Induction of AR Transactivation by DHT and E2

DHT 和 E2 诱导 AR 反式激活

• 批准号: 6524666
• 负责人: CHAWNSHANG CHANG
• 金额: $ 27.91万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524666
• 关键词: androgen receptor; cadherins; dihydrotestosterone; estradiol; gene induction /repression; gene mutation; hormone regulation /control mechanism; prostate; receptor binding; tissue /cell culture; transcription factor; transfection; yeast two hybrid system

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.

描述（由申请人提供） 雄激素通过雄激素受体（AR）发挥作用， 发育和生理过程，包括发育和 前列腺的保养然而，最近有证据表明，AR可以 在存在17 β-雌二醇（E2）的情况下， AR协同调节因子ARA 70。在啮齿动物模型中，新生儿暴露于外源性 雌激素导致成人前列腺大小的剂量依赖性改变， 组织学然而，靶向破坏雌激素受体（ER）a和P 在小鼠中没有最终显示ER在前列腺发育中的作用， 这可能表明外源性雌激素可能至少部分地 通过AR来影响前列腺的生长。雌激素和雄激素是 结构相似，主要差异发生在C-3位， 类固醇A环，其中二羟基睾酮（DHT）携带酮基， E2带有酚羟基。研究AR的氨基酸残基 介导E2诱导AR转录的能力， 通过这些辅助调节子区分DHT和E2结合的AR，我们 在具体目标I中提出分离AR的突变， 对DHT有反应，但对E2无反应。在特定目标2中，我们将分离AR突变体， 优先选择E2。在特定目标3中，我们将分离特定 与DHT或E2结合的AR差异性相互作用的辅助调节因子。在特定 目的4、探讨DHT或E2诱导AR基因转录的机制 在AR辅助调节剂的存在下。在第五章中，我们将 确定前列腺细胞中E2诱导AR转录的作用。的 这项提议的成功不仅使我们能够了解E2如何调节 AR转录，但也将提供关于AR转录的信息， 反应不同的配体，这可能最终导致新的治疗 前列腺癌的治疗方法