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F508-CFTR
1 Division of Pulmonary Medicine, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; and 2 Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland 21287
The most common mutation of
the cystic fibrosis transmembrane conductance regulator
(CFTR), 
F508, is a trafficking mutant that has prolonged
associations with molecular chaperones and is rapidly degraded, at
least in part by the ubiquitin-proteasome system. Sodium
4-phenylbutyrate (4PBA) improves F508-CFTR trafficking and function
in vitro in cystic fibrosis epithelial cells and in vivo. To further
understand the mechanism of action of 4PBA, we tested the hypothesis
that 4PBA modulates the targeting of F508-CFTR for ubiquitination
and degradation by reducing the expression of Hsc70 in cystic fibrosis
epithelial cells. IB3-1 cells (genotype F508/W1282X) that were
treated with 0.05-5 mM 4PBA for 2 days in culture demonstrated a
dose-dependent reduction in Hsc70 protein immunoreactivity and mRNA
levels. Immunoprecipitation with Hsc70-specific antiserum demonstrated
that Hsc70 and CFTR associated under control conditions and that
treatment with 4PBA reduced these complexes. Levels of immunoreactive
Hsp40, Hdj2, Hsp70, Hsp90, and calnexin were unaffected by 4PBA
treatment. These data suggest that 4PBA may improve F508-CFTR
trafficking by allowing a greater proportion of mutant CFTR to escape
association with Hsc70.
cystic fibrosis; cystic fibrosis transmembrane conductance regulator; chaperones; Hsc70; phenylbutyrate
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