Binding of p53 to the KIX domain of CREB binding protein - A potential link to human T-cell leukemia virus, type I-associated leukemogenesis

The pleiotropic cellular coactivator CREB binding protein (CBP) plays a cri tical role in supporting p53-dependent tumor suppressor functions. p53 has been shown to directly interact with a carboxyl-terminal region of CBP for recruitment of the coactivator to p53-responsive genes. In this report, we identify the KM domain as a new p53 contact point on CBP. We show that both recombinant and endogenous forms of p53 specifically interact with KM. We demonstrate that the activation domain of p53 participates in KM binding an d provide evidence showing that this interaction is critical for p53 transa ctivation function. The human T-cell leukemia virus, type-I-encoded oncopro tein Tax is a well established repressor of p53 transcription function. Lik e p53, Tax also binds to KIX. The finding that both transcription factors b ind to a common region of CBP suggests that coactivator competition may acc ount for the observed repression. We demonstrate reciprocal repression betw een Tax and p53 in transient transfection assays, supporting the idea of in tracellular coactivator competition. We biochemically confirm coactivator c ompetition by directly showing that both transcription factors bind to KM i n a mutually exclusive fashion. These data provide molecular evidence for t he observed intracellular competition and suggest that Tax inhibits p53 fun ction by abrogating a novel p53-KIX interaction. Thus, Tax competition for the p53-KIX complex may be a pivotal event in the human T-cell leukemia vir us, type I transformation pathway.