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

64 Citations (Scopus)

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

Fingerprint

Transforming Growth Factors
Fibrosis
Early Growth Response Protein 1
Growth
Fibroblasts
Serum Response Element
MAP Kinase Kinase 1
Messenger RNA
Skin
Mitogen-Activated Protein Kinase 3
Pulmonary Fibrosis
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase Kinases
Bleomycin
Transcriptional Activation
Signal Transduction
Phosphotransferases
Up-Regulation
Collagen
Biopsy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Bhattacharyya, Swati ; Chen, Shu Jen ; Wu, Minghua ; Warner-Blankenship, Matthew ; Ning, Hongyan ; Lakos, Gabriella ; Mori, Yasuji ; Chang, Eric ; Nihijima, Chihiro ; Takehara, Kazuhiro ; Feghali-Bostwick, Carol ; Varga, John. / Smad-independent transforming growth factor-β regulation of early growth response-1 and sustained expression in fibrosis : Implications for scleroderma. In: American Journal of Pathology. 2008 ; Vol. 173, No. 4. pp. 1085-1099.
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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.",
author = "Swati Bhattacharyya and Chen, {Shu Jen} and Minghua Wu and Matthew Warner-Blankenship and Hongyan Ning and Gabriella Lakos and Yasuji Mori and Eric Chang and Chihiro Nihijima and Kazuhiro Takehara and Carol Feghali-Bostwick and John Varga",
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Bhattacharyya, S, Chen, SJ, 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, vol. 173, no. 4, pp. 1085-1099. https://doi.org/10.2353/ajpath.2008.080382

Smad-independent transforming growth factor-β regulation of early growth response-1 and sustained expression in fibrosis : Implications for scleroderma. / Bhattacharyya, Swati; Chen, Shu Jen; Wu, Minghua; Warner-Blankenship, Matthew; Ning, Hongyan; Lakos, Gabriella; Mori, Yasuji; Chang, Eric; Nihijima, Chihiro; Takehara, Kazuhiro; Feghali-Bostwick, Carol; Varga, John.

In: American Journal of Pathology, Vol. 173, No. 4, 01.01.2008, p. 1085-1099.

Research output: Contribution to journalArticle

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T1 - Smad-independent transforming growth factor-β regulation of early growth response-1 and sustained expression in fibrosis

T2 - Implications for scleroderma

AU - Bhattacharyya, Swati

AU - Chen, Shu Jen

AU - Wu, Minghua

AU - Warner-Blankenship, Matthew

AU - Ning, Hongyan

AU - Lakos, Gabriella

AU - Mori, Yasuji

AU - Chang, Eric

AU - Nihijima, Chihiro

AU - Takehara, Kazuhiro

AU - Feghali-Bostwick, Carol

AU - Varga, John

PY - 2008/1/1

Y1 - 2008/1/1

N2 - 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.

AB - 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.

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