Ultrastructural localization of variant forms of cystic fibrosis transmembrane conductance regulator in human bronchial epithelial of xenografts

American Journal of Respiratory Cell and Molecular Biology
Y YangJ M Wilson

Abstract

Cystic fibrosis (CF) is caused by mutations in the gene encoding a cyclic adenosine monophosphate (cAMP)-regulated chloride (CI) channel called the CF transmembrane conductance regulator (CFTR). Previous in vitro studies have indicated that the most common mutation, delta F508 CFTR (a deletion of phenylalanine 508), encodes a protein that is trapped in the endoplasmic reticulum (ER), leading to loss of cAMP-regulated CI transport at the plasma membrane. Another common variant, G551D CFTR (a G-->D missense mutation at position 551), is properly transported to the plasma membrane but is unresponsive to cAMP. These hypotheses are based primarily on studies in culture cells. We have attempted to extend the in vitro experiments by characterizing the molecular pathogenesis of the common mutations, delta F508 and G551D, in the context of a more relevant setting, the pseudostratified epithelium of a proximal human airway. Recombinant adenoviruses were used to transduce normal and variant forms of CFTR into surface epithelial cells of human bronchial xenografts grown in nu/nu mice. Recombinant forms of CFTR RNA and protein were expressed at levels that exceed expression of the endogenous gene. Immunolocalization of CFTR at the light and...Continue Reading

Citations

Dec 1, 1996·Pediatric Pulmonology·E Kerem, B Kerem
Dec 2, 2000·Current Opinion in Pulmonary Medicine·L R Choo-Kang, P L Zeitlin
Dec 31, 1998·American Journal of Respiratory Cell and Molecular Biology·S N SmithE W Alton
Dec 1, 1995·The Journal of Clinical Investigation·J M Wilson
Mar 15, 2006·Biochemical and Biophysical Research Communications·Suparna NanuaMarc B Hershenson
Apr 11, 2007·Paediatric Respiratory Reviews·Peter T P Bye, Mark R Elkins

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