associated ectodermal disorders, the physiological role of the p63 C-terminus is poorly understood. We report here that deletion of the p63 C-terminus in mice leads to ectodermal malformation and hypoplasia, accompanied by a reduced proliferative capacity of epidermal progenitor cells. Notably, unlike the p63-null condition, we find that p63 C-terminus deficiency promotes expression of the cyclin-dependent kinase inhibitor p21Waf1/Cip1 (Cdkn1a), a factor associated with reduced proliferative capacity of both hematopoietic and neuronal stem cells. These data suggest that the p63 C-terminus plays a key role in the cell cycle progression required to maintain the proliferative potential of stem cells of many different lineages. Mechanistically, we show that loss of Cα, the predominant C-terminal p63 variant in epithelia, promotes the transcriptional activity of TAp63 and also impairs the dominantnegative activity of ΔNp63, thereby controlling p21 Waf1/Cip1 expression. We propose that the p63 C-terminus links cell cycle control and the proliferative potential of epidermal progenitor cells via mechanisms that equilibrate TAp63 and ΔNp63 isoform function.

A global analysis of the complex landscape of isoforms and regulatory networks of p63 in human cells and tissues

“…This is in agreement with the emerging general view that in a given condition, the transcriptome from protein coding loci is dominated by one major transcript per gene and often that same transcript is expressed across many cell-types [ 52 ]. Further support for the biological importance of the p63α isoform comes from recently generated mouse knockouts, which demonstrates that the C-terminus is vital to p63 function during embryonic development [ 53 ]. Similar in vivo biochemical studies for the p63β and γ as well as other minor isoforms will shed light on their functional significance.…”

P63 expression plays a role in developmental rate, embryo size, and local morphogenesis

“…In the p63 mutant, tissue hypoplasia due to the loss of a functional p63 program (Truong et al, 2006) and hobbled cell growth and proliferation may collectively limit embryo body growth and size. Also, p63 is implicated in somatic growth by data from adult mice and cancerous tumor tissues that link p63 to insulin-like growth factor signaling, cell cycle regulation, and metabolism (e.g., Nahor et al, 2005;Truong et al, 2006;D'Aquanno et al, 2014;Suzuki et al, 2015). Locally, compromised epithelial integrity interrupts requisite signaling leading to failed patterning and subsequent loss of specific body parts (e.g., limbs, teeth).…”

DNA replication timing alterations identify common markers between distinct progeroid diseases

“…in progeroid syndromes. Consistently, p63 −/− mice have epidermal developmental defects and a shorter life span (25)(26)(27)(28), and TP63 is required for proper skin stratification (29,30). Moreover, TP63 deficiency induces cellular senescence and causes accelerated aging phenotypes in mice (31).…”