AJP - Lung Cellular and Molecular Physiology, Vol 268, Issue 4 615-L624, Copyright © 1995 by American Physiological Society
Functional activation of the cystic fibrosis trafficking mutant delta F508-CFTR by overexpression
S. H. Cheng, S. L. Fang, J. Zabner, J. Marshall, S. Piraino, S. C. Schiavi, D. M. Jefferson, M. J. Welsh and A. E. Smith
Genzyme Corporation, Framingham, Massachusetts 01701, USA.
The most common mutation in the gene associated with cystic fibrosis (CF)
causes deletion of phenylalanine at residue 508 (delta F508) of the 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 retains
significant phosphorylation-regulated chloride (Cl-) channel activity,
processes capable of restoring the mislocalized delta F508-CFTR to the
correct cellular destination may have therapeutic benefit. Here we report
one such process that involves overexpression of the mutant protein and
appears to result in the escape of a small amount of delta F508-CFTR to the
plasma membrane. In recombinant cells where expression of delta F508-CFTR
is controlled by the metallothionein promoter, this effect can be brought
about by treatment with sodium butyrate. Although cAMP-activated Cl-
channel activity could also be detected in immortalized human airway
epithelial cells homozygous for the delta F508 mutation at the single cell
level, treatment with butyrate did not generate a measurable
cAMP-stimulated Cl- current in polarized monolayers of primary CF airway
epithelia. However, the observation that overexpression can effect the
presence of recombinant delta F508-CFTR at the plasma membrane suggests
that perhaps other butyrate-like compounds that are more potent and more
specific for the promoter of the CF gene may be efficacious in alleviating
the Cl- channel defect associated with CF.
