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TGF‐β/SMAD4 signaling pathway activates the HAS2–HA system to regulate granulosa cell state
Author(s) -
Li Xinyu,
Du Xing,
Yao Wang,
Pan Zengxiang,
Li Qifa
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29134
Subject(s) - cd44 , signal transduction , microbiology and biotechnology , transforming growth factor , biology , cell signaling , cell , biochemistry
Both TGF‐β/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‐β/SMAD4 signaling pathway and HA system in GCs is not well known. Here, we report that the TGF‐β/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‐β/SMAD4 signaling pathway. However, there was no feedback regulation of the TGF‐β/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‐β/SMAD4 signaling pathway controls the GC state and alters the structural components of GCs in porcine ovaries.