Article ; Online: Essential Roles of RNA-binding Protein HuR in Activation of Hepatic Stellate Cells Induced by Transforming Growth Factor-β1.
2016 Volume 6, Page(s) 22141
Abstract: RNA-binding protein HuR mediates transforming growth factor (TGF)-β1-induced profibrogenic actions ... by promoting its binding to HuR. Pharmacological or siRNA-induced SphK1 inhibition abrogated HuR-mediated HSC ... unclear. This study was designed to investigate the role of HuR in TGF-β1-induced SphK1 expression and ...
| 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. |
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| MeSH term(s) | Adult ; Aged ; Animals ; ELAV-Like Protein 1/metabolism ; Female ; Hepatic Stellate Cells/physiology ; Humans ; Liver Cirrhosis/pathology ; Male ; Mice, Inbred ICR ; Middle Aged ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; RNA-Binding Proteins/metabolism ; Transforming Growth Factor beta1/metabolism |
| Chemical Substances | ELAV-Like Protein 1 ; ELAVL1 protein, human ; Elavl1 protein, mouse ; RNA-Binding Proteins ; Transforming Growth Factor beta1 ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-) |
| Language | English |
| Publishing date | 2016-02-25 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2615211-3 |
| ISSN | 2045-2322 ; 2045-2322 |
| ISSN (online) | 2045-2322 |
| ISSN | 2045-2322 |
| DOI | 10.1038/srep22141 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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