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J. Biol. Chem., Vol. 281, Issue 47, 36124-36131, November 24, 2006

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Control of the p53-p21^CIP1 Axis by E2f1, E2f2, and E2f3 Is Essential for G₁/S Progression and Cellular Transformation^*

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

The E2F family of transcription factors is believed to have an essential role in the control of cellular proliferation by regulating the transcription of genes involved in cell cycle progression. Previous work has demonstrated that the targeted inactivation of E2f1, E2f2, and E2f3 results in elevated p21^CIP1 protein levels, loss of E2F target gene expression, and cell cycle arrest at G₁/S and G₂/M, suggesting a strict requirement for these E2Fs in the control of normal cellular proliferation. We now demonstrate that E2f1, E2f2, and E2f3 are also required for oncogene-mediated transformation of mouse embryonic fibroblasts. Analysis of synchronized populations of mouse embryonic fibroblasts revealed that the inactivation of p21^CIP1 restores the ability of E2f1-3-deficient cells to enter and transit through G₁/S (but not G₂/M). In contrast, loss of p53 restored the ability of these cells to progress through both G₁/S and mitosis, leading to their continued proliferation. The inactivation of p53 (but not p21^CIP1) rendered E2f1-3-deficient cells sensitive to transformation and tumorigenesis. These results suggest that the negative regulation of the p53-p21^CIP1 axis by the E2F1-3 factors is critical for cell cycle progression and cellular transformation.

Received for publication, May 1, 2006 , and in revised form, September 27, 2006.

^* This work was funded by National Institutes of Health Grants R01CA85619, R01CA82259, R01HD047470, and P01CA097189 (to G. L.) and K01CA104079 (to H. I. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of an American Cancer Society fellowship.

² To whom correspondence should be addressed: Dept. of Molecular Virology, Immunology, and Medical Genetics, Dept. of Molecular Genetics, Comprehensive Cancer Ctr., Ohio State University, Columbus, OH 43210. Tel.: 614-688-4567; Fax: 614-292-3312; E-mail: gustavo.leone{at}osumc.edu.

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