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Mol Cell Biol. 2011 Sep;31(18):3700-9. doi: 10.1128/MCB.05448-11. Epub 2011 Jul 26.

TSC-22 promotes transforming growth factor β-mediated cardiac myofibroblast differentiation by antagonizing Smad7 activity.

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The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.


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.

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