Regulation of Notch1 gene expression by p53 in epithelial cells.
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.
Yugawa
Takashi
T
Virology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Handa
Keisuke
K
Narisawa-Saito
Mako
M
Ohno
Shin-ichi
S
Fujita
Masatoshi
M
Kiyono
Tohru
T
D000818:Animals; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D020411:Oligonucleotide Array Sequence Analysis; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; C068651:E6 protein, Human papillomavirus type 16; C497761:NOTCH1 protein, human; D009856:Oncogene Proteins, Viral; D051881:Receptor, Notch1; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D012313:RNA