Androgen receptor (AR) NH2- and COOH-terminal interactions result in the differential influences on the AR-mediated transactivation and cell growth
Androgen receptor (AR) NH2- and COOH-terminal interactions result in the differential influences on the AR-mediated transactivation and cell growth
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DOI：
10.1210/me.2004-0190
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发表时间：
2005-02-01
影响因子：
--
通讯作者：
Chang, CS
中科院分区：
文献类型：
--
作者：
Hsu, CL;Chen, YL;Chang, CS
早期的研究表明，雄激素受体（AR）的NH 2-和COOH-末端（N-C）的相互作用对完整的AR功能很重要。然而，这些相互作用对AR体内效应的影响仍不清楚。在这里，我们测试了一些AR相关肽和辅助调节子，以确定它们对AR N-C相互作用，AR反式激活和AR辅助调节子功能的影响。结果表明，AR共激活剂ARA 70 N、凝溶胶蛋白、ARA 54和SRC-1等均能增强AR的反式激活，但对N-C相互作用的影响不同。相反，AR辅阻遏物ARA 67和Rad 9可以抑制AR反式激活，其中ARA 67增强AR N-C相互作用，Rad 9抑制AR N-C相互作用。此外，配体AR C末端相关肽可以阻断AR N-C相互作用，但只有选择性肽可以阻断AR反式激活和辅助调节功能。我们发现所有测试的肽在5 α-二氢睾酮的存在下都可以不同程度地抑制前列腺癌LNCaP细胞的生长，但是只有测试的含FXXLF的肽，而不是含FXXMF的肽，可以抑制前列腺癌CWR 22 R细胞的生长。总之，这些结果表明，AR N-C相互作用的影响可能并不总是与AR介导的反式激活和/或AR介导的细胞生长的类似影响相关。因此，通过靶向AR N-C相互作用设计的药物作为前列腺癌治疗的治疗干预可能会面临不可预测的体内效应。
Early reports showed that androgen receptor (AR) NH2- and COOH-terminal (N-C) interaction was important for full AR function. However, the influence of these interactions on the AR in vivo effects remains unclear. Here we tested some AR-associated peptides and coregulators to determine their influences on AR N-C interaction, AR transactivation, and AR coregulator function. The results showed that AR coactivators such as ARA70N, gelsolin, ARA54, and SRC-1 can enhance AR transactivation but showed differential influences on the N-C interaction. In contrast, AR corepressors ARA67 and Rad9 can suppress AR transactivation, with ARA67 enhancing and Rad9 suppressing AR N-C interaction. Furthermore, liganded AR C terminus-associated peptides can block AR N-C interaction, but only selective peptides can block AR transactivation and coregulator function. We found all the tested peptides can suppress prostate cancer LNCaP cell growth at different levels in the presence of 5alpha-dihydrotestosterone, but only the tested FXXLF-containing peptides, not FXXMF-containing peptides, can suppress prostate cancer CWR22R cell growth. Together, these results suggest that the effects of AR N-C interactions may not always correlate with similar effects on AR-mediated transactivation and/or AR-mediated cell growth. Therefore, drugs designed by targeting AR N-C interaction as a therapeutic intervention for prostate cancer treatment may face unpredictable in vivo effects.