Tyrosine Kinase c-Src Constitutes a Bridge between Cystic Fibrosis Transmembrane Regulator Channel Failure and MUC1 Overexpression in Cystic Fibrosis

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.

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

“…Having said this, the question arises -how might CFTR regulate MUC4 expression? Recent findings have clearly indicated that CFTR regulates the expression of several genes, including mucins (Tabary et al, 1999;Steagall et al, 2000;Gonzalez-Guerrico et al, 2002;Estell et al, 2003). CFTR regulates the MUC1 expression in CF-tracheobronchial epithelial cells via a mechanism that is mediated by c-src activation (Gonzalez-Guerrico et al, 2002).…”

“…Recent findings have clearly indicated that CFTR regulates the expression of several genes, including mucins (Tabary et al, 1999;Steagall et al, 2000;Gonzalez-Guerrico et al, 2002;Estell et al, 2003). CFTR regulates the MUC1 expression in CF-tracheobronchial epithelial cells via a mechanism that is mediated by c-src activation (Gonzalez-Guerrico et al, 2002). Moreover, studies conducted in CFTR-knockout mice have demonstrated the aberrant mucus accumulation in the intestine (Thomsson et al, 2002), and MUC1 has been reported to be an important contributor to the CF intestinal phenotype (Hinojosa-Kurtzberg et al, 2003).…”

“…Our interest in investigating the association between CFTR and MUC4 mucin expression was incited from the recent reports indicating the involvement of the CFTR dysfunction in the aberrant expression and biochemical properties of mucins (Gonzalez-Guerrico et al, 2002;Thomsson et al, 2002;Malmberg et al, 2006). In an effort to elucidate the association between CFTR and MUC4, we examined the expression of CFTR and the MUC4 mucin in normal pancreas and pancreatic adenocarcinoma cells.…”

MUC1 Initiates Src-CrkL-Rac1/Cdc42–Mediated Actin Cytoskeletal Protrusive Motility after Ligating Intercellular Adhesion Molecule-1

“…The 72-amino-acid cytoplasmic domain of MUC1 (MUC1-CD) contains seven highly conserved tyrosine residues, four of which are confirmed phosphorylation sites and construct potential docking motifs for SH2 or SH3 domain -containing proteins, such as Src family kinases and growth factor receptor binding protein 2 (12,13). Thus far, epidermal growth factor receptor (14,15), PKCy (16), and Src (14,17,18) have been found to physically associate with and phosphorylate MUC1-CD. This indicates that MUC1, although without intrinsic kinase activity (19), could function as a scaffold protein in signal transduction.…”

A LacZ-based transgenic mouse for detection of somatic gene repair events in vivo

“…Moreover, in our hands, singlestranded DNA oligonucleotides have produced very consistent results supporting recent data from the laboratory of Yoon. 30,31 When correcting the tyrosinase gene in albino mouse melanocytes, ODNs produced pigmented cells, indicating gene repair in 60% of experiments, while RDOs produced pigmented cells in only 10%.…”