First Author | Liang N | Year | 2011 |
Journal | Endocrinology | Volume | 152 |
Issue | 8 | Pages | 3213-25 |
PubMed ID | 21586554 | Mgi Jnum | J:174886 |
Mgi Id | MGI:5141371 | Doi | 10.1210/en.2011-0102 |
Citation | Liang N, et al. (2011) Steroidogenic Factor-1 Is Required for TGF-{beta}3-Mediated 17{beta}-Estradiol Synthesis in Mouse Ovarian Granulosa Cells. Endocrinology 152(8):3213-25 |
abstractText | The TGF-beta 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-beta3 in follicular development. In this study, we found that TGF-beta3 was predominantly expressed in granulosa cells of mouse ovarian follicles, and it significantly promoted 17beta-estradiol (E(2)) release in a dose-dependent manner. The orphan nuclear receptor steroidogenic factor-1 (SF-1) was required in TGF-beta3-induced Cyp19a1 (a key rate-limiting enzyme for estrogen biosynthesis) expression and E(2) release. Additionally, TGF-beta3 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-beta3 may be mediated through functional interactions between SF-1 and mothers against decapentaplegic homolog (Smad)3 (a mediator of TGF-beta signaling pathway), because disruption of the interaction abolished the synergistic effects of SF-1, Smad3, and TGF-beta3 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-beta signaling in affecting E(2) production. Taken together, our data provide mechanistic insights into the roles of SF-1 in TGF-beta3-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. |