Induction of AR Transactivation by DHT and E2

DHT 和 E2 诱导 AR 反式激活

• 批准号: 6790025
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790025
• 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

项目成果

Androgen suppresses PML protein expression in prostate cancer CWR22R cells.

雄激素抑制前列腺癌 CWR22R 细胞中 PML 蛋白的表达。

• DOI: 10.1016/j.bbrc.2003.12.060
• 发表时间: 2004
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Yang,Lin;Yeh,Shauh-Der;Xie,Shaozhen;Altuwaijri,Saleh;Ni,Jing;Hu,Yueh-Chiang;Chen,Yen-Ta;Bao,Bo-Ying;Su,Ching-Hua;Chang,Chawnshang
• 通讯作者: Chang,Chawnshang

Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor.

• DOI: 10.1084/jem.20031233
• 发表时间: 2003-12-15
• 期刊: The Journal of experimental medicine
• 作者: Yeh S;Hu YC;Wang PH;Xie C;Xu Q;Tsai MY;Dong Z;Wang RS;Lee TH;Chang C
• 通讯作者: Chang C

Activation of mitogen-activated protein kinase pathway by the antiandrogen hydroxyflutamide in androgen receptor-negative prostate cancer cells.

雄激素受体阴性前列腺癌细胞中抗雄激素羟基氟他胺激活丝裂原激活蛋白激酶途径。

• 发表时间: 2002
• 期刊: Cancer research.
• 作者: Lee,Yi-Fen;Lin,Wen-Jye;Huang,Jiaoti;Messing,EdwardM;Chan,FrankyL;Wilding,George;Chang,Chawnshang
• 通讯作者: Chang,Chawnshang

Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells.

• DOI: 10.1016/s0006-291x(03)00792-7
• 发表时间: 2003-06
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Lin Yang;Liang Wang;Hui-Kuan Lin;Pu-Yeh Kan;Shaozhen Xie;M. Tsai;Peng-Hui Wang;Yen-Ta Chen;Chawnshang Chang

Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator.

• 发表时间: 2003-08
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: K. Nishimura;H. Ting;Y. Harada;T. Tokizane;N. Nonomura;Hong-Yo Kang;Hong-Chiang Chang;S. Yeh;H. Miyamoto;M. Shin;K. Aozasa;A. Okuyama;Chawnshang Chang