Altered Biogenesis of DeltaF508-CFTR Following Treatment with Doxorubicin
Maitra, R., & Hamilton, J. (2007). Altered Biogenesis of DeltaF508-CFTR Following Treatment with Doxorubicin. Cellular Physiology and Biochemistry, 20(5), 465-472.
Cystic fibrosis (CF) is caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common of these mutations is deletion of a phenylalanine residue at position 508 (DeltaF508), which accounts for n70% of all CF alleles. This mutation interferes with the biogenesis and maturation of DeltaF508-CFTR to the plasma membrane. However, DeltaF508-CFTR can partially function upon proper localization. Thus, pharmacological correction of DeltaF508-CFTR maturation holds promise in CF therapy. Our previous studies indicate that a single non-cytotoxic dose of the anthracycline doxorubicin (Dox) significantly increase DeltaF508-CFTR-associated chloride secretion in MDCK cells by increasing the expression of this protein at the apical plasma membrane. We report here that Dox alters the biogenesis of DeltaF508-CFTR. Treatment with Dox increases the resistance of DeltaF508-CFTR to trypsin digestion, possibly by expediting protein folding. Further, treatment with Dox reduces the amount of polyubiquitinated DeltaF508-CFTR in cells and prolongs the half-life of this protein. Concomitantly, treatment with Dox decreases the association of DeltaF508-CFTR with HSP70 but does not alter the expression of major HSP70 family members. Based on these results, we propose that Dox expedites the folding and maturation of DeltaF508-CFTR by acting as a pharmacological chaperone, which consequently promotes the functional expression of this protein in MDCK cells. Copyright (c) 2007 S. Karger AG, Basel