Regulation of Notch1 gene expression by p53 in epithelial cells

Takashi Yugawa, Keisuke Handa, Mako Narisawa-Saito, Shin Ichi Ohno, Masatoshi Fujita, Tohru Kiyono

研究成果: Article査読

144 被引用数 (Scopus)

抄録

The E6 protein of cervical cancer-associated human papillomaviruses (HPVs) is known to suppress keratinocyte differentiation through unidentified mechanisms. Notch1 is a determinant of keratinocyte differentiation and functions as a tumor suppressor in mammalian epidermis. Here, we report that the Notch1 gene is a novel target of p53 and can be down-regulated by E6 through p53 degradation in normal human epithelial cells. Thus, inactivation of p53 by E6 or short-hairpin RNA (shRNA) resulted in reduced Notch1 expression at the transcription level, and a p53-responsive element could be identified in the Notch1 promoter. The expression of E6, p53 shRNA, or Notch1 shRNA suppressed both spontaneous keratinocyte differentiation in culture and its induction upon DNA damage. Furthermore, the induction of Notch1 and differentiation makers as well as thickening of the epidermal layer upon UV irradiation was observed in wild-type but not in p53-deficient mouse skin. Together, our findings not only demonstrate a novel link between p53 and Notch1 in keratinocyte differentiation upon genotoxic stress but also suggest a novel tumor suppressor mechanism of p53 in the development of squamous cell carcinomas, including HPV-induced tumors.

本文言語English
ページ(範囲)3732-3742
ページ数11
ジャーナルMolecular and cellular biology
27
10
DOI
出版ステータスPublished - 2007 5月
外部発表はい

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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