Gene Research Center, Key Laboratory of Glycoconjugate Research Ministry of Public Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.
J Cell Biochem. 2010 Apr 1;109(5):1013-24. doi: 10.1002/jcb.22484.
The androgen-signaling pathway plays critical roles in normal prostate development, benign prostatic hyperplasia, established prostate cancer, and in prostate carcinogenesis. In this study, we report that trihydrophobin 1 (TH1) is a potent negative regulator to attenuate the androgen signal-transduction cascade through promoting androgen receptor (AR) degradation. TH1 interacts with AR both in vitro and in vivo, decreases the stability of AR, and promotes AR ubiquitination in a ligand-independent manner. TH1 also associates with AR at the active androgen-responsive prostate-specific antigen (PSA) promoter in the nucleus of LNCaP cells. Decrease of endogenous AR protein by TH1 interferes with androgen-induced luciferase reporter expression and reduces endogenous PSA expression. Taken together, these results indicate that TH1 is a novel regulator to control the duration and magnitude of androgen signal transduction and might be directly involved in androgen-related developmental, physiological, and pathological processes.
雄激素信号通路在正常前列腺发育、良性前列腺增生、已建立的前列腺癌以及前列腺癌发生中发挥着关键作用。在这项研究中，我们报告三亲水性蛋白 1（TH1）是一种有效的负调节剂，通过促进雄激素受体（AR）降解来减弱雄激素信号转导级联。TH1 在体外和体内均与 AR 相互作用，降低 AR 的稳定性，并以配体非依赖性方式促进 AR 泛素化。TH1 还与 LNCaP 细胞中活跃的雄激素反应性前列腺特异性抗原（PSA）启动子处的 AR 核内结合。TH1 减少内源性 AR 蛋白会干扰雄激素诱导的荧光素酶报告基因表达，并降低内源性 PSA 表达。总之，这些结果表明 TH1 是一种控制雄激素信号转导持续时间和幅度的新型调节剂，可能直接参与与雄激素相关的发育、生理和病理过程。
