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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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Regulation of Notch1 gene expression by p53 in epithelial cells

Takashi Yugawa1, Keisuke Handa, Mako Narisawa-Saito

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

Molecular and Cellular Biology
|March 14, 2007
PubMed

Insights

Human papillomaviruses (HPVs) E6 protein suppresses keratinocyte differentiation by degrading p53, which down-regulates Notch1. This reveals a new p53 tumor suppressor mechanism in skin cancers.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The E6 protein of human papillomaviruses (HPVs) inhibits keratinocyte differentiation via unknown pathways.
  • Notch1 is crucial for keratinocyte differentiation and acts as a tumor suppressor in the skin.

Purpose of the Study:

  • To elucidate the mechanism by which HPV E6 protein suppresses keratinocyte differentiation.
  • To identify the role of p53 and Notch1 in this process and in skin tumor development.

Main Methods:

  • Investigated the interaction between HPV E6, p53, and Notch1 in human epithelial cells.
  • Utilized short-hairpin RNA (shRNA) to inactivate p53 and Notch1.
  • Analyzed Notch1 promoter activity and keratinocyte differentiation markers.
  • Examined UV-induced skin responses in wild-type and p53-deficient mouse models.

Main Results:

  • HPV E6 down-regulates Notch1 expression by promoting p53 degradation.
  • p53 directly regulates Notch1 transcription via a responsive element in its promoter.
  • Inactivation of p53 or Notch1 impairs keratinocyte differentiation, both spontaneously and after DNA damage.
  • UV irradiation induces Notch1 and epidermal thickening in wild-type but not p53-deficient mouse skin.

Conclusions:

  • Established a novel link between p53 and Notch1 in regulating keratinocyte differentiation under genotoxic stress.
  • Identified a new tumor suppressor function of p53 in squamous cell carcinoma development, including HPV-associated cancers.

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