Essential Roles of RNA-binding Protein HuR in Activation of Hepatic Stellate Cells Induced by Transforming Growth Factor-?1.
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ABSTRACT: RNA-binding protein HuR mediates transforming growth factor (TGF)-?1-induced profibrogenic actions. Up-regulation of Sphingosine kinase 1 (SphK1) is involved in TGF-?1-induced activation of hepatic stellate cells (HSCs) in liver fibrogenesis. However, the molecular mechanism of TGF-?1 regulates SphK1 remains unclear. This study was designed to investigate the role of HuR in TGF-?1-induced SphK1 expression and identify a new molecular mechanism in liver fibrogenensis. In vivo, HuR expression was increased, translocated to cytoplasm, and bound to SphK1 mRNA in carbon tetrachloride- and bile duct ligation-induced mouse fibrotic liver. HuR mRNA expression had a positive correlation with mRNA expressions of SphK1 and fibrotic markers, ?-smooth muscle actin (?-SMA) and Collagen ?1(I), respectively. In vitro, up-regulation of SphK1 and activation of HSCs stimulated by TGF-?1 depended on HuR cytoplasmic accumulation. The effects of TGF-?1 were diminished when HuR was silenced or HuR cytoplasmic translocation was blocked. Meanwhile, overexpression of HuR mimicked the effects of TGF-?1. Furthermore, TGF-?1 prolonged half-life of SphK1 mRNA by promoting its binding to HuR. Pharmacological or siRNA-induced SphK1 inhibition abrogated HuR-mediated HSC activation. In conclusion, our data suggested that HuR bound to SphK1 mRNA and played a crucial role in TGF-?1-induced HSC activation.
SUBMITTER: Ge J
PROVIDER: S-EPMC4766441 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
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