| Title | TGF{beta}1-mediated Activation of the Smooth Muscle {alpha}-Actin Gene in Human Pulmonary Myofibroblasts Is Inhibited by TNF{alpha} via MEK1-dependent Induction of the Egr-1 Transcriptional Repressor. | | Author(s) | Liu X, Kelm RJ, Strauch AR | | Institution | Department of Physiology and Cell Biology and the Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH 43210; Departments of Medicine and Biochemistry, Cardiovascular Research Institute, University of Vermont College of Medicine, Burlington, VT 05405. | | Source | Mol Biol Cell 2009 Mar 4. | | Abstract | Monitoring Editor: Carl-Henrik Heldin Transforming growth factor beta1 (TGFbeta1) is a mediator of myofibroblast differentiation in healing wounds where it activates transcription of the smooth muscle alpha-actin (SMalphaA) gene via dynamic interplay of nuclear activators and repressors. Targeting components of TGFbeta1 signaling may be an effective strategy for controlling myofibroblasts in chronic fibrotic diseases. We examined the ability of proinflammatory tumor necrosis factor alpha (TNF-alpha) to antagonize TGFbeta1-mediated human pulmonary myofibroblast differentiation. TNF-alpha abrogated TGFbeta1-induced SMalphaA gene expression at the level of transcription without disrupting phosphorylation of regulatory Smads. Intact Mek-Erk kinase signaling was required for myofibroblast repression by TNF-alpha via induction of the Egr-1 DNA-binding protein. Egr-1 bound to the GC-rich SPUR activation element in the SMalphaA promoter and potently suppressed Smad3- and TGFbeta1-mediated transcription. Reduction in Smad binding to the SMalphaA promoter in TNF-alpha-treated myofibroblasts was accompanied by an increase in Egr-1 and YB-1 repressor binding suggesting that the molecular mechanism underlying repression may involve competitive interplay between Egr-1, YB-1 and Smads. The ability of TNF-alpha to attenuate myofibroblast differentiation via modulation of a Mek1/Erk/Egr-1 regulatory-axis may be useful in designing new therapeutic targets to offset destructive tissue remodeling in chronic fibrotic disease. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19261809 |
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