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1 Division of Pulmonary Medicine, Children's Hospital of Philadelphia, and 2 Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Intracellular trafficking of the 
F508
cystic fibrosis transmembrane conductance regulator (CFTR) is repaired
by sodium 4-phenylbutyrate (4PBA) by an undetermined mechanism. 4PBA
downregulates protein and mRNA expression of the heat shock cognate
protein HSC70 (the constitutively expressed member of the 70-kDa heat
shock protein family) by ~40-50% and decreases formation of a
HSC70-F508 CFTR complex that may be important in the intracellular
degradation of F508 CFTR. We examined the potential mechanisms by
which 4PBA decreases HSC70 mRNA and protein expression. In IB3-1 cells,
1 mM 4PBA did not alter the activity of the Chinese hamster ovary HSC70
promoter or of a human HSC70 promoter fragment in luciferase reporter
assays nor did it alter HSC70 mRNA synthesis in nuclear runoff assays.
In contrast, preincubation with 4PBA increased the rate of HSC70 mRNA
degradation by ~40%. The initial rate of 35S-HSC70
protein synthesis in 4PBA-treated IB3-1 cells was reduced by ~40%,
consistent with the steady-state mRNA level, whereas its rate of
degradation was unaltered by 4PBA. 4PBA also reduced the steady-state
accumulation of 35S-HSC70 by ~40%. These data suggest
that 4PBA decreases the expression of HSC70 mRNA and protein by
inducing cellular adaptations that result in the decreased stability of
HSC70 mRNA.
cystic fibrosis; cystic fibrosis transmembrane conductance regulator chaperones; 70-kilodalton heat shock protein constitutive form; messenger ribonucleic acid
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