We have been using the 708 large T antigen encoded by simian virus 40 (SV40) to probe mechanisms of cell proliferation and death. T antigen is sufficient to induce transformation in a number of cell-types in culture. However, in transgenic mouse systems the effect of T antigen expression is cell-type dependent with responses ranging from induction of hyperplasia or carcinoma to cell death. Furthermore, T antigen possesses multiple transforming functions and which function(s) is(are) required for transformation also depends on the cell-type. We have been studying the mouse intestine to explore the regulation of cellular growth control. The intestine consists of the crypts, which contain stem cells and a proliferating cell population, and the villi, which are composed of growth-arrested, terminally differentiated cells. Expression of large T antigen in enterocytes induces their reentry into the cell cycle resulting in an intestinal hyperplasia that is dependent upon the interaction of T antigen with the Rb-family of tumor suppressors. Furthermore, an amino-terminal fragment of T antigen (dl1137) that inactivates Rb but is missing the p53 interaction domain, also induces hyperplasia. We conclude that the induction of enterocyte proliferation requires an interaction of T antigen with one or more members of the Rb-family. Interestingly, while the intestines of mice expressing dl1137 remain at hyperplasia, those expressing wild-type T antigen progress with age to dysplasia. Thus, dysplasia requires carboxy-terminal of T antigen. We have shown that T antigen interaction with p53 does not play a role in either induction of hyperplasia or dysplasia. In this application, we seek to: (1) understand the mechanism of T antigen-induced hyperplasia; and, (2) identify the T antigen target and cellular pathway(s) required for progression to dysplasia. ? ?
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