title: Essential Roles of RNA-binding Protein HuR in Activation of Hepatic Stellate Cells Induced by Transforming Growth Factor-β1.
abstract: RNA-binding protein HuR mediates transforming growth factor (TGF)-β1-induced profibrogenic actions. Up-regulation of Sphingosine kinase 1 (SphK1) is involved in TGF-β1-induced activation of hepatic stellate cells (HSCs) in liver fibrogenesis. However, the molecular mechanism of TGF-β1 regulates SphK1 remains unclear. This study was designed to investigate the role of HuR in TGF-β1-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, α-smooth muscle actin (α-SMA) and Collagen α1(I), respectively. In vitro, up-regulation of SphK1 and activation of HSCs stimulated by TGF-β1 depended on HuR cytoplasmic accumulation. The effects of TGF-β1 were diminished when HuR was silenced or HuR cytoplasmic translocation was blocked. Meanwhile, overexpression of HuR mimicked the effects of TGF-β1. Furthermore, TGF-β1 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-β1-induced HSC activation.
authors.affiliation: Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ge
authors.affiliation: Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
authors.forename: Na
authors.initials: N
authors.lastname: Chang
authors.affiliation: Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
authors.forename: Zhongxin
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Duan
authors.affiliation: Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D005260:Female; D055166:Hepatic Stellate Cells / Q000502:physiology*; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D008813:Mice, Inbred ICR; D008875:Middle Aged; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D000067780:ELAV-Like Protein 1; D017853:Phosphotransferases (Alcohol Group Acceptor); D016601:RNA-Binding Proteins; D053773:Transforming Growth Factor beta1; D000099157:Sphingosine Kinase; C098770:ELAVL1 protein, human; C000593997:Elavl1 protein, mouse