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J Biol Chem ; 291(18): 9540-53, 2016 Apr 29.
Article in English | MEDLINE | ID: mdl-26861876

ABSTRACT

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 αvß6 integrin. Expression of the αvß6 integrin is dramatically increased in IPF. How αvß6 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 αvß6 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 αvß6 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.


Subject(s)
Antigens, Neoplasm/biosynthesis , Gene Expression Regulation , Integrins/biosynthesis , Pulmonary Fibrosis/metabolism , Signal Transduction , Transcription, Genetic , ets-Domain Protein Elk-1/metabolism , Animals , Antigens, Neoplasm/genetics , Cell Line, Transformed , Humans , Integrins/genetics , Mice , Mice, Knockout , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/pathology , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , ets-Domain Protein Elk-1/genetics
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