title: Reduced Ets Domain-containing Protein Elk1 Promotes Pulmonary Fibrosis via Increased Integrin αvβ6 Expression.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with high mortality. Active TGFβ1 is considered central to the pathogenesis of IPF. A major mechanism of TGFβ1 activation in the lung involves the epithelially restricted αvβ6 integrin. Expression of the αvβ6 integrin is dramatically increased in IPF. How αvβ6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the β6 subunit gene (ITGB6) promoter acting to markedly repress basal gene transcription, which responds to both the Ets domain-containing protein Elk1 (Elk1) and the glucocorticoid receptor (GR). Both Elk1 and GR can regulate αvβ6 integrin expression in vitro We demonstrate Elk1 binding to the ITGB6 promoter basally and that manipulation of Elk1 or Elk1 binding alters ITGB6 promoter activity, gene transcription, and αvβ6 integrin expression. Crucially, we find that loss of Elk1 causes enhanced Itgb6 expression and exaggerated lung fibrosis in an in vivo model of fibrosis, whereas the GR agonist dexamethasone inhibits Itgb6 expression. Moreover, Elk1 dysregulation is present in epithelium from patients with IPF. These data reveal a novel role for Elk1 regulating ITGB6 expression and highlight how dysregulation of Elk1 can contribute to human disease.
authors: From the Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom, amanda.tatler@nottingham.ac.uk.
authors: Amanda L
authors: http://orcid.org/0000-0002-4644-4614
authors: AL
authors: Tatler
authors: From the Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom.
authors: Anthony
authors: A
authors: Habgood
authors: From the Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom.
authors: Joanne
authors: J
authors: Porte
authors: From the Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom.
authors: Alison E
authors: AE
authors: John
authors: From the Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom.
authors: Anastasios
authors: A
authors: Stavrou
authors: From the Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom.
authors: Emily
authors: E
authors: Hodge
authors: From the Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom.
authors: Cheryl
authors: C
authors: Kerama-Likoko
authors: Biogen Inc., Cambridge, Massachusetts 02142.
authors: Shelia M
authors: SM
authors: Violette
authors: Biogen Inc., Cambridge, Massachusetts 02142.
authors: Paul H
authors: PH
authors: Weinreb
authors: From the Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom.
authors: Alan J
authors: AJ
authors: Knox
authors: the Centre for Respiratory Research, University College London, London WC1E 6JF, United Kingdom, the Centre for Cell Therapy and Regenerative Medicine, University of Western Australia, Crawley WA 6009, Australia.
authors: Geoffrey
authors: G
authors: Laurent
authors: the Department of Medicine, University of Cambridge and Papworth Hospital NHSFT, Cambridge CB2 0SP, United Kingdom.
authors: Helen
authors: H
authors: Parfrey
authors: the Department of Medicine, University of California, San Francisco, San Francisco, California 94143.
authors: Paul John
authors: PJ
authors: Wolters
authors: the Division of Pathology, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom, and.
authors: William
authors: W
authors: Wallace
authors: the Interfaculty Institute of Cell Biology, Tübingen University, Tübingen 72076, Germany.
authors: Siegfried
authors: S
authors: Alberti
authors: the Interfaculty Institute of Cell Biology, Tübingen University, Tübingen 72076, Germany.
authors: Alfred
authors: A
authors: Nordheim
authors: From the Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom.
authors: Gisli
authors: G
authors: Jenkins
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D002461:Cell Line, Transformed; D005786:Gene Expression Regulation; D006801:Humans; D016023:Integrins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; C494112:ELK1 protein, human; C494113:Elk1 protein, mouse; D016023:Integrins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D050807:ets-Domain Protein Elk-1; C073878:integrin alphavbeta6
keywords: elk1; fibrosis; gene regulation; integrin; lung; pulmonary fibrosis