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

Cynthia Timmers, Nidhi Sharma, Rene Opavsky, Baidehi Maiti, Lizhao Wu, Juan Wu, Daniel Orringer, Prashant Trikha, Harold I. Saavedra, Gustavo Leone

Research output: Contribution to journalArticle

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Abstract

E2F-mediated control of gene expression is believed to have an essential role in the control of cellular proliferation. Using a conditional gene-targeting approach, we show that the targeted disruption of the entire E2F activator subclass composed of E2f1, E2f2, and E2f3 in mouse embryonic fibroblasts leads to the activation of p53 and the induction of p53 target genes, including p21C1P1. Consequently, cyclin-dependent kinase activity and retinoblastoma (Rb) phosphorylation are dramatically inhibited, leading to Rb/E2F-mediated repression of K2F target gene expression and a severe block in cellular proliferation. Inactivation of p53 in E2f1-, E2f2-, and E2/3-deficient cells, either by spontaneous mutation or by conditional gene ablation, prevented the induction of p21CIP1 and many other p53 target genes. As a result, cyclin-dependent kinase activity, Rb phosphorylation, and E2F target gene expression were restored to nearly normal levels, rendering cells responsive to normal growth signals. These findings suggest that a critical function of the E2F1, E2F2, and E2F3 activators is in the control of a p53-dependent axis that indirectly regulates E2F-mediated transcriptional repression and cellular proliferation.

Original languageEnglish (US)
Pages (from-to)65-78
Number of pages14
JournalMolecular and cellular biology
Volume27
Issue number1
DOIs
Publication statusPublished - Jan 1 2007

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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