The neoplastic transforming function of the SV40 large T antigen (T) and the adenoviral E1A product(s) depends, in part, upon binding by T/E1A to a series of cellular proteins, two of which, pRB and p53 [binds to T only], are known tumor suppressor gene products. The results of genetic analyses strongly suggest that, in the case of pRB-T binding, T dominates pRB and perturbs one or more aspects of its growth suppression function. This application will focus on another cellular protein which also binds to T and E1A-p107. Genetic analyses indicate that binding of this protein is also linked to the performance of T/E1A transforming function. Moreover, it and pRB, in part, interact physically with the same T and E1A sequences. A third protein, p300, is a known E1A binding element, and preliminary data suggest that it may bind to T as well. Again, genetic analyses strongly suggest a link between binding to these proteins and maintenance of their transforming function. Circumstantial evidence points to the possibility that p107 and p300 are also tumor suppressor gene products. The proposed experimental plan is aimed primarily at understanding how p107 and p300 function normally and how binding of two dominant DNA tumor viral oncogene products affects them.
