SMAD4 feedback regulates the canonical TGF-β signaling pathway to control granulosa cell apoptosis.
SMAD4 feedback regulates the canonical TGF-β signaling pathway to control granulosa cell apoptosis.
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SMAD4 反馈调节经典 TGF-β 信号通路以控制颗粒细胞凋亡
DOI：
10.1038/s41419-017-0205-2
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发表时间：
2018-02-02
影响因子：
9
通讯作者：
Li Q
中科院分区：
文献类型：
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作者：
Du X;Pan Z;Li Q;Liu H;Li Q
典型的TGF-β信号从细胞表面转导到细胞质，然后易位到细胞核中，这一过程涉及配体（TGF-β1）、受体（TGFBR 2/1）、受体激活的SMAD（SMAD 2/3）和常见的SMAD（SMAD 4）。在这里，我们提供的证据表明，SMAD 4，经典的TGF-β信号通路的核心组成部分，通过反馈机制调节猪颗粒细胞（GC）中的经典TGF-β信号通路。全基因组分析和qRT-PCR显示SMAD 4影响GC中miRNA的生物合成。有趣的是，典型TGF-β信号传导途径的II型受体TGFBR 2在SMAD 4沉默的GC中下调，并且被发现是SMAD 4抑制的miRNA的共同靶标。miR-425是SMAD 4沉默的GC中最显著升高的miRNA，介导了TGF-β信号通路的SMAD 4反馈调节。这是通过转录因子SMAD 4和miR-425启动子之间的直接相互作用以及miR-425和TGFBR 2 3′-UTR之间的直接相互作用实现的。此外，miR-425通过靶向TGFBR 2和经典TGF-β信号通路增强GC凋亡，这被SMAD 4和TGF-β1挽救。总的来说，我们的研究结果表明，在典型的TGF-β信号通路中存在正反馈机制。本研究还为经典TGF-β信号通路调节GC功能和卵泡发育的机制提供了新的见解。
Canonical TGF-β signals are transduced from the cell surface to the cytoplasm, and then translocated into the nucleus, a process that involves ligands (TGF-β1), receptors (TGFBR2/1), receptor-activated SMADs (SMAD2/3), and the common SMAD (SMAD4). Here we provide evidence that SMAD4, a core component of the canonical TGF-β signaling pathway, regulates the canonical TGF-β signaling pathway in porcine granulosa cells (GCs) through a feedback mechanism. Genome-wide analysis and qRT-PCR revealed that SMAD4 affected miRNA biogenesis in GCs. Interestingly, TGFBR2, the type II receptor of the canonical TGF-β signaling pathway, was downregulated in SMAD4-silenced GCs and found to be a common target of SMAD4-inhibited miRNAs. miR-425, the most significantly elevated miRNA in SMAD4-silenced GCs, mediated the SMAD4 feedback regulation of the TGF-β signaling pathway. This was accomplished through a direct interaction between the transcription factor SMAD4 and the miR-425 promoter, and a direct interaction between miR-425 and the TGFBR2 3′-UTR. Furthermore, miR-425 enhanced GC apoptosis by targeting TGFBR2 and the canonical TGF-β signaling pathway, which was rescued by SMAD4 and TGF-β1. Overall, our findings demonstrate that a positive feedback mechanism exists within the canonical TGF-β signaling pathway. This study also provides new insights into mechanism underlying the canonical TGF-β signaling pathway, which regulates GC function and follicular development.
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DOI：
10.1073/pnas.1612024114
发表时间：
2016-12-20
影响因子：
11.1
作者：
Fedeli, Maya;Riba, Michela;Casorati, Giulia
通讯作者：
Casorati, Giulia
影响因子：
64.8
作者：
Davis, Brandi N.;Hilyard, Aaron C.;Hata, Akiko
通讯作者：
Hata, Akiko
影响因子：
8
作者：
Liu T;Zhao M;Liu J;He Z;Zhang Y;You H;Huang J;Lin X;Feng XH
通讯作者：
Feng XH
影响因子：
21.3
作者：
Bai, RY;Koester, C;Duyster, J
通讯作者：
Duyster, J
影响因子：
8
作者：
通讯作者：
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