title: BARD1 mediates TGF-β signaling in pulmonary fibrosis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland. Pierre-Alain.Andre@unige.ch.|Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland. Pierre-Alain.Andre@unige.ch.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: André
authors.affiliation: Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia. cecilia.prele@uwa.edu.au.|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. cecilia.prele@uwa.edu.au.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Prêle
authors.affiliation: Comprehensive Pneumology Center Ludwig Maximilians University, University Hospital Grosshadern and Helmholtz Zentrum München, Munich, Germany. sarah.vierkotten@helmholtz-muenchen.de.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vierkotten
authors.affiliation: Department of Pediatrics and Pathology/Immunology, University of Geneva, Geneva, Switzerland. Stephanie.Carnesecchi@unige.ch.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Carnesecchi
authors.affiliation: Department of Pediatrics and Pathology/Immunology, University of Geneva, Geneva, Switzerland. Yves.Donati@unige.ch.
authors.forename: Yves
authors.initials: Y
authors.lastname: Donati
authors.affiliation: Centre for Inflammation and Tissue Repair, University College London, London, UK. r.chambers@ucl.ac.uk.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chambers
authors.affiliation: Department of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland. Jean-Claude.Pache@hcuge.ch.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Pache
authors.affiliation: INSERM, Unité 1152, University of Paris Diderot and Hopital Bichat, Paris, France. bruno.crestani@bch.aphp.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
authors.affiliation: Department of Pediatrics and Pathology/Immunology, University of Geneva, Geneva, Switzerland. Constance.barazzone@unige.ch.
authors.forename: Constance
authors.initials: C
authors.lastname: Barazzone-Argiroffo
authors.affiliation: Comprehensive Pneumology Center Ludwig Maximilians University, University Hospital Grosshadern and Helmholtz Zentrum München, Munich, Germany. melanie.koenigshoff@helmholtz-muenchen.de.
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: 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. geoff.laurent@uwa.edu.au.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Laurent
authors.affiliation: Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland. irmgard.irminger@unige.ch.|Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland. irmgard.irminger@unige.ch.|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. irmgard.irminger@unige.ch.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Irminger-Finger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D001761:Bleomycin; C102449:BARD1 protein, human; C491163:Bard1 protein, mouse; D044767:Ubiquitin-Protein Ligases