Reduced Ets Domain-containing Protein Elk1 Promotes Pulmonary Fibrosis via Increased Integrin αvβ6 Expression.
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.
['Tatler|Amanda L|AL|http://orcid.org/0000-0002-4644-4614', 'Habgood|Anthony|A|', 'Porte|Joanne|J|', 'John|Alison E|AE|', 'Stavrou|Anastasios|A|', 'Hodge|Emily|E|', 'Kerama-Likoko|Cheryl|C|', 'Violette|Shelia M|SM|', 'Weinreb|Paul H|PH|', 'Knox|Alan J|AJ|', 'Laurent|Geoffrey|G|', 'Parfrey|Helen|H|', 'Wolters|Paul John|PJ|', 'Wallace|William|W|', 'Alberti|Siegfried|S|', 'Nordheim|Alfred|A|', 'Jenkins|Gisli|G|']
D000818:Animals D000951:Antigens, Neoplasm D002461:Cell Line, Transformed D005786:Gene Expression Regulation D006801:Humans D016023:Integrins D051379:Mice D018345:Mice, Knockout D011658:Pulmonary Fibrosis D015398:Signal Transduction D014158:Transcription, Genetic D053773:Transforming Growth Factor beta1 D050807:ets-Domain Protein Elk-1
elk1 pulmonary fibrosis fibrosis integrin lung gene regulation