Regulation of Notch1 gene expression by p53 in epithelial cells
Regulation of Notch1 gene expression by p53 in epithelial cells
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DOI：
10.1128/mcb.02119-06
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发表时间：
2007-05-01
影响因子：
5.3
通讯作者：
Kiyono, Tohru
中科院分区：
文献类型：
--
作者：
Yugawa, Takashi;Handa, Keisuke;Kiyono, Tohru
已知宫颈癌相关人乳头瘤病毒 (HPV) 的 E6 蛋白可通过不明机制抑制角质形成细胞分化。 Notch1 是角质形成细胞分化的决定因素，并在哺乳动物表皮中充当肿瘤抑制因子。在这里，我们报道Notch1基因是p53的一个新靶标，并且可以在正常人上皮细胞中通过p53降解被E6下调。因此，E6 或短发夹 RNA (shRNA) 使 p53 失活导致转录水平的 Notch1 表达减少，并且可以在 Notch1 启动子中鉴定出 p53 响应元件。 E6、p53 shRNA 或 Notch1 shRNA 的表达抑制培养物中的自发角质形成细胞分化及其在 DNA 损伤时的诱导。此外，在野生型小鼠皮肤中观察到了 Notch1 和分化标志物的诱导以及紫外线照射后表皮层的增厚，但在 p53 缺陷小鼠皮肤中却没有观察到。总之，我们的研究结果不仅证明了 p53 和 Notch1 在基因毒性应激下角质形成细胞分化中的新联系，而且还表明 p53 在鳞状细胞癌（包括 HPV 诱导的肿瘤）发展中的新肿瘤抑制机制。
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.