title: Up-regulation of RACK1 by TGF-β1 promotes hepatic fibrosis in mice.
abstract: Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injury, and activation of quiescent hepatic stellate cells (HSCs) into a myofibroblast-like phenotype is considered as the central event of liver fibrosis. RACK1, the receptor for activated C-kinase 1, is a classical scaffold protein implicated in numerous signaling pathways and cellular processes; however, the role of RACK1 in liver fibrosis is little defined. Herein, we report that RACK1 is up-regulated in activated HSCs in transforming growth factor beta 1 (TGF-β1)-dependent manner both in vitro and in vivo, and TGF-β1 stimulates the expression of RACK1 through NF-κB signaling. Moreover, RACK1 promotes TGF-β1 and platelet-derived growth factor (PDGF)-mediated activation of pro-fibrogenic pathways as well as the differentiation, proliferation and migration of HSCs. Depletion of RACK1 suppresses the progression of TAA-induced liver fibrosis in vivo. In addition, the expression of RACK1 in fibrogenic cells also positively correlates well with the stage of liver fibrosis in clinical cases. Our results suggest RACK1 as a downstream target gene of TGF-β1 involved in the modulation of liver fibrosis progression in vitro and in vivo, and propose a strategy to target RACK1 for liver fibrosis treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Jia
authors.forename: Fangfang
authors.initials: F
authors.lastname: Duan
authors.forename: Peike
authors.initials: P
authors.lastname: Peng
authors.forename: Linlin
authors.initials: L
authors.lastname: Sun
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Liu
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Weicheng
authors.initials: W
authors.lastname: Wu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ruan
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D000075370:Receptors for Activated C Kinase; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D009479:Neuropeptides; C090294:RACK1 protein, mouse; D000075370:Receptors for Activated C Kinase; D053773:Transforming Growth Factor beta1
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