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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

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


Authors

AMANDA TATLER AMANDA.TATLER@NOTTINGHAM.AC.UK
Principal Research Fellow

Anthony Habgood

Joanne Porte

Alison E. John

Anastasios Stavrou

Emily Hodge

Cheryl Kerama-Likoko

Shelia M. Violette

Paul H. Weinreb

Alan J. Knox

Geoffrey Laurent

Helen Parfrey

Paul John Wolters

William Wallace

Siegfried Alberti

Alfred Nordheim

Gisli Jenkins



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

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