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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
Summary
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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