Smad-independent transforming growth factor-β regulation of early growth response-1 and sustained expression in fibrosis: Implications for scleroderma

Swati Bhattacharyya, Shu Jen Chen, Minghua Wu, Matthew Warner-Blankenship, Hongyan Ning, Gabriella Lakos, Yasuji Mori, Eric Chang, Chihiro Nihijima, Kazuhiro Takehara, Carol Feghali-Bostwick, John Varga*

*Corresponding author for this work

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) plays a key role in scleroderma pathogenesis. The transcription factor early growth response-1 (Egr-1) mediates the stimulation of collagen transcription elicited by TGF-β and is necessary for the development of pulmonary fibrosis in mice. Here, we report that TGF-β causes a time- and dose-dependent increase in Egr-1 protein and mRNA levels and enhanced transcription of the Egr-1 gene via serum response elements in normal fibroblasts. The ability of TGF-β to stimulate Egr-1 was preserved in Smad3-null mice and in explanted Smad3-null fibroblasts. The response was blocked by a specific mitogen-activated protein kinase kinase 1 (MEK1) inhibitor but not by an ALK5 kinase inhibitor. Furthermore, MEK1 was phosphorylated by TGF-β, which was sufficient to drive Egr-1 transactivation. Stimulation by TGF-β enhanced the transcriptional activity of Elk-1 via the MEK-extracellular signal-regulated kinase 1/2 pathway. Bleomycin-induced scleroderma in the mouse was accompanied by increased Egr-1 accumulation in lesional fibroblasts. Furthermore, biopsies of lesional skin and lung from patients with scleroderma showed increased Egr-1 levels, which were highest in early diffuse disease. Moreover, both Egr-1 mRNA and protein were elevated in explanted scleroderma skin fibroblasts in vitro. Together, these findings define a Smad-independent TGF-β signal transduction mechanism that underlies the stimulation of Egr-1, demonstrate for the first time sustained Egr-1 up-regulation in fibrotic lesions and suggests that Egr-1 has a role in the induction and progression of fibrosis.

Original languageEnglish (US)
Pages (from-to)1085-1099
Number of pages15
JournalAmerican Journal of Pathology
Volume173
Issue number4
DOIs
StatePublished - Jan 1 2008

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Bhattacharyya, S., Chen, S. J., Wu, M., Warner-Blankenship, M., Ning, H., Lakos, G., Mori, Y., Chang, E., Nihijima, C., Takehara, K., Feghali-Bostwick, C., & Varga, J. (2008). Smad-independent transforming growth factor-β regulation of early growth response-1 and sustained expression in fibrosis: Implications for scleroderma. American Journal of Pathology, 173(4), 1085-1099. https://doi.org/10.2353/ajpath.2008.080382