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E2F-like elements in p27(Kip1) promoter specifically sense deregulated E2F activity

Eiko Ozono1, Hideyuki Komori, Ritsuko Iwanaga

  • 1Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|December 17, 2008
PubMed

Insights

The p27(Kip1) gene distinguishes between normal and abnormal E2F activity. It uses unique E2F-like elements to suppress cell cycle progression when the RB tumor suppressor pathway is compromised.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Cancer Biology

Background:

  • The RB tumor suppressor pathway and its target, the E2F transcription factor, are critical for cell proliferation and tumor suppression.
  • The p27(Kip1) gene, an inhibitor of cyclin-dependent kinases, negatively regulates E2F activity.
  • Ectopic E2F1 expression induces p27(Kip1), but normal growth stimulation does not, suggesting differential gene response to E2F activity.

Purpose of the Study:

  • To investigate how the p27(Kip1) gene distinguishes between deregulated and physiological E2F activity.
  • To identify the regulatory elements within the p27(Kip1) promoter responsible for this discrimination.

Main Methods:

  • Analysis of the p27(Kip1) promoter activity in response to varying E2F activation states.
  • Site-directed mutagenesis of E2F-binding elements within the p27(Kip1) promoter.
  • In vivo chromatin immunoprecipitation assays to assess E2F binding to promoter elements.

Main Results:

  • The p27(Kip1) promoter contains E2F-like elements that specifically respond to deregulated E2F activity.
  • These E2F-like elements are activated by forced pRb inactivation but not by serum-induced physiological E2F activity.
  • The endogenous p27(Kip1) gene exhibits a similar response pattern to these E2F-like elements.
  • Ectopically expressed E2F1 binds to these E2F-like elements in vivo, unlike physiologically activated E2F1 or E2F4.

Conclusions:

  • The p27(Kip1) gene utilizes specific E2F-like elements to sense deregulated E2F activity.
  • This sensing mechanism allows p27(Kip1) to suppress inappropriate cell cycle progression when the RB pathway is disrupted.
  • This provides a novel insight into how cells maintain tumor suppression in response to RB pathway dysfunction.

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