Multiple mechanisms influence regulation of the cystic fibrosis transmembrane conductance regulator gene promoter

Marzena A. Lewandowska, Fabricio F. Costa, Jared M. Bischof, Sarah H. Williams, Marcelo B. Soares, Ann Harris*

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) gene is driven by a promoter that cannot alone account for the temporal and tissue-specific regulation of the gene. This has led to the search for additional regulatory elements that cooperate with the basal promoter to achieve coordinated expression. We previously identified two alternative upstream exons of the gene that were mutually exclusive of the first exon, and one of which showed temporal regulation in the human and sheep lung. We now demonstrate that this alternative splice product generates a stable protein, which initiates translation at an ATG in exon 4, and thus lacks the N terminus of CFTR. The other splice variant inhibits translation of the protein. In a search for the promoter used by the upstream exons, we identified a novel element that contributes to the activity of the basal CFTR promoter in airway epithelial cells, but does not function independently. Finally, we demonstrate that, in primary airway cells, skin fibroblasts, and both airway and intestinal cell lines, the CFTR promoter is unmethylated, irrespective of CFTR expression status. Thus, methylation is not the main cause of inactivation of CFTR transcription.

Original languageEnglish (US)
Pages (from-to)334-341
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume43
Issue number3
DOIs
StatePublished - Sep 1 2010

Keywords

  • Alternative exons
  • CFTR promoter
  • Methylation

ASJC Scopus subject areas

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

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