Activating transcription factor 3 regulates canonical TGF? signalling in systemic sclerosis

Mallano T, Palumbo-Zerr K, Zerr P, Zeller B, Beyer C, Dees C, Huang J, Hai T, Distler O, Schett G, Distler J, Ramming A (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

Book Volume: 75

Pages Range: 586-92

Journal Issue: 3

DOI: 10.1136/annrheumdis-2014-206214

Abstract

Activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element binding (CREB) family of transcription factors, regulates cellular response to stress including oxidative stress. The aim of this study was to analyse the role of ATF3 in fibroblast activation in systemic sclerosis (SSc).ATF3 was analysed by reverse transcription quantitative PCR, western blot and immunohistochemistry. ATF3 knockout fibroblasts and mice were used to study the functional role of ATF3. Knockdown experiments, reporter assays and coimmunoprecipitation were performed to study the effects of ATF3 on Smad and activation protein 1 (AP-1) signalling. The role of c-Jun was analysed by costaining, specific inactivation and coimmunoprecipitation.Transforming growth factor-? (TGF?) upregulates the expression of ATF3 in SSc fibroblasts. ATF3-deficient fibroblasts were less sensitive to TGF?, whereas ectopic expression of ATF3 enhanced the profibrotic effects of TGF?. Mechanistically, ATF3 interacts with Smad3 directly on stimulation with TGF? and regulates Smad activity in a c-Jun-dependent manner. Knockout of ATF3 protected mice from bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active TGF? receptor I. Reporter assays and analyses of the expression of Smad target genes demonstrated that binding of ATF3 regulates the transcriptional activity of Smad3.We demonstrate for the first time a key role for ATF3 in fibrosis. Knockout of the ATF3 gene reduced the stimulatory effect of TGF? on fibroblasts by interfering with canonical Smad signalling and protected the mice from experimental fibrosis in two different models. ATF3 might thus be a candidate for molecular targeted therapies for SSc.

Authors with CRIS profile

Tatjana Mallano Department of Medicine 3 – Rheumatology and Immunology Pawel Zerr Department of Medicine 3 – Rheumatology and Immunology Barbara Zeller Medizinische Fakultät Christian Beyer Department of Medicine 3 – Rheumatology and Immunology Clara Dees Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose Andreas Ramming Department of Medicine 3 – Rheumatology and Immunology

Involved external institutions

Ohio State University US United States (USA) (US) Universitätsspital Zürich (USZ) CH Switzerland (CH)

How to cite

APA:

Mallano, T., Palumbo-Zerr, K., Zerr, P., Zeller, B., Beyer, C., Dees, C.,... Ramming, A. (2016). Activating transcription factor 3 regulates canonical TGF? signalling in systemic sclerosis. Annals of the Rheumatic Diseases, 75(3), 586-92. https://doi.org/10.1136/annrheumdis-2014-206214

MLA:

Mallano, Tatjana, et al. "Activating transcription factor 3 regulates canonical TGF? signalling in systemic sclerosis." Annals of the Rheumatic Diseases 75.3 (2016): 586-92.

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