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J. Biol. Chem., Vol. 281, Issue 30, 21183-21197, July 28, 2006

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The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor- and Mediates Stimulation of Collagen Gene Expression^*

From the Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Transforming growth factor- (TGF-) stimulates collagen synthesis and accumulation, and aberrant TGF- signaling is implicated in pathological organ fibrosis. Regulation of type I procollagen gene (COL1A2) transcription by TGF- involves the canonical Smad signaling pathway as well as additional protein and lipid kinases, coactivators, and DNA-binding transcription factors that constitute alternate non-Smad pathways. By using Affymetrix microarrays to detect cellular genes whose expression is regulated by Smad3, we identified early growth response factor-1 (EGR-1) as a novel Smad3-inducible gene. Previous studies implicated Egr-1 in cell growth, differentiation, and survival. We found that TGF- induced rapid and transient accumulation of Egr-1 protein and mRNA in human skin fibroblasts. In transient transfection assays, TGF- stimulated the activity of the Egr-1 gene promoter, as well as that of a minimal Egr-1-responsive reporter construct. Furthermore, TGF- enhanced endogenous Egr-1 interaction with a consensus Egr-1-binding site element and with GC-rich DNA sequences of the human COL1A2 promoter in vitro and in vivo. Forced expression of Egr-1 by itself caused dose-dependent up-regulation of COL1A2 promoter activity and further enhanced the stimulation induced by TGF-. In contrast, the TGF- response was abrogated when the Egr-1-binding sites of the COL1A2 promoter were mutated or deleted. Furthermore, Egr-1-deficient embryonic mouse fibroblasts showed attenuated TGF- responses despite intact Smad activation, and forced expression of ectopic EGR-1 in these cells could restore COL1A2 stimulation in a dose-dependent manner. Taken together, these findings identify Egr-1 as a novel intracellular TGF- target that is necessary for maximal stimulation of collagen gene expression in fibroblasts. The results therefore implicate Egr-1 in the profibrotic responses elicited by TGF- and suggest that Egr-1 may play a new and important role in the pathogenesis of fibrosis.

Received for publication, April 6, 2006

^* This work was supported by Grants AR-42309 and AR-49025 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Rheumatology, Northwestern University, Feinberg School of Medicine. M-300 McGaw, 240 E. Huron St., Chicago, IL 60611. Tel.: 312-503-0368; Fax: 312-503-0994; E-mail: j-varga{at}northwestern.edu.

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