Journal
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
Volume 7, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2019.00243
Keywords
transcriptional regulation; hepatic stellate cell; post-translational modification; signal transduction; liver fibrosis
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Funding
- National Natural Science Foundation of China [81971504, 81725001]
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Trans-differentiation of quiescent hepatic stellate cells (HSC) to myofibroblasts is a hallmark event in liver fibrosis. Previous studies have led to the discovery that myocardin-related transcription factor A (MRTF-A) is a key regulator of HSC trans-differentiation or, activation. In the present study we investigated the interplay between MRTFA and c-Abl (encoded by Abl1), a tyrosine kinase, in this process. We report that hepatic expression levels of c-Abl were down-regulated in MRTF-A knockout (KO) mice compared to wild type (WT) littermates in several different models of liver fibrosis. MRTFA deficiency also resulted in c-Abl down-regulation in freshly isolated HSCs from the fibrotic livers of mice. MRTF-A knockdown or inhibition repressed c-Abl in cultured HSCs in vitro. Further analyses revealed that MRTF-A directly bound to the Abl1 promoter to activate transcription by interacting with Sp1. Reciprocally, pharmaceutical inhibition of c-Abl suppressed MRTF-A activity. Mechanistically, c-Abl activated extracellular signal-regulated kinase (ERK), which in turn phosphorylated MRTF-A and promoted MRTF-A nuclear trans-localization. In conclusion, our data suggest that a c-Abl-MRTF-A positive feedback loop contributes to HSC activation and liver fibrosis.
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