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植物雌激素结合素可刺激雌激素相关受体 γ(ERRγ)的转录活性。

Transcriptional activity of estrogen-related receptor γ (ERRγ) is stimulated by the phytoestrogen equol.

机构信息

Institute of Biomedicine/Physiology, Biomedicum Helsinki, University of Helsinki, Finland.

出版信息

J Steroid Biochem Mol Biol. 2011 Jan;123(1-2):46-57. doi: 10.1016/j.jsbmb.2010.11.001. Epub 2010 Nov 5.

Abstract

Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor lacking identified natural ligands. The synthetic estrogen receptor ligands 4-hydroxytamoxifen and diethylstilbestrol have, however, been shown to bind to and abolish the constitutive transcriptional activity of ERRγ. Certain phytoestrogens were recently reported to act as agonists of the related ERRα. We investigated whether phytoestrogens also modulated the transcriptional activity of ERRγ. We analyzed a selection of phytoestrogens for their potential agonistic or antagonistic activity on ERRγ. In transiently transfected PC-3 and U2-OS cells equol stimulated the transcriptional activity of ERRγ and enhanced its interaction with the coactivator GRIP1. The agonistic effect of equol was abolished by 4-hydroxytamoxifen. Equol induced a conformational change in the ERRγ ligand-binding domain. Based on structural models of the ERRγ ligand-binding domain, we were able to introduce mutations that modulated the agonistic potential of equol. Finally, equol enhanced the growth inhibitory effect of ERRγ on the prostate cancer PC-3 cells. In conclusion, we have demonstrated that the phytoestrogen equol acts as an ERRγ agonist.

摘要

雌激素相关受体γ(ERRγ)是一种孤儿核受体,缺乏已鉴定的天然配体。然而,合成的雌激素受体配体 4-羟基他莫昔芬和己烯雌酚已被证明可以结合并消除 ERRγ 的组成型转录活性。最近有报道称某些植物雌激素是相关 ERRα 的激动剂。我们研究了植物雌激素是否也调节 ERRγ 的转录活性。我们分析了一系列植物雌激素,以研究它们对 ERRγ 的潜在激动或拮抗活性。在瞬时转染的 PC-3 和 U2-OS 细胞中,雌马酚刺激 ERRγ 的转录活性,并增强其与共激活因子 GRIP1 的相互作用。雌马酚的激动作用被 4-羟基他莫昔芬所消除。雌马酚诱导 ERRγ 配体结合域的构象变化。基于 ERRγ 配体结合域的结构模型,我们能够引入突变来调节雌马酚的激动潜力。最后,雌马酚增强了 ERRγ 对前列腺癌 PC-3 细胞的生长抑制作用。总之,我们已经证明植物雌激素雌马酚是 ERRγ 的激动剂。

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