Norberg, H Starkhammar, J-H Svensson Switzerland �C M Borner, R Hermann, D K?berle, R Morant, O Pagani, C Sessa, R Stahel Thailand �C S Chakrapee-Sirisuk selleck Crizotinib United Kingdom �C N Bailey, F Daniel, D Dunlop, T Iveson, R James, E Levine, A Makris, A McDonald, L Samuel, M Soukop, W Steward, C Topham Uruguay �C IM Muse USA �C J Eckardt, G Gross, G Justice, L Kalman, R Kerr, CG Leichman, E Levine, V Malhotra, R Pelley, MC Perry, J Posey, M Saleh, J Salvatore, J Wooldridge
Cystic fibrosis (CF), the most common lethal inherited disease among Caucasians, is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a cAMP-activated low-conductance chloride channel localized in the apical plasma membrane of secretory epithelial cells (Crawford et al.

1991). The most frequent mutation in the CFTR protein is a deletion of the phenylalanine at position 508 (��F508). This mutation belongs to a class of mutation in which CFTR protein fails to be properly processed and trafficked to plasma membrane (Cheng et al. 1990; Kartner et al. 1992). ��F508 CFTR is retained in the endoplasmic reticulum�CGolgi intermediate compartment (ERGIC) (Gilbert et al. 1998), then degraded by the ubiquitin-proteasome pathway (Jensen et al. 1995). The severe reduction or absence of CFTR in the apical plasma membrane of epithelial cells impairs several intracellular processes, including ionic exchange, in particular with enhanced Na+ absorption (Boucher et al. 1988) and reduced HCO3 ? secretion in the intestine (Pratha et al. 2000) and pancreas (Kopelman et al.

1988; Smith and Welsh 1992; Lebenthal et al. 1993; Choi et al. 2001). Various studies using CF cells have demonstrated changes in the expression and/or intracellular trafficking of secreted or membrane proteins, Cilengitide including MRP8 and MRP14 (migration inhibitory factor-related proteins) (Fanjul et al. 1995), the Na+/H+ exchanger (NHE3) (Ahn et al. 2001), Cl?/HCO3 ? exchangers, such as the downregulated in adenoma (DRA) or the putative anion transporter (PAT1) (Greeley et al. 2001), and the carbonic anhydrase IV (CA IV) (Fanjul et al. 2002). Regarding CA IV, usually transported to plasma membranes via the Golgi complex (Mairal et al.