Journal article
Functional activation of the cystic fibrosis trafficking mutant delta F508-CFTR by overexpression
American journal of physiology. Lung cellular and molecular physiology, Vol.268(4), pp.L615-L624
04/01/1995
DOI: 10.1152/ajplung.1995.268.4.L615
PMID: 7733303
Abstract
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.
Details
- Title: Subtitle
- Functional activation of the cystic fibrosis trafficking mutant delta F508-CFTR by overexpression
- Creators
- Seng H Cheng - Genzyme Corporation, Framingham, Massachusetts 01701, USAShaona L Fang - Genzyme Corporation, Framingham, Massachusetts 01701, USAJoseph Zabner - Genzyme Corporation, Framingham, Massachusetts 01701, USAJohn Marshall - Genzyme Corporation, Framingham, Massachusetts 01701, USASusan Piraino - Genzyme Corporation, Framingham, Massachusetts 01701, USASusan C Schiavi - Genzyme Corporation, Framingham, Massachusetts 01701, USADouglas M Jefferson - Genzyme Corporation, Framingham, Massachusetts 01701, USAMichael J Welsh - Genzyme Corporation, Framingham, Massachusetts 01701, USAAlan E Smith - Genzyme Corporation, Framingham, Massachusetts 01701, USA
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Lung cellular and molecular physiology, Vol.268(4), pp.L615-L624
- DOI
- 10.1152/ajplung.1995.268.4.L615
- PMID
- 7733303
- NLM abbreviation
- Am J Physiol Lung Cell Mol Physiol
- ISSN
- 1040-0605
- eISSN
- 1522-1504
- Publisher
- American Physiological Society
- Language
- English
- Date published
- 04/01/1995
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Neurosurgery; Internal Medicine
- Record Identifier
- 9984020896802771
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