Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China.
Endocrinology. 2011 Aug;152(8):3213-25. doi: 10.1210/en.2011-0102. Epub 2011 May 17.
The TGF-β superfamily members are indicated to play key roles in ovarian follicular development, such as granulosa cell proliferation, estrogens, and progesterone production. However, little is known about the roles of TGF-β3 in follicular development. In this study, we found that TGF-β3 was predominantly expressed in granulosa cells of mouse ovarian follicles, and it significantly promoted 17β-estradiol (E(2)) release in a dose-dependent manner. The orphan nuclear receptor steroidogenic factor-1 (SF-1) was required in TGF-β3-induced Cyp19a1 (a key rate-limiting enzyme for estrogen biosynthesis) expression and E(2) release. Additionally, TGF-β3 enhanced the binding of SF-1 to endogenous ovary-specific Cyp19a1 type II promoter, as evidenced by chromatin immunoprecipitation assays. The enhanced effect of SF-1 by TGF-β3 may be mediated through functional interactions between SF-1 and mothers against decapentaplegic homolog (Smad)3 (a mediator of TGF-β signaling pathway), because disruption of the interaction abolished the synergistic effects of SF-1, Smad3, and TGF-β3 on Cyp19a1 mRNA expression. RNA interference and chromatin immunoprecipitation studies also demonstrated that Smad3 was required for SF-1 binding to Cyp19a1 type II promoter and activation of Cyp19a1. Smad3 thus acts as a point of convergence that involves integration of SF-1 and TGF-β signaling in affecting E(2) production. Taken together, our data provide mechanistic insights into the roles of SF-1 in TGF-β3-mediated E(2) synthesis. Understanding of potential cross-points between extracellular signals affecting estrogen production will help to discover new therapeutic targets in estrogen-related diseases.
TGF-β 超家族成员被表明在卵巢卵泡发育中发挥关键作用，例如颗粒细胞增殖、雌激素和孕激素的产生。然而，关于 TGF-β3 在卵泡发育中的作用知之甚少。在这项研究中，我们发现 TGF-β3 主要在小鼠卵巢卵泡的颗粒细胞中表达，并且它以剂量依赖的方式显著促进 17β-雌二醇（E2）的释放。孤儿核受体类固醇生成因子-1（SF-1）是 TGF-β3 诱导 Cyp19a1（雌激素生物合成的关键限速酶）表达和 E2 释放所必需的。此外，TGF-β3 通过染色质免疫沉淀实验增强了 SF-1 与内源性卵巢特异性 Cyp19a1 型 II 启动子的结合。TGF-β3 对 SF-1 的增强作用可能是通过 SF-1 和母亲对抗 decapentaplegic 同源物（Smad）3（TGF-β 信号通路的介质）之间的功能相互作用介导的，因为破坏相互作用会消除 SF-1、Smad3 和 TGF-β3 对 Cyp19a1 mRNA 表达的协同作用。RNA 干扰和染色质免疫沉淀研究还表明 Smad3 是 SF-1 结合 Cyp19a1 型 II 启动子和激活 Cyp19a1 所必需的。因此，Smad3 作为一个汇聚点，涉及 SF-1 和 TGF-β 信号在影响 E2 产生中的整合。总之，我们的数据提供了 SF-1 在 TGF-β3 介导的 E2 合成中的作用的机制见解。了解影响雌激素产生的细胞外信号之间的潜在交叉点将有助于发现与雌激素相关疾病相关的新治疗靶点。
