ABCMdb

PMID: 11739639

Dormer RL, Derand R, McNeilly CM, Mettey Y, Bulteau-Pignoux L, Metaye T, Vierfond JM, Gray MA, Galietta LJ, Morris MR, Pereira MM, Doull IJ, Becq F, McPherson MA
Correction of delF508-CFTR activity with benzo(c)quinolizinium compounds through facilitation of its processing in cystic fibrosis airway cells.
J Cell Sci. 2001 Nov;114(Pt 22):4073-81., [PubMed]

Sentences

No. Mutations Sentence Comment

15 ABCC7 p.Gly551Asp We also showed a similar pharmacological effect in nasal cells freshly isolated from a delF508/G551D CF patient. Login to comment 22 ABCC7 p.Trp1282* IB3-1 cells (delF508/W1282X) (a generous gift of P. Zeitlin) (Zeitlin et al., 1991) were routinely cultured in 5% CO2 incubators in LHC-8 medium (Biofluids Inc., Rockville, MO) supplemented with 10% fetal bovine serum and 100 U/ml penicillin/streptomycin. Login to comment 50 ABCC7 p.Gly551Asp Incubation and fixation of nasal epithelial cells Airway epithelial cells obtained by nasal brushing were from five non-CF individuals, four delF508/delF508 CF individuals and one delF508/G551D CF individual undergoing flexible bronchoscopy under sedation. Login to comment 164 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Effect of MPB compounds on the location of CFTR from delF508/G551D cystic fibrosis individuals The technique allows us to investigate the effect of MPB compounds on other naturally occurring genotypes and we show CFTR distribution in cells obtained from nasal brushings from a CF individual with a delF508/G551D genotype. Login to comment 170 ABCC7 p.Gly551Asp Thus MPB-91 dramatically changed the cellular distribution of mutant CFTR from a perinuclear towards an apical location in nasal cells from a delF508/G551D CF patient. Login to comment 180 ABCC7 p.Gly551Asp Effect of MPB-91 on confocal immunofluorescent labelling of CFTR in ∆F508/G551D cystic fibrosis epithelial cells from nasal brushings. Images show CFTR immunofluorescence in green with the nucleus counterstained with propidium iodide (red). Login to comment 207 ABCC7 p.Gly551Asp Their application to the majority of CF patients is highlighted by our results in the present report that nasal cells obtained from a compound heterozygote individual (delF508/G551D) have an altered CFTR location similar to delF508/delF508 cells. Login to comment 208 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp The data suggest that delF508-CFTR is more strongly expressed than G551D or that its restriction to the endoplasmic reticulum also retains G551D. Login to comment 209 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Incubation of delF508/G551D cells with MPB-91 markedly altered the location of mutant CFTR towards a wild-type distribution, although we cannot distinguish whether the apically located CFTR is delF508 or G551D. Login to comment 210 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Thus, MPB-91 provides a new class of compounds that not only activate G551D-CFTR (R.D., L.B.-P. and F.B., unpublished) but also traffic mutant CFTR to the apical membrane in CF compound heterozygotes with a delF508/G551D mutation. Login to comment 211 ABCC7 p.Gly551Asp In conclusion, the present study demonstrates that benzoquinolizinium compounds, which directly activate wild-type (Becq et al., 1999) and G551D-CFTR Cl-channels (R.D., L.B.-P. and F.B., unpublished), have a dramatic effect in restoring defective chloride transport in CF cells by increasing delF508-CFTR at the apical membrane. This is a major step forward in the goal of devising a rational drug treatment aimed at repair or rescue of the activity of the mutant cystic fibrosis gene protein and has implications for other disorders of protein trafficking (Aridor and Balch, 1999). Login to comment