DNA tumor virus SV40 has proven to be a valuable tool in the study of transformation of cells in culture and of tumorigenesis in animals. SV40 encodes an oncoprotein, large T antigen (Tag). The transforming activity of Tag has been linked to its ability to bind to and modulate the function of cellular proteins such as the retinoblastoma tumor suppressor gene product pRb and related proteins p107 and p130. Tag binds to and alters the phosphorylation stat of p107 and p130. Sequences within the amino terminal 82 residues of Tag that are not necessary for this binding are also required for the effect. This region of Tag has been implicated in transformation and replication and contains the putative binding domain for heat shock cognate protein 70 (Hsc70) which interacts with Tag. The principal aims of this research proposal are: 1) To determine whether Hsc70 binding to Tag is required for alteration of p107 and p130 phosphorylation by use of Tag mutants that can not bind Hsc70, 2) To study the influence of Hsc70 interaction with Tag on the replication and tranformation activities of Tag, 3) To generate Hsc70 mutants defective in ATP binding and ATP hydrolysis and use them to study the functional contribution of Hsc70 to Tag mediated events.
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