The transcription factor SMAD4 and miR-10b contribute to E2 release and cell apoptosis in ovarian granulosa cells by targeting CYP19A1
The transcription factor SMAD4 and miR-10b contribute to E2 release and cell apoptosis in ovarian granulosa cells by targeting CYP19A1
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转录因子 SMAD4 和 miR-10b 通过靶向 CYP19A1 促进卵巢颗粒细胞 E2 释放和细胞凋亡
DOI：
10.1016/j.mce.2018.04.012
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发表时间：
2018-11-15
影响因子：
4.1
通讯作者：
Li, Qifa
中科院分区：
文献类型：
--
作者：
Li, Qiqi;Du, Xing;Li, Qifa
细胞色素P450家族19亚家族A成员1 （CYP19A1）基因编码雌二醇（E2）合成的关键酶芳香化酶，在猪卵泡闭锁期间下调。然而，其在卵泡闭锁中的作用和转录抑制机制在很大程度上是未知的。在本研究中，我们发现CYP19A1基因刺激猪颗粒细胞（GCs） E2释放并抑制细胞凋亡。SMAD4是一种抗凋亡调节因子，是猪CYP19A1基因的转录因子，通过直接结合CYP19A1基因启动子区域内的SMAD4结合元件（SBE），增强CYP19A1在猪GCs中的表达和功能。此外，我们发现促凋亡因子miR-10b直接与猪CYP19A1 mRNA的3'-UTR相互作用，抑制其在猪GCs中的表达和功能。总的来说，我们证明了CYP19A1是滤泡闭锁的抑制剂，并受SMAD4和miR-10b的调节。这些发现进一步揭示了CYP19A1在类固醇激素合成和GC凋亡中的作用机制，并为探索类固醇依赖性生殖疾病的治疗方法提供了分子靶点。
The cytochrome P450 family 19 subfamily A member 1 (CYP19A1) gene, encodes aromatase, a key enzyme in estradiol (E2) synthesis, and is down-regulated during porcine follicular atresia. However, its role in and the mechanism of transcriptional repression in follicular atresia is largely unknown. In the present study, we show that the CYP19A1 gene stimulates E2 release and inhibits cell apoptosis in porcine granulosa cells (GCs). SMAD4, an anti-apoptotic moderator, was identified as a transcription factor of the porcine CYP19A1 gene and enhanced the expression and function of CYP19A1 in porcine GCs through direct binding to a SMAD4-binding element (SBE) within the promoter region of CYP19A1 gene. Moreover, we found that miR-10b, a pro-apoptotic factor, directly interacted with 3'-UTR of the porcine CYP19A1 mRNA, inhibiting its expression and function in porcine GCs. Collectively, we demonstrated that CYP19A1 is an inhibitor of follicular atresia and is regulated by both SMAD4 and miR-10b. These findings provide further insight into the mechanisms of CYP19A1 in steroid hormone synthesis and GC apoptosis and provide molecular targets for exploring methods of treatment for steroid-dependent reproductive disorders.