Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator.
Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator.
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发表时间：
2003-08
期刊：
影响因子：
11.2
通讯作者：
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
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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
抗雄激素的部分激动剂作用已被充分证明，并且这种作用被前列腺癌细胞中衍生的突变雄激素受体（AR）放大。在这里，我们报告的凝溶胶蛋白（GSN）作为AR相关蛋白的鉴定。羟氟沙星（HF）和雄激素一样，可以剂量依赖性方式促进AR和GSN之间的相互作用。GSN通过其COOH末端结构域与AR DNA结合结构域和配体结合结构域相互作用。免疫定位研究表明，GSN在核转位过程中与AR相互作用。功能分析还表明，GSN增强AR活性的存在下，无论是雄激素或HF。代表AR DNA结合结构域和配体结合结构域的部分区域的两个肽可以阻断GSN增强的AR活性。在雄激素耗竭后，GSN的表达在LNCaP细胞、LNCaP异种移植物和人前列腺肿瘤中增强。在HF存在下，增加GSN的表达增强AR活性。总之，这些数据表明，HF的弱雄激素效应可能会通过在雄激素消融治疗后增加GSN的量来放大。因此，阻断AR和GSN之间的相互作用可能成为治疗前列腺癌的潜在治疗靶点。
The partial agonist effect of antiandrogens has been well documented, and such effect is amplified by derived mutant androgen receptors (ARs) in prostate cancer cells. Here we report the identification of gelsolin (GSN) as an AR-associated protein. Hydroxyflutamide (HF), as well as androgens, can promote the interaction between AR and GSN in a dose-dependent manner. GSN interacts with AR DNA-binding domain and ligand-binding domain via its COOH-terminal domain. Immunolocalization studies show that GSN interacts with AR during nuclear translocation. Functional analyses additionally demonstrate that GSN enhances AR activity in the presence of either androgen or HF. Two peptides representing partial regions of the AR DNA-binding domain and the ligand-binding domain can block the GSN-enhanced AR activity. The expression of GSN is enhanced in LNCaP cells, LNCaP xenografts, and human prostate tumors after androgen depletion. Increasing expression of GSN enhances the AR activity in the presence of HF. Together, these data suggest that the weak androgenic effect of HF may be amplified by increasing the amount of GSN after androgen ablation treatment. Therefore, blockage of the interaction between AR and GSN could become a potential therapeutic target for the treatment of prostate cancer.