Abstract
Cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) chloride channel, is associated in the respiratory system with the accumulation of mucus and impaired lung function. The role of the CFTR channel in the regulation of the intracellular pathways that determine the overexpression of mucin genes is unknown. Using differential display, we have observed the differential expression of several mRNAs that may correspond to putative CFTR-dependent genes. One of these mRNAs was further characterized, and it corresponds to the tyrosine kinase c-Src. Additional results suggest that c-Src is a central element in the pathway connecting the CFTR channel with MUC1 overexpression and that the overexpression of mucins is a primary response to CFTR malfunction in cystic fibrosis, which occurs even in the absence of bacterial infection.
Highlights
It has been clearly established that mutations in the cystic fibrosis transmembrane regulator (CFTR)1 chloride channel are responsible for cystic fibrosis (CF) [1], the role of this channel, besides transporting chloride anions, is largely unknown [2]
We used a cultured cell line derived from a CF patient (CFDE cells) and the same cell line transfected with WT CFTR (CFDE/ 6RepCFTR cells) [14]
Applying differential display to CFDE and CFDE/6RepCFTR cells, we found differential expression of different genes that may be under CFTR regulation, as the lower or higher levels of several of the genes products observed in CFDE/6RepCFTR cells reverted to CFDE levels after treatment with the chloride channel inhibitor, nitro-2-(3-phenylpropylamino)benzoic acid (NPPB)
Summary
It has been clearly established that mutations in the cystic fibrosis transmembrane regulator (CFTR) chloride channel are responsible for cystic fibrosis (CF) [1], the role of this channel, besides transporting chloride anions, is largely unknown [2]. The main issue has been the difficulty in establishing whether mucin overexpression is a response to subsequent infections with Pseudomonas aeruginosa or whether failure of the CFTR channel is primarily responsible for this overexpression. Using differential display [4, 5] and cultured tracheobronchial CFDE cells, we have identified the tyrosine kinase c-Src [6] as a bridge connecting CFTR failure with the overexpression of MUC1. These results suggests that the overexpression of mucins in the airways is a primary effect due to CFTR malfunction and that this occurs before any P. aeruginosa infection
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