Association of β-catenin with P-Smad3 but not LEF-1 dissociates in vitro profibrotic from anti-inflammatory effects of TGF-β1

被引：57

作者：

Tian, Xinrui ^{[1
,2
]}

Zhang, Jianlin ^{[1
,3
]}

Tan, Thian Kui ^{[1
]}

Lyons, J. Guy ^{[4
]}

Zhao, Hong ^{[1
,3
]}

Niu, Bo ^{[5
]}

Lee, So Ra ^{[1
]}

Tsatralis, Tania ^{[1
]}

Zhao, Ye ^{[1
]}

Wang, Ya ^{[1
]}

Cao, Qi ^{[1
]}

Wang, Changqi ^{[1
]}

Wang, Yiping ^{[1
]}

Lee, Vincent W. S. ^{[1
]}

Kahn, Michael ^{[6
]}

Zheng, Guoping ^{[1
]}

Harris, David C. H. ^{[1
]}

机构：

[1] Univ Sydney, Westmead Millennium Inst, Ctr Transplantat & Renal Res, Sydney, NSW 2145, Australia

[2] Shanxi Med Univ, Hosp 2, Dept Resp Med, Taiyuan 030001, Shanxi, Peoples R China

[3] Shanxi Med Univ, Dept Biochem & Mol Biol, Taiyuan 030001, Shanxi, Peoples R China

[4] Royal Prince Alfred Hosp, Sydney Canc Ctr, Sydney Head & Neck Canc Inst, Sydney, NSW 2006, Australia

[5] Capital Inst Pediat, Beijing 100020, Peoples R China

[6] Univ So Calif, Norris Comprehens Canc Ctr, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA

来源：

JOURNAL OF CELL SCIENCE | 2013年 / 126卷 / 01期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

TGF-beta; 1; beta-Catenin; P-Smad3; Epithelial-mesenchymal transition; Fibrosis; Inflammation; EPITHELIAL-MESENCHYMAL TRANSITION; GROWTH-FACTOR-BETA; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; MECHANISMS; INHIBITION; ACTIVATION; PATHWAYS; EMT; PHOSPHORYLATION;

D O I：

10.1242/jcs.103036

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Transforming growth factor beta 1 (TGF-beta 1) is known to be both anti-inflammatory and profibrotic. Cross-talk between TGF-beta/Smad and Wnt/beta-catenin pathways in epithelial-mesenchymal transition (EMT) suggests a specific role for beta-catenin in profibrotic effects of TGF-beta 1. However, no such mechanistic role has been demonstrated for beta-catenin in the anti-inflammatory effects of TGF-beta 1. In the present study, we explored the role of beta-catenin in the profibrotic and anti-inflammatory effects of TGF-beta 1 by using a cytosolic, but not membrane, beta-catenin knockdown chimera (F-TrCP-Ecad) and the beta-catenin/CBP inhibitor ICG-001. TGF-beta 1 induced nuclear Smad3/beta-catenin complex, but not beta-catenin/LEF-1 complex or TOP-flash activity, during EMT of C1.1 (renal tubular epithelial) cells. F-TrCP-Ecad selectively degraded TGF-beta 1-induced cytoplasmic beta-catenin and blocked EMT of C1.1 cells. Both F-TrCP-Ecad and ICG-001 blocked TGF-beta 1-induced Smad3/beta-catenin and Smad reporter activity in C1.1 cells, suggesting that TGF-beta 1-induced EMT depends on beta-catenin binding to Smad3, but not LEF-1 downstream of Smad3, through canonical Wnt. In contrast, in J774 macrophages, the beta-catenin level was low and was not changed by interferon-c (IFN-gamma) or lipopolysaccharide (LPS) with or without TGF-beta 1. TGF-beta 1 inhibition of LPS-induced TNF-alpha and IFN-gamma-stimulated inducible NO synthase (iNOS) expression was not affected by F-TrCP-Ecad, ICG-001 or by overexpression of wild-type beta-catenin in J774 cells. Inhibition of beta-catenin by either F-TrCP-Ecad or ICG-001 abolished LiCl-induced TOP-flash, but not TGF-beta 1-induced Smad reporter, activity in J774 cells. These results demonstrate for the first time that beta-catenin is required as a co-factor of Smad in TGF-beta 1-induced EMT of C1.1 epithelial cells, but not in TGF-beta 1 inhibition of macrophage activation. Targeting beta-catenin may dissociate the TGF-beta 1 profibrotic and anti-inflammatory effects.

引用

页码：67 / 76

页数：10

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