Gain-of-function p53 mutants have widespread genomic locations partially overlapping with p63

Abstract

p53 and p63 are transcription factors -TFs- playing master roles in the DNA-damage response and in the development and maintenance of pluristratified epithelia, respectively. p53 mutations are common in epithelial tumors and HaCaT keratinocytes harbor two p53 alleles -H179Y and R282Q- with gain-of-function (GOF) activity. Indeed, functional inactivation of mutp53 affects the growth rate of HaCaT. We investigated the strategy of mutp53, by performing ChIP-Seq experiments of mutp53 and p63 and analyzed the transcriptome after mutp53 inactivation. Mutp53 bind to 7135 locations in vivo, with a robust overlap with p63. De novo motifs discovery recovered a p53/p63RE with high information content in sites bound by p63 and mutp53/p63, but not by mutp53 alone: these sites are rather enriched in elements of other TFs. The HaCaT p63 locations are only partially overlapping with those of normal keratinocytes; importantly, and enriched in mutp53 sites which delineate a functionally different group of target genes. Our data favour a model whereby mutp53 GOF mutants act both by tethering growth-controlling TFs and highjacking p63 to new locations.

miR-205 regulates basement membrane deposition in human prostate: implications for cancer development

“…To guide the search for p63 sites in prostate cells, we made use of our chromatin immunoprecipitation-sequencing (ChIP-Seq) data obtained in human HaCaT keratinocytes, 14 where miR-205 expression is fundamental. 15 We noticed two peaks of p63, at a À 13 Kb and þ 2 Kb from the recently identified 16 miR-205 transcriptional start site (TSS; Figure 2a).…”

Molecular dynamics of the full-length p53 monomer

“…120 The p53 protein is highly conserved in its structure from C. elegans, D. melanogaster to H. sapiens. [121][122][123][124][125][126] While the DBD domain is highly conserved among vertebrates and invertebrates, the C terminus varies, resulting in a change from dimeric structure to a tetramer in the vertebrates. [127][128][129] The more ancient members of the family include p73, involved in cancer, 130 neurodevelopment, 131,132 and aging, 133 and p63, involved in epidermal development, 119,[134][135][136] cancer, [137][138][139][140][141] reproduction, 142 and heart development.…”

The aggregation of mutant p53 produces prion-like properties in cancer

“…9 This co-aggregation occurs despite the existence of only 38% homology in the oligomerization domain of these proteins. 56 Nevertheless, the interaction between mutant p53 and p63 has been shown to be related to important gain-of-function effects in cancer that appear to be the result of either the enhanced expression of genes targeted by p63 57,58 or the binding of p63-p53 to unusual DNA sequences rather than to the loss of p63 DNA binding ability. 59 The existence of multiple isoforms of these three proteins further complicates these interactions and their effects, and the interactions between these proteins may lead to different cellular fates.…”