Functional activation of the cystic fibrosis trafficking mutant delta F508-CFTR by overexpression.

  title={Functional activation of the cystic fibrosis trafficking mutant delta F508-CFTR by overexpression.},
  author={S. H. Cheng and S L Fang and Joseph Zabner and John Marshall and Susan Piraino and Susan C. Schiavi and Douglas M. Jefferson and Michael J. Welsh and A. E. Smith},
  journal={The American journal of physiology},
  volume={268 4 Pt 1},
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… 
A domain mimic increases DeltaF508 CFTR trafficking and restores cAMP-stimulated anion secretion in cystic fibrosis epithelia.
It is concluded that expression of a NBF1 domain mimic may be useful for correction of the DeltaF508 CFTR protein trafficking defect in cystic fibrosis epithelia.
Functional Enhancement of CFTR Expression by Mitomycin C
It is reported that mitomycin C (MMC) elicits such a response by increasing CFTR mRNA and protein expression in T-84 and HT-29 cells at very low, non-cytotoxic, pharmacologically relevant concentrations (0.1 µM) leading to enhanced chloride secretion, suggesting that MMC may be a useful compound for understanding CFTR regulation and biogenesis.
ΔF508 in cystic fibrosis: willing but not able
  • K. Southern
  • Biology
    Archives of disease in childhood
  • 1997
The molecular biology of the ΔF508 mutation, a codon deletion, accounts for the vast majority of cystic fibrosis, and greater understanding of the molecular consequences may answer this question and lead to therapeutic opportunities.
Pharmacologic restoration of αδF508 CFTR-mediated chloride current
The hypothesis of this discussion is that the short chain fatty acids, butyrate and 4-phenylbutyrate, up-regulate mature CFTR at the plasma membrane and evidence that these compounds regulate CFTR production and maturation in part through effects on molecular chaperones in CF cells in culture is discussed.
Partial restoration of cAMP-stimulated CFTR chloride channel activity in ΔF508 cells by deoxyspergualin.
Deoxyspergualin treatment of immortalized human CF epithelial cells (ΔF508) and cells expressing recombinant ΔF508-CFTR partially restored cAMP-stimulated CFTR Cl-channel activity at the plasma membrane, and agents capable of altering the normal functioning of cellular chaperones may provide yet another means of restoring CFtr Cl- channel activity to CF subjects harboring this class of mutations.
Modulation of deltaF508 cystic fibrosis transmembrane regulator trafficking and function with 4-phenylbutyrate and flavonoids.
A combination of chronic treatment with 4-PBA or select flavonoids, followed by acute flavonoid exposure, may be beneficial in cystic fibrosis.
Rescuing protein conformation: prospects for pharmacological therapy in cystic fibrosis.
The recognition that the majority of cases of CF are the result of a defect in biogenesis or intracellular trafficking of the protein, and that the mutant protein retains at least partial function, has stimulated an intensive search for therapeutic strategies aimed at rescuing the function of the mutant CFTR.
Activation of endogenous deltaF508 cystic fibrosis transmembrane conductance regulator by phosphodiesterase inhibition.
It is found that, 36Cl- efflux can be stimulated 19-61% above baseline by beta-adrenoreceptor agonists and cGI-phosphodiesterase inhibitors in transformed nasal polyp cells homozygous for the deltaF508 mutation.
Targeted Therapy for Cystic Fibrosis
The strategy is aimed at improving the regulation of epithelial ion transport by mutant CFTRs in a mutation-specific fashion, and holds great promise for the development of novel therapies aimed at correcting the underlying pathophysiology of CF.
Defects in Processing and Trafficking of Cystic Fibrosis Transmembrane Conductance Regulator
Understanding the processing and trafficking of CFTR may give a clue to the question as to how the expression and residual function of ΔF508-CFTR can be enhanced, and may lead to the development of new pharmacological tools for the treatment of cystic fibrosis.