Reduced Ets domain-containing protein Elk1 promotes pulmonary fibrosis via increased integrin ?v?6 expression

Tatler, Amanda L.; Habgood, Anthony; Porte, Joanne; John, Alison E.; Stavrou, Anastasios; Hodge, Emily; Kerama-Likoko, Cheryl; Violette, Shelia M.; Weinreb, Paul H.; Knox, Alan J.; Laurent, Geoffrey; Parfrey, Helen; Wolters, Paul John; Wallace, William; Alberti, Siegfried; Nordheim, Alfred; Jenkins, Gisli

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with high mortality. Active TGF?1 is considered central to the pathogenesis of IPF. A major mechanism of TGF?1 activation in the lung involves the epithelially restricted ?v?6 integrin. Expression of the ?v?6 integrin is dramatically increased in IPF. How ?v?6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the ?6 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 ?v?6 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 ?v?6 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.

• Journal Article Type: Article
• Acceptance Date: Feb 9, 2016
• Online Publication Date: Feb 11, 2016
• Publication Date: Apr 29, 2016
• Deposit Date: Aug 17, 2018
• Publicly Available Date: Jan 22, 2019
• Print ISSN: 0021-9258
• Publisher: American Society for Biochemistry and Molecular Biology
• Peer Reviewed: Peer Reviewed
• Volume: 291
• Issue: 18
• Pages: 9540-9553
• DOI: https://doi.org/10.1074/jbc.M115.692368
• Public URL: https://nottingham-repository.worktribe.com/output/1113317
• Publisher URL: http://www.jbc.org/content/291/18/9540
• PMID: 26861876