Mechanism(s) of AR gene repression in prostate cancer

描述（由申请人提供）：提案摘要：雄激素受体（AR）是配体激活转录因子核受体家族的成员，是男性生殖道调节以及肌肉发育和维持过程的关键调节因子。然而，此外，该受体的不适当信号传导与前列腺癌的发病机制有关（1，2）。因此，尽管雄激素在治疗性腺功能减退和恶病质方面具有临床效用，但其对前列腺功能的不良副作用限制了其应用。这一发现强调了对以组织选择性方式表现出雄激素作用的化合物的需要。这类化合物，现在称为选择性雄激素受体调节剂（SARM），直到最近才被考虑。现在认为，组织/过程选择性雄激素将通过利用配体促进受体与一种辅因子优先相互作用的能力来开发（3，4）。尽管迄今为止该领域的大部分工作集中在确定AR-辅因子在基因活化过程中的作用，但我们已经清楚地看到，缺乏对辅因子在负调控基因转录中的作用的研究。因此，我们已经使用（a）经典基因阵列研究来鉴定几百个基因，其表达在前列腺癌细胞中被雄激素下调，（B）高通量蛋白质-蛋白质相互作用筛选来分离265种与配体激活的AR相互作用的蛋白质，和（c）化学筛选来定义允许辅因子差异募集到AR的小分子。有了这些关键的工具，我们就可以开始确定对AR介导的靶基因阻遏作用重要的辅因子。为了完成这些目标，我们提出了以下具体目标：目标1：AR配体的机制属性的定义，使其能够抑制基因转录目标2：AR介导的基因阻遏所需的辅因子的鉴定目标3：AR和辅因子募集到AR阻遏基因的鉴定和比较分析相关性：据估计，2006年将有234，460名男性被诊断患有前列腺癌，27，350名男性将死于前列腺癌。因此，由于雄激素受体（AR）在前列腺癌中的作用，鉴定可以将AR的积极作用与消极作用分离的前列腺癌治疗和预防是非常必要的。其中提出的研究将有助于这些发现。

DESCRIPTION (provided by applicant): Proposal Summary: The androgen receptor (AR), a member of the nuclear receptor family of ligand activated transcription factors, is a key regulator of the processes involved in the regulation of the male reproductive tract and in the development and maintenance of muscle. In addition however, inappropriate signaling by this receptor is implicated in the pathogenesis of prostate cancer (1,2). Thus, although androgens have clinical utility for the treatment of hypogonadism and cachexia, the untoward side effects with respect to prostate function have limited their use. This finding highlights the need for compounds whose androgenic actions are manifest in a tissue selective manner. Compounds of this class, now referred to as Selective Androgen Receptor Modulators (SARMs) were not comtemplated until recently. It is now considered that tissue/process selective androgens will be developed by exploiting the ability of ligands to facilitate the preferential interaction of the receptor with one cofactor over another (3,4). Whereas the majority of work in the field to date has focused on defining the roles of AR-cofactors in the process of.gene activation it has become clear to us that an examination of the roles of cofactors in negatively regulated gene transcription is lacking. Thus we have used (a) classical gene array studies to identify several hundred genes whose expression is downregulated by androgens in prostate cancer cells, (b) high throughput protein-protein interaction screens to isolate 265 proteins that interact with ligand activated AR and (c) chemical screens to define small molecules that permit the differential recruitment of cofactors to AR. With these key tools in hand we are in a good position to begin to define the cofactors that are important for AR- mediated target gene repression. To complete these goals, we propose the following specific aims: Aim 1: Definition of the mechanistic attributes of an AR-ligand that enable it to suppress gene transcription Aim 2: Identification of the cofactors required for AR-mediated gene repression Aim 3: Identification and comparative analysis of AR and cofactor recruitment to AR repressed genes Relevance: It is estimated in 2006, 234,460 men will be diagnosed with and 27,350 men will die from prostate cancer. Thus, due to the role of androgen receptor (AR) in prostate cancer, the identification of prostate cancer treatments and preventatives that can uncouple the positive effects from the negative effects of AR are of high necessity. The studies proposed within will assist in such discoveries.