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Journal of Virology, December 2007, p. 13191-13199, Vol. 81, No. 23
0022-538X/07/$08.00+0     doi:10.1128/JVI.01658-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Intestinal Hyperplasia Induced by Simian Virus 40 Large Tumor Antigen Requires E2F2

M. Teresa Sáenz-Robles,^1, Jennifer A. Markovics,^1,, Jean-Leon Chong,^2, Rene Opavsky,² Robert H. Whitehead,³ Gustavo Leone,² and James M. Pipas^1*

Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260,¹ Department of Molecular Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210,² Cellular and Animal Modeling Core, Vanderbilt Digestive Research Center, Vanderbilt University, Nashville, Tennessee 37232³

Received 30 July 2007/ Accepted 5 September 2007

The simian virus 40 large T antigen contributes to neoplastic transformation, in part, by targeting the Rb family of tumor suppressors. There are three known Rb proteins, pRb, p130, and p107, all of which block the cell cycle by preventing the transcription of genes regulated by the E2F family of transcription factors. T antigen interacts directly with Rb proteins and disrupts Rb-E2F complexes both in vitro and in cultured cells. Consequently, T antigen is thought to inhibit transcriptional repression by the Rb family proteins by disrupting their interaction with E2F proteins, thus allowing E2F-dependent transcription and the expression of cellular genes needed for entry into S phase. This model predicts that active E2F-dependent transcription is required for T-antigen-induced transformation. To test this hypothesis, we have examined the status of Rb-E2F complexes in murine enterocytes. Previous studies have shown that T antigen drives enterocytes into S phase, resulting in intestinal hyperplasia, and that the induction of enterocyte proliferation requires T-antigen binding to Rb proteins. In this paper, we show that normal growth-arrested enterocytes contain p130-E2F4 complexes and that T-antigen expression destroys these complexes, most likely by stimulating p130 degradation. Furthermore, unlike their normal counterparts, enterocytes expressing T antigen contain abundant levels of E2F2 and E2F3a. Concomitantly, T-antigen-induced intestinal proliferation is reduced in mice lacking either E2F2 alone or both E2F2 and E2F3a, but not in mice lacking E2F1. These studies support a model in which T antigen eliminates Rb-E2F repressive complexes so that specific activator E2Fs can drive S-phase entry.

Published ahead of print on 12 September 2007.

M.T.S.-R., J.A.M., and J.-L.C. contributed equally to this work.

Present address: Department of Pathology, SFGH, University of California—San Francisco, San Francisco, CA 94110.