SMAD4 Feedback Activates the Canonical TGF-β Family Signaling Pathways.
SMAD4 Feedback Activates the Canonical TGF-β Family Signaling Pathways.
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SMAD4 反馈激活经典 TGF-β 家族信号通路
DOI：
10.3390/ijms221810024
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发表时间：
2021-09-16
影响因子：
5.6
通讯作者：
Du X
中科院分区：
文献类型：
--
作者：
Liu L;Li Q;Yang L;Li Q;Du X
TGF-β家族信号通路，包括TGF-β和BMP途径，通过下游SMADS广泛参与健康和疾病的调节，这些SMAD也受到多种经过验证的机制的调节，例如遗传调节，表观遗传调节和反馈调节。但是，尚不清楚R-SMADS或CO-SMAD是否可以反馈调节颗粒细胞中TGF-β家族信号通路（GC）。 TGF-β配体水平通过与其上游受体的核心启动子相互作用，SMAD4充当转录因子，反馈激活其转录。通过与三个共同激活因子（C-JUN，CREB1和SP1）相互作用，包括ACVR1B，BMPR2和TGFBR2在内的上游接收器。 SMAD4介导的反馈调节上游受体通过相互的芯片分析首次表明我们的发现表明SMAD4反馈激活GCS中的规范TGF-β家族信号通路，该途径改善和扩展了调节机制，尤其是卵巢GC中TGF-β家族信号通路的反馈调节模式。
TGF-β family signaling pathways, including TGF-β and BMP pathways, are widely involved in the regulation of health and diseases through downstream SMADs, which are also regulated by multiple validated mechanisms, such as genetic regulation, epigenetic regulation, and feedback regulation. However, it is still unclear whether R-SMADs or Co-SMAD can feedback regulate the TGF-β family signaling pathways in granulosa cells (GCs). In this study, we report a novel mechanism underlying the feedback regulation of TGF-β family signaling pathways, i.e., SMAD4, the only Co-SMAD, positive feedback activates the TGF-β family signaling pathways in GCs with a basal level of TGF-β ligands by interacting with the core promoters of its upstream receptors. Mechanistically, SMAD4 acts as a transcription factor, and feedback activates the transcription of its upstream receptors, including ACVR1B, BMPR2, and TGFBR2, of the canonical TGF-β signaling pathways by interacting with three coactivators (c-JUN, CREB1, and SP1), respectively. Notably, three different interaction modes between SMAD4 and coactivators were identified in SMAD4-mediated feedback regulation of upstream receptors through reciprocal ChIP assays. Our findings in the present study indicate for the first time that SMAD4 feedback activates the canonical TGF-β family signaling pathways in GCs, which improves and expands the regulatory mechanism, especially the feedback regulation modes of TGF-β family signaling pathways in ovarian GCs.
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
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作者：
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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
影响因子：
9
作者：
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影响因子：
7.2
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影响因子：
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