Article: Altered biogenesis of deltaF508-CFTR following treatment with doxorubicin.
2007 Volume 20, Issue 5, Page(s) 465–472
Abstract: 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 (Delta F508), which accounts for approximately ... ...
| Abstract | 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 (Delta F508), which accounts for approximately 70% of all CF alleles. This mutation interferes with the biogenesis and maturation of Delta F508-CFTR to the plasma membrane. However, Delta F508-CFTR can partially function upon proper localization. Thus, pharmacological correction of Delta F508-CFTR maturation holds promise in CF therapy. Our previous studies indicate that a single non-cytotoxic dose of the anthracycline doxorubicin (Dox) significantly increase Delta F508-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 Delta F508-CFTR. Treatment with Dox increases the resistance of Delta F508-CFTR to trypsin digestion, possibly by expediting protein folding. Further, treatment with Dox reduces the amount of polyubiquitinated Delta F508-CFTR in cells and prolongs the half-life of this protein. Concomitantly, treatment with Dox decreases the association of Delta F508-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 Delta F508-CFTR by acting as a pharmacological chaperone, which consequently promotes the functional expression of this protein in MDCK cells. |
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| MeSH term(s) | Animals ; Cell Line ; Cystic Fibrosis Transmembrane Conductance Regulator/biosynthesis ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Dogs ; Doxorubicin/pharmacology ; HSP70 Heat-Shock Proteins/metabolism ; Peptide Hydrolases/metabolism ; Phenylalanine/genetics ; Phenylalanine/metabolism ; Protein Binding ; Sequence Deletion/genetics ; Ubiquitin/metabolism |
| Chemical Substances | HSP70 Heat-Shock Proteins ; Ubiquitin ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Phenylalanine (47E5O17Y3R) ; Doxorubicin (80168379AG) ; Peptide Hydrolases (EC 3.4.-) |
| Language | English |
| Publishing date | 2007-06-04 |
| Publishing country | Germany |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1067572-3 |
| ISSN | 1421-9778 ; 1015-8987 |
| ISSN (online) | 1421-9778 |
| ISSN | 1015-8987 |
| DOI | 10.1159/000107530 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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