Open AccessTSC-22 Promotes Transforming Growth Factor β-Mediated Cardiac Myofibroblast Differentiation by Antagonizing Smad7 Activity
Author(s) -
Xiaohua Yan,
Zhang Junyu,
Pei Lin,
Peng Wang,
Hua Xue,
Long Zhang,
Xia Gao,
Xingang Zhao,
Yuanheng Ning,
Ye-Guang Chen
Publication year - 2011
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.05448-11
Subject(s) - myofibroblast , transforming growth factor , downregulation and upregulation , biology , gene silencing , cardiac fibrosis , transforming growth factor beta , phosphorylation , fibrosis , signal transduction , receptor , microbiology and biotechnology , fibronectin , smad , smad2 protein , r smad , cancer research , growth factor , medicine , gene , tgf alpha , extracellular matrix , biochemistry
Transforming growth factor β (TGF-β) plays a critical role in tissue fibrosis. The duration and intensity of TGF-β signaling are tightly regulated. Here we report that TSC-22 (TGF-β-stimulated clone 22) facilitates TGF-β signaling by antagonizing Smad7 activity to increase receptor stability. TSC-22 enhances TGF-β-induced Smad2/3 phosphorylation and transcriptional responsiveness. The stimulatory effect of TSC-22 is dependent on Smad7, as silencing Smad7 expression abolishes it. TSC-22 interacts with TGF-β type I receptor TβRI and Smad7 in mutually exclusive ways and disrupts the association of Smad7/Smurfs with TβRI, thereby preventing ubiquitination and degradation of the receptor. We also found that TSC-22 can promote the differentiation of cardiac myofibroblasts by increasing expression of the fibrotic genes for α-smooth muscle actin (α-SMA), PAI-1, fibronectin, and collagen I, which is consistent with upregulation of TSC-22, phospho-Smad2/3, and the fibrotic genes in isoproterenol-induced rat myocardial fibrotic hearts. Taken together with the notion that TGF-β induces TSC-22 expression, our findings suggest that TSC-22 regulates TGF-β signaling via a positive-feedback mechanism and may contribute to myocardial fibrosis.