Studies will be carried out on the mechanisms by which polyoma virus's middle T and small t antigens transform cultured fibroblasts. Middle T is thought to transform by binding to and modulating the activities of certain key cellular proteins. Similarly small t is thought to carry out its helper role in transformation via binding host cell proteins. In the past the identification and study of these cellular proteins has been a facile and efficient route to knowledge about intracellular signaling pathways involved in growth factor action and transformation. The applicant's studies in the current grant period will focus on three complementary aspects of middle T antigen: First a series of newly developed techniques will be utilized to search for additional cellular proteins which are bound by middle and small t antigens. Second he will continue our work on two known binding proteins, Pi 3 kinase and hsc70. In the case of Pi3 kinase he will define the mechanisms by which it causes enhanced apoptosis in Rat 1 fibroblasts and down regulates EGF receptor function. In the case of hsc70 he will study how its binding partner on T antigens, the so called dnaJ domain, functions in small and middle T. Finally he will utilize a newly developed class of middle T mutations, the Rescue Mutants, to extend the use of Middle T in studying cellular signaling.
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