Up-regulation of RACK1 by TGF-β1 promotes hepatic fibrosis in mice.
Up-regulation of RACK1 by TGF-β1 promotes hepatic fibrosis in mice.
复制标题
DOI：
10.1371/journal.pone.0060115
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Gu J
中科院分区：
文献类型：
--
作者：
Jia D;Duan F;Peng P;Sun L;Liu X;Wang L;Wu W;Ruan Y;Gu J
肝纤维化代表了对慢性肝损伤的持续伤口愈合反应的结果，并且静止的肝星状细胞（HSC）活化成肌纤维母细胞样表型被认为是肝纤维化的中心事件。RACK 1是活化的C-激酶1的受体，是一种经典的支架蛋白，涉及许多信号通路和细胞过程;然而，RACK 1在肝纤维化中的作用很少被定义。本文报道了RACK 1在体外和体内均以转化生长因子β 1（TGF-β1）依赖的方式在活化的HSC中上调，TGF-β1通过NF-κB信号刺激RACK 1的表达。此外，RACK 1促进TGF-β1和血小板衍生生长因子（PDGF）介导的促纤维化途径的活化以及HSC的分化、增殖和迁移。RACK 1的消耗抑制体内TAA诱导的肝纤维化的进展。此外，RACK 1在肝纤维化细胞中的表达也与临床病例中肝纤维化的分期呈正相关。我们的研究结果提示RACK 1作为TGF-β1的下游靶基因参与了体内外肝纤维化的调控，并提出了以RACK 1为靶点治疗肝纤维化的策略。
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.
登录
查看更多内容
DOI：
10.1111/j.1440-1746.2011.07006.x
发表时间：
2012-03-01
影响因子：
4.1
作者：
Inagaki, Yutaka;Higashiyama, Reiichi;Higashi, Kiyoshi
通讯作者：
Higashi, Kiyoshi
DOI：
10.1007/978-1-59745-019-5_13
发表时间：
2010-01-01
期刊：
MOUSE CELL CULTURE: METHODS AND PROTOCOLS
影响因子：
--
作者：
Li, Wan-Chun;Ralphs, Kate L.;Tosh, David
通讯作者：
Tosh, David
影响因子：
5.3
作者：
Nagashio, Ryo;Sato, Yuichi;Okayasu, Isao
通讯作者：
Okayasu, Isao
影响因子：
3.6
作者：
Choi, DS;Young, H;Messing, RO
通讯作者：
Messing, RO
影响因子：
13.5
作者：
Geerts, A;Eliasson, C;Pekny, M
通讯作者：
Pekny, M