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1 Department of Physiology, Johns Hopkins Univeristy School of Medicine, Baltimore, MD, USA
2 Department of Pediatrics, Johns Hopkins Univeristy School of Medicine, Baltimore, MD, USA
3 Department of Medicine, Johns Hopkins Univeristy School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: jwright{at}jhmi.edu.
Most individuals with cystic fibrosis (CF) carry one or two mutations that result in a maturation defect of the full-length CFTR protein. The 
F508 mutation results in a mutant protein that is degraded by the proteasome instead of progressing to the apical membrane where it functions as a cyclic AMP-regulated chloride channel. 4-phenylbutyrate (PBA) modulates heat shock protein expression and promotes trafficking of F508 thus permitting maturation and membrane insertion. The goal of this study was to gain insight into the genetic mechanism of PBA action through a large-scale analysis of gene expression. The Affymetrix genome spanning U133 microarray set was used to compare mRNA expression in untreated IB3-1 cell line cultures levels with cultures treated with 1mM PBA for 12 and 24 hr. The most notable changes in mRNA levels were transient elevations in heat shock proteins. The majority of genes down regulated throughout the application period were functionally associated with control of gene expression. Another set of genes increased in expression starting at 24 hr suggesting these are downstream effects of altered gene expression initiated by PBA. More than a third of the genes in this late expressing set were identified as having potential significance in understanding the pathology of cystic fibrosis. Our results demonstrate the usefulness of gene expression profile analysis in understanding the consequences of 4-phenylbutyrate treatment and provide insights in how this drug exerts its effect on the trafficking of CFTR.
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