The main goal of this work is to understand how SV40 large T Ag(T), adenovirus EIA, and HPV E7 function as neoplastic transforming elements. They operate, in part, through strong, specific interactions with the nuclear pocket proteins (pRB, p107, p130). The latter function as biochemical regulators of the E2F family of transcription factors. pRB participates as a major GIIS progression control element, in part, through specific interactions with selected members of the E2F family. In the next granting period, we propose to investigate the significance of mounting evidence that pRB and the other pocket protein(s) also have DNA damage-associated cell cycle checkpoint control function(s) which contribute to their transformation repression function. The contribution of pocket protein/ E2F interactions to these processes will also be explored, along with the mechanisms by which RB and E2F-l serve their tumor suppression function. Finally, we will continue our efforts to understand how E2F-4,5, and a newly discovered species, E2F-6, a transcriptional repression, operate with special emphasis on understanding whether they normally function as proliferation controlling proteins.
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