The University of Texas Medical School at Houston, TX 77030, USA.
Biochem J. 2010 Apr 14;427(3):499-511. doi: 10.1042/BJ20091631.
We previously demonstrated that the Groucho protein AES (amino-terminal enhancer of split) functions as a co-repressor of the AR (androgen receptor). It physically interacts with the N-terminal domain of AR and inhibits AR-driven transcription, but the molecular mechanism of its action remained unclear. In the present paper we report that the AES protein contains one inhibitory domain, and one positive and one negative regulatory domain. The negative regulatory domain inhibits AES dimerization and AES-mediated inhibition of AR-driven transcription through an interaction with the inhibitory domain. The positive regulatory domain blocked this interaction and relieved the inhibitory effect. In addition, we discovered mechanisms by which AES regulates AR transcriptional activity, which included disruption of the interaction between the AR N-terminal and C-terminal domains, and inhibition of AR-DNA interaction. Although AES broadly inhibited the activity of androgen-dependent luciferase reporters in a transient transfection assay, it selectively regulated the expression of endogenous androgen-dependent genes in prostate cancer cells.
我们之前的研究表明，Groucho 蛋白 AES（split 的氨基末端增强子）作为 AR（雄激素受体）的共抑制因子发挥作用。它与 AR 的 N 端结构域相互作用，抑制 AR 驱动的转录，但其作用的分子机制尚不清楚。在本文中，我们报告 AES 蛋白含有一个抑制结构域，一个正调节结构域和一个负调节结构域。负调节结构域通过与抑制结构域相互作用，抑制 AES 二聚化和 AES 介导的 AR 驱动转录抑制。正调节结构域阻断了这种相互作用，从而解除了抑制作用。此外，我们发现 AES 调节 AR 转录活性的机制，包括破坏 AR N 端和 C 端结构域之间的相互作用，以及抑制 AR-DNA 相互作用。虽然 AES 在瞬时转染试验中广泛抑制雄激素依赖性荧光素酶报告基因的活性，但它选择性地调节前列腺癌细胞中内源性雄激素依赖性基因的表达。
