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Molecular and Cellular Biology, May 2007, p. 3732-3742, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.02119-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Regulation of Notch1 Gene Expression by p53 in Epithelial Cells{triangledown} ,{ddagger}

Takashi Yugawa, Keisuke Handa,{dagger} Mako Narisawa-Saito, Shin-ichi Ohno, Masatoshi Fujita, and Tohru Kiyono*

Virology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

Received 13 November 2006/ Returned for modification 15 December 2006/ Accepted 3 March 2007

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.

* Corresponding author. Mailing address: 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3547-5275. Fax: 81-3-3543-2181. E-mail: tkiyono{at}gan2.res.ncc.go.jp

{triangledown} Published ahead of print on 12 March 2007.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} Present address: Department of Operative Dentistry and Endodontology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Ishikari-Tobetu, Hokkaido 061-0293, Japan.

Molecular and Cellular Biology, May 2007, p. 3732-3742, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.02119-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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