ΔNp63α repression of the Notch1 gene supports the proliferative capacity of normal human keratinocytes and cervical cancer cells

Takashi Yugawa, Mako Narisawa-Saito, Yuki Yoshimatsu, Kei Haga, Shin Ichi Ohno, Nagayasu Egawa, Masatoshi Fujita, Tohru Kiyono

研究成果: Contribution to journalArticle査読

43 被引用数 (Scopus)

抄録

The p53 family member p63 is a master regulator of epithelial development. One of its isoforms, ΔNp63α, is predominantly expressed in the basal cells of stratified epithelia and plays a fundamental role in control of regenerative potential and epithelial integrity. In contrast to p53, p63 is rarely mutated in human cancers, but it is frequently overexpressed in squamous cell carcinomas (SCC). However, its functional relevance to tumorigenesis remains largely unclear. We previously identified the Notch1 gene as a novel transcriptional target of p53. Here, we show that ΔNp63α functions as a transcriptional repressor of the Notch1 gene through the p53-responsive element. Knockdown of p63 caused upregulation of Notch1 expression and marked reduction in proliferation and clonogenicity of both normal human keratinocytes and cervical cancer cell lines overexpressing ΔNp63α. Concomitant silencing of Notch1 significantly rescued this phenotype, indicating the growth defect induced by p63 deficiency to be, at least in part, attributable to Notch1 function. Conversely, overexpression of ΔNp63α decreased basal levels of Notch1, increased proliferative potential of normal human keratinocytes, and inhibited both p53-dependent and p53-independent induction of Notch1 and differentiation markers upon genotoxic stress and serum exposure, respectively. These results suggest that ΔNp63α maintains the self-renewing capacity of normal human keratinocytes and cervical cancer cells partly through transcriptional repression of the Notch1 gene and imply a novel pathogenetical significance of frequently observed overexpression of ΔNp63α together with p53 inactivation in SCCs.

本文言語英語
ページ(範囲)4034-4044
ページ数11
ジャーナルCancer Research
70
10
DOI
出版ステータス出版済み - 5 15 2010
外部発表はい

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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