Reduced ets domain-containing protein Elk1 promotes pulmonary fibrosis via increased integrin avß6 expression

A.L. Tatler, A. Habgood, J. Porte, A.E. John, A. Stavrou, E. Hodge, C. Kerama-Likoko, S.M. Violette, P.H. Weinreb, A.J. Knox, Geoff Laurent, H. Parfrey, P.J. Wolters, W. Wallace, S. Alberti, A. Nordheim, G. Jenkins

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with high mortality. Active TGFß1 is considered central to the pathogenesis of IPF. A major mechanism of TGFß1 activation in the lung involves the epithelially restricted avß6 integrin. Expression of the avß6 integrin is dramatically increased in IPF. How avß6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the ß6 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 avß6 integrin expression in vitro.Wedemonstrate Elk1 binding to the ITGB6 promoter basally and that manipulation of Elk1 or Elk1 binding alters ITGB6 promoter activity, gene transcription, and avß6 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 regulatingITGB6expression and highlight how dysregulation of Elk1 can contribute to human disease.
Original languageEnglish
Pages (from-to)9540-9553
Number of pages14
JournalJournal of Biological Chemistry
Volume291
Issue number18
DOIs
Publication statusPublished - 2016

Fingerprint

Dive into the research topics of 'Reduced ets domain-containing protein Elk1 promotes pulmonary fibrosis via increased integrin avß6 expression'. Together they form a unique fingerprint.

Cite this