Induction of AR Transactivation by DHT and E2

描述(由申请人提供) 雄激素通过雄激素受体(AR)发挥作用，调节广谱 发育和生理过程，包括发育和 对前列腺的维护。然而，最近的研究表明，AR可以 17-雌二醇(E_2)在体外转录激活 AR协同调节器ARA70。在啮齿动物模型中，新生儿暴露于外源性 雌激素引起剂量依赖性的成人前列腺大小和 组织学。然而，雌激素受体(ER)a和P的靶向性干扰 在小鼠身上并没有确凿的表明ER在前列腺发育中的作用， 潜在地表明，外源性雌激素可能至少在一定程度上起作用 通过AR影响前列腺生长。雌激素和雄激素是 在结构上相似，主要差异出现在C-3位置 二羟基睾酮(DHT)携带酮基的类固醇A环 E2带有一个酚羟基。研究AR的氨基酸残基 介导E2诱导AR转录的能力及其机制 通过它，共同调节者区分DHT和E2结合的AR，我们 在特定的目标I中提出分离AR的转录突变 对DHT有反应，但不对E2有反应。在特定的目标2中，我们将分离AR突变体 优先对雌二醇组作出反应。在特定目标3中，我们将分离特定的 协同调节因子与DHT或E2结合的AR有差异地相互作用。具体而言 目的：探讨DHT或E_2诱导AR转录的机制 在AR共同监管者在场的情况下。最后，在具体目标5中，我们将 确定雌激素对前列腺细胞AR转录的诱导作用。这个 这一提议的成功不仅将使我们了解E2是如何调节的 AR转录，但也将提供有关AR在 对不同配体的反应，最终可能导致新的治疗方法 前列腺癌的治疗方法。

DESCRIPTION (Provided by the applicant) Androgens, acting through the androgen receptor (AR), mediate a wide spectrum of developmental and physiological processes, including the development and maintenance of the prostate. However, it has recently been shown that AR can be transcriptionally activated in vitro by 17(3-estradiol (E2) in the presence of the AR coregulator ARA70. In rodent models, neonatal exposure to exogenous estrogen results in a dose dependent alteration of adult prostate size and histology. However, targeted disruption of the estrogen receptors (ER) a and P in mice do not conclusively show a role for either ER in prostate development, potentially indicating that exogenous estrogens may be acting at least in part through AR to influence prostate growth. Estrogens and androgens are structurally similar with the major difference occurring at the C-3 position of the steroidal A-ring where dihydroxytestosterone (DHT) carries a keto group and E2 carries a phenolic hydroxyl. To investigate the amino acid residues of AR that mediate the ability of E2 to induce AR transcription, and the mechanism through which coregulators differentiate between DHT- and E2-bound AR, we propose in Specific Aim I to isolate mutations of AR that transcriptionally respond to DHT but not E2. In Specific Aim 2, we will isolate AR mutants the preferentially respond to E2. In Specific Aim 3, we will isolate specific coregulators that differentially interact with DHT- or E2-bound AR. In Specific Aim 4, we will determine the mechanism of DHT or E2 induced transcription of AR in the presence of AR coregulators. Finally, in Specific Aim 5 we will determine the effect of E2 induction of AR transcription in prostate cells. The success of this proposal will not only allow us to understand how E2 regulates AR transcription, but will also provide information on transcription by AR in response to different ligands, which may ultimately lead to novel therapeutic approaches to prostate cancer.