AR Coactivators, Mechanisms & Roles in Prostate Cancer

描述（由申请人提供）： 在过去的几年里，在阐明AR在前列腺癌中的作用以及AR调节转录的机制方面取得了重大进展。首先，已经清楚的是，AR的转录功能是通过称为共激活因子的多种蛋白质介导的。其次，除了在雄激素依赖性前列腺癌中的关键作用外，现在认为AR在大多数雄激素难治性前列腺癌中具有功能活性，实际上可能有助于雄激素非依赖性前列腺癌的发生和进展。尽管取得了这一重大进展，然而，不同的AR共激活因子调节AR激活的机制仍然知之甚少。由于大多数的AR辅激活剂已经通过瞬时转染试验进行了研究，这些辅因子调节AR活性的相关性和机制也应在染色质的背景下进行分析。在这个应用中，我们建议调查SRC家族共激活因子，p300，和RAN/ARA 24调节AR转录活性的染色质的背景下，通过使用非洲爪蟾卵母细胞作为模型系统的分子机制。此外，由于大多数AR辅激活因子是通过酵母双杂交筛选鉴定的，因此我们建议开发一种生物化学方法来研究和鉴定新的AR辅激活因子。最后，在我们的机制研究的基础上，我们建议产生显性负性辅激活因子分子，可用于抑制或阻断AR转录功能。我们相信这些分子可能是前列腺癌治疗的潜在治疗工具。

DESCRIPTION (provided by applicant): 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.