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E2f1, E2f2, and E2f3 control E2F target expression and cellular proliferation via a p53-dependent negative feedback

Cynthia Timmers1, Nidhi Sharma, Rene Opavsky

  • 1Human Cancer Genetics program, Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, The Ohio State University, 410 W. 12th Avenue, Columbus, OH 43210, USA.

Molecular and Cellular Biology
|December 15, 2006
PubMed

Insights

Disrupting E2F1, E2F2, and E2F3 activators in mouse cells activates p53, blocking cell proliferation. Restoring p53 function rescues proliferation, revealing a p53-dependent control of E2F activity.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • E2F transcription factors regulate cell cycle progression.
  • E2F activators (E2f1, E2f2, E2f3) are crucial for cellular proliferation.
  • The interplay between E2F and p53 in cell cycle control is complex.

Purpose of the Study:

  • To investigate the role of E2F1, E2F2, and E2F3 activators in cellular proliferation.
  • To elucidate the mechanism by which E2F activators control cell cycle progression.
  • To determine the involvement of p53 in the E2F-mediated proliferation pathway.

Main Methods:

  • Conditional gene targeting in mouse embryonic fibroblasts.
  • Disruption of E2f1, E2f2, and E2f3 genes.
  • Analysis of p53 activation and p53 target gene induction.
  • Assessment of cyclin-dependent kinase activity and retinoblastoma (Rb) phosphorylation.
  • Inactivation of p53 via spontaneous mutation or conditional gene ablation.

Main Results:

  • Targeted disruption of E2f1, E2f2, and E2f3 activated p53 and its target genes, including p21(CIP1).
  • This led to inhibition of cyclin-dependent kinase activity and Rb phosphorylation, causing a proliferation block.
  • Inactivation of p53 in E2F-deficient cells restored normal cell cycle progression and E2F target gene expression.

Conclusions:

  • E2F1, E2F2, and E2F3 activators control a p53-dependent pathway.
  • This pathway indirectly regulates E2F-mediated transcriptional repression.
  • The findings highlight a critical role for E2F activators in controlling cellular proliferation via p53.

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