title: Oxidant stress suppresses CFTR expression.
abstract: Epithelial mucous membranes are repeatedly exposed to oxidants and xenobiotics. CFTR plays a role in glutathione transepithelial flux and in defining the hydration and viscoelasticity of protective mucus. We therefore hypothesized that CFTR expression and function may be modulated by oxidant stress. A sublethal oxidant stress (tert-butylhydroquinone, BHQ) in CFTR-expressing epithelial cells (T84) induced a significant increase in cellular glutathione that was associated with an increase in expression of the gene encoding the heavy subunit of the rate-limiting enzyme for glutathione synthesis, gamma-glutamylcysteine synthetase (gamma-GCShs). CFTR gene expression was markedly decreased according to a time course that mirrored the changes in gamma-GCShs. Western blot analysis confirmed that the decrease in CFTR gene expression was associated with a decrease in CFTR protein. cAMP-dependent iodide efflux was also decreased by the oxidant stress. Nuclear run-on assays indicated that the oxidant stress had no effect on CFTR gene transcription, but the mRNA stability in the oxidant-stressed cells was markedly reduced. Furthermore, BHQ increased gamma-GCShs mRNA while decreasing CFTR mRNA in Calu-3 cells, and taurine chloramine induced similar effects in T84 cells. We conclude that suppression of CFTR expression may represent an adaptive response of mucosal epithelium to an exogenous oxidant stress.
authors.affiliation: Pulmonary Research Unit, Faculty of Medicine, Univ. of Sherbrooke, 3001, 12ième Ave. Nord, Sherbrooke, QC, Canada J1H 5N4. Andre.Cantin@USherbrooke.ca
authors.forename: André M
authors.initials: AM
authors.lastname: Cantin
authors.forename: Ginette
authors.initials: G
authors.lastname: Bilodeau
authors.forename: Cristine
authors.initials: C
authors.lastname: Ouellet
authors.forename: Jie
authors.initials: J
authors.lastname: Liao
authors.forename: John W
authors.initials: JW
authors.lastname: Hanrahan
mesh_terms: D000230:Adenocarcinoma; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004347:Drug Interactions; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity; D007457:Iodine Radioisotopes; D009077:Mucins / Q000494:pharmacology; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D013654:Taurine / Q000031:analogs & derivatives / Q000235:genetics / Q000633:toxicity
chemical_list: D000975:Antioxidants; D006873:Hydroquinones; D007457:Iodine Radioisotopes; D009077:Mucins; D016877:Oxidants; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D013654:Taurine; C043410:N-chlorotaurine; C018855:2-tert-butylhydroquinone; D000242:Cyclic AMP; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione