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J. Virol. doi:10.1128/JVI.00922-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Enterocyte Proliferation and Intestinal Hyperplasia Induced by Simian Virus 40 T Antigen Requires a Functional J domain

Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA

^* To whom correspondence should be addressed. Email: pipas{at}pitt.edu.

	Abstract

Transgenic mice expressing Simian virus 40 large T antigen in enterocytes develop intestinal hyperplasia that progress to dysplasia with age. This induction requires T antigen action on the Rb-family of tumor suppressors and is independent of the p53 pathway. In cell culture systems, the inactivation of Rb proteins requires both a J domain in TAg that interacts with hsc70 and an LXCXE motif that directs association with Rb proteins. Together these elements are sufficient to release E2Fs from their association with Rb family members. We have generated transgenic mice that express a J domain mutant (D44N) in villus enterocytes. In contrast to wild-type T antigen, the D44N mutant is unable to induce enterocyte proliferation. Histological and morphological examination revealed that mice expressing the J domain mutant have normal intestines without loss of growth control. Unlike mice expressing wild-type TAg, mice expressing D44N do not reduce the protein levels of p130 and are also unable to dissociate p130-E2F DNA binding complexes. Furthermore, mice expressing D44N in a null p130 background are still unable to develop hyperplasia. These studies demonstrate that the ectopic proliferation of enterocytes by T antigen requires a functional J domain and suggest that the J domain is necessary to inactivate all three pRb family members.