FUNCTIONAL ACTIVATION OF THE CYSTIC-FIBROSIS TRAFFICKING MUTANT DELTA-F508-CFTR BY OVEREXPRESSION

The most common mutation in the gene associated with cystic fibrosis ( CF) causes deletion of phenylalanine at residue 508 (Delta F508) of th e gene product called CFTR. This mutation results in the synthesis of a variant CFTR protein that is defective in its ability to traffic to the plasma membrane. Because earlier studies showed Delta F508-CFTR re tains significant phosphorylation-regulated chloride (Cl-) channel act ivity, processes capable of restoring the mislocalized Delta F508-CFTR to the correct cellular destination may have therapeutic benefit. Her e we report one such process that involves overexpression of the mutan t protein and appears to result in the escape of a small amount of Del ta F508-CFTR to the plasma membrane. In recombinant cells where expres sion of Delta F508-CFTR is controlled by the metallothionein promoter, this effect can be brought about by treatment with sodium butyrate. A lthough cAMP-activated Cl- channel activity could also be detected in immortalized human airway epithelial cells homozygous for the Delta F5 08 mutation at the single cell level, treatment with butyrate did not generate a measurable cAMP-stimulated Cl- current in polarized monolay ers of primary CF airway epithelia. However, the observation that over expression can effect the presence of recombinant Delta F508-CFTR at t he plasma membrane suggests that perhaps other butyrate-like compounds that are more potent and more specific for the promoter of the CF gen e may be efficacious in alleviating the Cl- channel defect associated with CF.