Significant progress has been made over the last several years in unraveling the roles of AR in prostate cancer and the mechanisms by which AR regulates transcription. First, it has become clear that the transcriptional function of AR is mediated through a diverse array of proteins termed coactivators. Second, in addition to its pivotal roles in androgen-dependent prostate cancer, AR is now believed to be functionally active in most androgen-refractory prostate cancer and may actually contribute to the occurrence and progression of androgen-independent prostate cancer. Despite of [sic] this significant progress, however, the mechanisms by which diverse AR coactivators modulate AR activation are still poorly understood. As most of the AR coactivators have been studied by transient transfection assays, the relevance and the mechanisms by which these cofactors modulate AR activity should also be analyzed in the context of chromatin. In this application, we propose to investigate the molecular mechanisms by which SRC family coactivators, p300, and Ran/ARA24 modulate AR transcriptional activity in the context of chromatin by using Xenopus oocytes as a model system. In addition, as most of AR coactivators are identified by yeast two hybrid screenings, we propose to develop a biochemical approach to study and identify new AR coactivators. Finally, on the basis of our mechanistic studies, we propose to generate dominant negative coactivator molecules that can be used to inhibit or block the AR transcriptional function. We believe such molecules could be the potential therapeutic tools for prostate cancer therapy.
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