This grant is designed to study the mechanisms underlying the effects of polyoma virus'Middle T (MT) antigen and SV40 virus'small t (st) antigen. Recent experiments have greatly increased interest in st. It has been found to play a key role in transforming telomerase-immortalized human epithelial cells in the Weinberg system and in selectively inducing apoptosis in tumor, but not normal, cell lines. Both effects of st are believed to arise from its interaction with a protein phosphatase, PP2A. The experiments in this grant will examine the molecular details by which st selectively inhibits certain isoforms of PP2A by displacing particular B-type subunits. Understanding these details may lead directly to cancer therapy. Similarly the experiments in the grant will study the mechanisms by which MT transforms human epithelial cells. In the last grant period we discovered a new class of mutants in MT that suggests the existence of a new MT binding protein hypothesized to be important in transformation. By using newly developed protocols for isolating all proteins which interact with a target protein, we hope to identify the hypothetical Protein X. Subsequent experiments will test the importance of Protein X in transformation. Once again it is proposed that understanding these mechanisms of MT-mediated transformation may lead to potential therapies for human cancers.
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