TSC-22 promotes transforming growth factor β-mediated cardiac myofibroblast differentiation by antagonizing Smad7 activity.
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.
Mesh Terms:
Animals, Cell Differentiation, Fibrosis, Fluorescent Antibody Technique, HEK293 Cells, Humans, Immunoblotting, Immunoprecipitation, Mice, Myocardium, Myofibroblasts, Phosphorylation, Protein-Serine-Threonine Kinases, RNA Interference, RNA, Small Interfering, Rats, Receptors, Transforming Growth Factor beta, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Smad2 Protein, Smad3 Protein, Smad7 Protein, Transforming Growth Factor beta, Ubiquitin-Protein Ligases, Ubiquitination
Animals, Cell Differentiation, Fibrosis, Fluorescent Antibody Technique, HEK293 Cells, Humans, Immunoblotting, Immunoprecipitation, Mice, Myocardium, Myofibroblasts, Phosphorylation, Protein-Serine-Threonine Kinases, RNA Interference, RNA, Small Interfering, Rats, Receptors, Transforming Growth Factor beta, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Smad2 Protein, Smad3 Protein, Smad7 Protein, Transforming Growth Factor beta, Ubiquitin-Protein Ligases, Ubiquitination
Mol. Cell. Biol.
Date: Sep. 01, 2011
PubMed ID: 21791611
View in: Pubmed Google Scholar
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