| Steroidogenic factor-1 (SF-1), a member of the orphan nuclear receptor superfamily, was first isolated from an adrenal cDNA library. It was shown to be expressed in the major steroidogenic organs and in the pituitary and ventromedial hypothalamus. SF-1 is a major activator of the Cyp19a1 expression, thus plays a key role in the process of steroid synthesis, adrenal and gonadal development, and sexual differentiation. Despite several studies have been shown many transcription factors have fuctional interactions with SF-1, we mainly focused on finding new transcription factors and exploring their roles in regulating the expression of Cyp19a1.At first, a new interacting partner of SF-1, Smad3, was found when we studied the role of SF-1 in TGF-β3-mediated E2 synthesis. Smad3, a mediator of TGF-βsignaling pathway, interacted specifically with SF-1 as proved by co-immunoprecipitation assay. In addition, the expression of Cyp19a1, a rate-limiting enzyme in E2 biosynthesis, can be synergistically promoted by the interaction between SF-1 and Smad3. Furthermore, knockdown of endogenous SF-1 abolished Smad3-induced Cyp19a1 mRNA expression, while knockdown of Smad3 by RNAi also attenuated SF-1 stimulation of Cyp19a1 mRNA in GCs. RNAi and ChIP studies also demonstrated that si-Smad3 and si-SF-1 decreased the binding of SF-1 and of Smad3 to Cyp19a1 PⅡ, respectively.Also, SF-1 was found to participate in TGF-β3-mediated proliferation of granulosa cells in ovarian folicullar development. The role of SF-1 in cell proliferation has never been reported, so our resuts provide a new perspective in studying the function of SF-1 in ovarian folicullar development.Taken together, our data provide a novel coactivator of SF-1 and their functional internation in TGF-β3-mediated E2 sythesis. Understanding of potential cross-points between extracellular signals affecting estrogen production will help to discover new therapeutic targets in estrogen-related diseases.
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