Oxidative stress regulates CFTR gene expression in human airway epithelial cells through a distal antioxidant response element

Zhaolin Zhang, Shih Hsing Leir, Ann Harris*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Cystic fibrosis transmembrane conductance regulator gene (CFTR) expression in human airway epithelial cells involves the recruitment of distal cis-regulatory elements, which are associated with airway-selective DNase hypersensitive sites at -44 kb and 235 kb from the gene. The -35-kb site encompasses an enhancer that is regulated by the immune mediators interferon regulatory factor 1 and 2 and by nuclear factor Y. Here we investigate the -44-kb element, which also has enhancer activity in vitro in airway epithelial cells but is inactive in intestinal epithelial cells. This site contains an antioxidant response element (ARE) that plays a critical role in its function in airway cell lines and primary human bronchial epithelial cells. The natural antioxidant sulforaphane (SFN) induces nuclear translocation of nuclear factor, erythroid 2-like 2 (Nrf2), a transcription factor that regulates genes with AREs in their promoters, many of which are involved in response to injury. Under normal conditions, the -44-kb ARE is occupied by the repressor BTB and CNC homology 1, basic leucine zipper transcription factor (Bach1), and v-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog K (MafK) heterodimers. After 2 hours of SFN treatment, Nrf2 displaces these repressive factors and activates CFTR expression. Site-directed mutagenesis shows that both the ARE and an adjacent NF-kB binding site are required for activation of the -44-kb element in airway epithelial cells. Moreover, this element is functionally linked to the -35-kb enhancer in modulating CFTR expression in response to environmental stresses in the airway.

Original languageEnglish (US)
Pages (from-to)387-396
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume52
Issue number3
DOIs
StatePublished - Mar 1 2015

Keywords

  • Airway epithelium
  • Antioxidant response element
  • CFTR gene expression
  • Oxidative stress

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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