The early-immediate gene EGR-1 is induced by transforming growth factor-β and mediates stimulation of collagen gene expression

Shu Jen Chen, Hongyan Ning, Wataru Ishida, Snezna Sodin-Semrl, Shinsuke Takagawa, Yasuji Mori, John Varga

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

Transforming growth factor-β (TGF-β) stimulates collagen synthesis and accumulation, and aberrant TGF-β signaling is implicated in pathological organ fibrosis. Regulation of type I procollagen gene (COL1A2) transcription by TGF-β 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-β induced rapid and transient accumulation of Egr-1 protein and mRNA in human skin fibroblasts. In transient transfection assays, TGF-β stimulated the activity of the Egr-1 gene promoter, as well as that of a minimal Egr-1-responsive reporter construct. Furthermore, TGF-β 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-β. In contrast, the TGF-β 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-β 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-β 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-β and suggest that Egr-1 may play a new and important role in the pathogenesis of fibrosis.

Original languageEnglish (US)
Pages (from-to)21183-21197
Number of pages15
JournalJournal of Biological Chemistry
Volume281
Issue number30
DOIs
StatePublished - Jul 28 2006

Fingerprint

Immediate-Early Genes
Transforming Growth Factors
Gene expression
Intercellular Signaling Peptides and Proteins
Collagen
Genes
Gene Expression
Fibroblasts
Fibrosis
Binding Sites
GC Rich Sequence
DNA sequences
Cell growth
Transcription
Microarrays
Collagen Type I
Protein Kinases
Transfection
Cell Differentiation
Assays

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Chen, Shu Jen ; Ning, Hongyan ; Ishida, Wataru ; Sodin-Semrl, Snezna ; Takagawa, Shinsuke ; Mori, Yasuji ; Varga, John. / The early-immediate gene EGR-1 is induced by transforming growth factor-β and mediates stimulation of collagen gene expression. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 30. pp. 21183-21197.
@article{03a115f288004c88a3d35c64db3ddec3,
title = "The early-immediate gene EGR-1 is induced by transforming growth factor-β and mediates stimulation of collagen gene expression",
abstract = "Transforming growth factor-β (TGF-β) stimulates collagen synthesis and accumulation, and aberrant TGF-β signaling is implicated in pathological organ fibrosis. Regulation of type I procollagen gene (COL1A2) transcription by TGF-β 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-β induced rapid and transient accumulation of Egr-1 protein and mRNA in human skin fibroblasts. In transient transfection assays, TGF-β stimulated the activity of the Egr-1 gene promoter, as well as that of a minimal Egr-1-responsive reporter construct. Furthermore, TGF-β 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-β. In contrast, the TGF-β 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-β 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-β 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-β and suggest that Egr-1 may play a new and important role in the pathogenesis of fibrosis.",
author = "Chen, {Shu Jen} and Hongyan Ning and Wataru Ishida and Snezna Sodin-Semrl and Shinsuke Takagawa and Yasuji Mori and John Varga",
year = "2006",
month = "7",
day = "28",
doi = "10.1074/jbc.M603270200",
language = "English (US)",
volume = "281",
pages = "21183--21197",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "30",

}

The early-immediate gene EGR-1 is induced by transforming growth factor-β and mediates stimulation of collagen gene expression. / Chen, Shu Jen; Ning, Hongyan; Ishida, Wataru; Sodin-Semrl, Snezna; Takagawa, Shinsuke; Mori, Yasuji; Varga, John.

In: Journal of Biological Chemistry, Vol. 281, No. 30, 28.07.2006, p. 21183-21197.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The early-immediate gene EGR-1 is induced by transforming growth factor-β and mediates stimulation of collagen gene expression

AU - Chen, Shu Jen

AU - Ning, Hongyan

AU - Ishida, Wataru

AU - Sodin-Semrl, Snezna

AU - Takagawa, Shinsuke

AU - Mori, Yasuji

AU - Varga, John

PY - 2006/7/28

Y1 - 2006/7/28

N2 - Transforming growth factor-β (TGF-β) stimulates collagen synthesis and accumulation, and aberrant TGF-β signaling is implicated in pathological organ fibrosis. Regulation of type I procollagen gene (COL1A2) transcription by TGF-β 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-β induced rapid and transient accumulation of Egr-1 protein and mRNA in human skin fibroblasts. In transient transfection assays, TGF-β stimulated the activity of the Egr-1 gene promoter, as well as that of a minimal Egr-1-responsive reporter construct. Furthermore, TGF-β 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-β. In contrast, the TGF-β 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-β 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-β 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-β and suggest that Egr-1 may play a new and important role in the pathogenesis of fibrosis.

AB - Transforming growth factor-β (TGF-β) stimulates collagen synthesis and accumulation, and aberrant TGF-β signaling is implicated in pathological organ fibrosis. Regulation of type I procollagen gene (COL1A2) transcription by TGF-β 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-β induced rapid and transient accumulation of Egr-1 protein and mRNA in human skin fibroblasts. In transient transfection assays, TGF-β stimulated the activity of the Egr-1 gene promoter, as well as that of a minimal Egr-1-responsive reporter construct. Furthermore, TGF-β 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-β. In contrast, the TGF-β 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-β 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-β 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-β and suggest that Egr-1 may play a new and important role in the pathogenesis of fibrosis.

UR - http://www.scopus.com/inward/record.url?scp=33746374436&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746374436&partnerID=8YFLogxK

U2 - 10.1074/jbc.M603270200

DO - 10.1074/jbc.M603270200

M3 - Article

C2 - 16702209

AN - SCOPUS:33746374436

VL - 281

SP - 21183

EP - 21197

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 30

ER -