BARD1 mediates TGF-β signaling in pulmonary fibrosis

Respiratory Research

Irmgard Irminger-Finger³  Geoffrey J. Laurent³  Melanie Königshoff¹  Constance Barazzone-Argiroffo⁵  Bruno Crestani⁶  Jean-Claude Pache²  Rachel C. Chambers⁷  Yves Donati⁵  Stéphanie Carnesecchi⁵  Sarah Vierkotten¹  Cecilia M. Prêle³  Pierre-Alain André⁴ 

[1] Comprehensive Pneumology Center Ludwig Maximilians University, University Hospital Grosshadern and Helmholtz Zentrum München, Munich, Germany;Department of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland;Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia;Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland;Department of Pediatrics and Pathology/Immunology, University of Geneva, Geneva, Switzerland;INSERM, Unité 1152, University of Paris Diderot and Hopital Bichat, Paris, France;Centre for Inflammation and Tissue Repair, University College London, London, UK

关键词: Epithelial-mesenchymal transition (EMT);    Differential splicing;    Proliferation;    Apoptosis;    Lung fibrosis;    TGF-β;    BARD1;   

Others  :  1233517
DOI  :  10.1186/s12931-015-0278-3

 received in 2015-04-01, accepted in 2015-09-17,  发布年份 2015

【 摘 要 】

Background

Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-β signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1β, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis.

Methods

We investigated BARD1 expression as a function of TGF-β in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients.

Results

FL BARD1 and BARD1β were upregulated in response to TGF-β in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1β in fibrotic tissues.

Conclusion

Our data suggest that FL BARD1 and BARD1β might be mediators of pleiotropic effects of TGF-β. In particular BARD1β might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment.

【 授权许可】

   
2015 André et al.

【 图 表 】

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