TGF-β/SMAD4 signaling pathway activates the HAS2-HA system to regulate granulosa cell state
TGF-β/SMAD4 signaling pathway activates the HAS2-HA system to regulate granulosa cell state
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TGF-β/SMAD4信号通路激活HAS2-HA系统调节颗粒细胞状态
DOI：
10.1002/jcp.29134
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发表时间：
2019-09-06
影响因子：
5.6
通讯作者：
Li, Qifa
中科院分区：
文献类型：
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作者：
Li, Xinyu;Du, Xing;Li, Qifa
tgf - β /SMAD4信号通路和HAS2-HA系统均可调控哺乳动物卵巢颗粒细胞（GC）状态。然而，tgf - β /SMAD4信号通路与HA系统在GCs中的调控关系尚不清楚。在这里，我们报道了tgf - β /SMAD4信号通路通过直接结合HAS2启动子激活HAS2- ha系统，最终通过CD44-Caspase3轴控制GC状态。smad4通过直接与HAS2基因启动子区相互作用诱导HAS2表达、HAS2驱动HA分泌以及HAS2介导的GC状态（增殖和凋亡）。位于HAS2-HA系统下游的CD44-Caspase3轴也被SMAD4和tgf - β /SMAD4信号通路激活。然而，在GCs中，没有发现HAS2-HA系统对tgf - β /SMAD4信号通路的反馈调节。此外，我们发现miRNA-26b通过smad4依赖性和非依赖性机制减弱HAS2的表达。我们的研究结果提供了令人信服的证据，证明HAS2是SMAD4的直接转录靶点。他们还揭示了tgf - β /SMAD4信号通路控制猪卵巢GC状态和改变GC结构成分的新机制。
Both TGF-beta/SMAD4 signaling pathway and HAS2-HA system have been shown to control granulosa cell (GC) state in mammalian ovary. However, the regulatory relationship between TGF-beta/SMAD4 signaling pathway and HA system in GCs is not well known. Here, we report that the TGF-beta/SMAD4 signaling pathway activates the HAS2-HA system by binding directly to the HAS2 promoter, ultimately controlling the GC state via the CD44-Caspase3 axis. SMAD4-induced HAS2 expression, HAS2-driven HA secretion, and HAS2-mediated GC state (proliferation and apoptosis) by interacting directly with the promoter region of the HAS2 gene. The CD44-Caspase3 axis, located downstream of the HAS2-HA system, was also activated by SMAD4 and the TGF-beta/SMAD4 signaling pathway. However, there was no feedback regulation of the TGF-beta/SMAD4 signaling pathway by the HAS2-HA system in GCs. In addition, we found that miRNA-26b attenuated HAS2 expression via SMAD4-dependent and -independent mechanisms. Our findings provide compelling evidence that HAS2 is a direct transcriptional target of SMAD4. They also reveal a novel mechanism by which the TGF-beta/SMAD4 signaling pathway controls the GC state and alters the structural components of GCs in porcine ovaries.