SMAD4 feedback regulates the canonical TGF-? signaling pathway to control granulosa cell apoptosis.

ABSTRACT: Canonical TGF-? signals are transduced from the cell surface to the cytoplasm, and then translocated into the nucleus, a process that involves ligands (TGF-?1), 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-? signaling pathway, regulates the canonical TGF-? 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-? 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-? 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-? signaling pathway, which was rescued by SMAD4 and TGF-?1. Overall, our findings demonstrate that a positive feedback mechanism exists within the canonical TGF-? signaling pathway. This study also provides new insights into mechanism underlying the canonical TGF-? signaling pathway, which regulates GC function and follicular development.

SUBMITTER: Du X 

PROVIDER: S-EPMC5833407 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature