title: Steroidogenic factor-1 is required for TGF-beta3-mediated 17beta-estradiol synthesis in mouse ovarian granulosa cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ning
authors.initials: N
authors.lastname: Liang
authors.forename: Yinglei
authors.initials: Y
authors.lastname: Xu
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Yin
authors.forename: Guidong
authors.initials: G
authors.lastname: Yao
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.forename: Guishuan
authors.initials: G
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Lian
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics; D004958:Estradiol / Q000096:biosynthesis*; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D051900:Smad3 Protein / Q000502:physiology; D054339:Steroidogenic Factor 1 / Q000502:physiology*; D015533:Transcriptional Activation; D053782:Transforming Growth Factor beta3 / Q000502:physiology*
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D054339:Steroidogenic Factor 1; D053782:Transforming Growth Factor beta3; C515058:steroidogenic factor 1, mouse; D004958:Estradiol; D001141:Aromatase