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M604152200v1
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Papers In Press, published online ahead of print September 27, 2006
J. Biol. Chem, 10.1074/jbc.M604152200
Submitted on May 1, 2006
Revised on September 27, 2006
Accepted on September 27, 2006

Control of the p53-p21CIP1 Axis by E2f1, E2f2 and E2f3 is essential for G1/S progression and cellular transformation

Nidhi Sharma, Cynthia Timmers, Prashant Trikha, Harold I. Saavedra, Amanda Obery, and Gustavo Leone

Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH 43210

Corresponding Author: gustavo.leone{at}osumc.edu

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 demonstrated that the targeted inactivation of E2f1, E2f2 and E2f3 results in elevated p21CIP1 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 (MEFs). Analysis of synchronized populations of MEFs revealed that the inactivation of p21CIP1 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 p21CIP1 rendered E2f1-3 deficient cells sensitive to transformation and tumorigenesis. These results suggest that the negative regulation of the p53-p21CIP1 axis by the E2F1-3 factors is critical for cell cycle progression and cellular transformation.


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