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Molecular and Cellular Biology, January 2007, p. 65-78, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.02147-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

E2f1, E2f2, and E2f3 Control E2F Target Expression and Cellular Proliferation via a p53-Dependent Negative Feedback Loop{triangledown}

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

Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Department of Molecular Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210

Received 4 November 2005/ Returned for modification 7 December 2005/ Accepted 9 October 2006

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 p21CIP1. Consequently, cyclin-dependent kinase activity and retinoblastoma (Rb) phosphorylation are dramatically inhibited, leading to Rb/E2F-mediated repression of E2F target gene expression and a severe block in cellular proliferation. Inactivation of p53 in E2f1-, E2f2-, and E2f3-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.

* Correspondingauthor. Mailing address: 410 W. 12th Avenue, Rm. 455B, Columbus, OH 43210. Phone: (614) 688-4567. Fax: (614) 292-3312. E-mail: gustavo.leone{at}osumc.edu.

{triangledown} Published ahead of print on 30 October 2006.

{ddagger} Present address: Novartis Institute for Biomedical Research, Models of Disease Center, 250 Massachusetts Avenue, Cambridge, MA 02139.

Molecular and Cellular Biology, January 2007, p. 65-78, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.02147-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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