SV4O induces tumors in animals and transforms cells in culture by altering the activities of key regulatory circuits that govern cell proliferation and death. Two viral proteins, large T antigen and small t antigen, contribute to tumorigenesis. Small t antigen acts, in part, by inhibiting the pp2A phosphatase. The transforming activity of large T antigen requires its intervention on the Rb and p53 tumor suppressor pathways. Large T antigen directly associates with all three members of the Rb-family and with p53. T antigen mutants that fail to associate with Rb or p53 are defective for some aspect of transformation. We have shown that the amino-terminal 82 amino acids of large and small T antigens is a J domain and that both of these proteins function as DnaJ molecular chaperones. Furthermore, we have shown that the J domain acts in cis with the Rb-binding motif to effect T antigen-mediated release of E2F from Rb. Thus, T antigen does not simply sequester Rb, but rather participates in catalytic disruption of multiprotein complexes containing Rb and E2F. Date from our laboratory, as well as others, also indicates that T antigen does not block p53 function by simple sequestration. During the next period of support we will: (1) explore the mechanism by which the J domain contributes to T antigen action on Rb/E2F complexes. (2) determine how T antigen action on RbIE2F contributes to the transformed phenotype. (3) determine the mechanisms used by T antigen to block p53 function.
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