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F508 CFTR in an epithelial monolayer
1 Gregory Fleming James Cystic Fibrosis Research Center, Departments of 2 Physiology and Biophysics and 5 Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294; 3 University Medical School of Pécs, Pécs H-7624, Hungary; and 4 Department of Pediatrics, Northwestern University Medical School, Evanston, Illinois 60201
The 
F508 mutation leads to retention of cystic fibrosis
transmembrane conductance regulator (CFTR) in the endoplasmic reticulum and rapid degradation by the proteasome and other proteolytic systems.
In stably transfected LLC-PK1
(porcine kidney) epithelial cells, F508 CFTR conforms to this
paradigm and is not present at the plasma membrane. When
LLC-PK1 cells or human nasal polyp cells derived from a F508 homozygous patient are grown on plastic dishes and treated with an epithelial differentiating agent (DMSO, 2%
for 4 days) or when LLC-PK1 cells
are grown as polarized monolayers on permeable supports, plasma
membrane F508 CFTR is significantly increased. Moreover, when
confluent LLC-PK1 cells expressing
F508 CFTR were treated with DMSO and mounted in an Ussing chamber, a
further increase in cAMP-activated short-circuit current (i.e., ~7
µA/cm2;
P < 0.00025 compared with untreated
controls) was observed. No plasma membrane CFTR was detected after DMSO
treatment in nonepithelial cells (mouse L cells) expressing F508
CFTR. The experiments describe a way to augment F508 CFTR maturation
in epithelial cells that appears to act through a novel mechanism and
allows insertion of functional F508 CFTR in the plasma membranes of
transporting cell monolayers. The results raise the possibility that
increased epithelial differentiation might increase the delivery of
F508 CFTR from the endoplasmic reticulum to the Golgi, where the
F508 protein is shielded from degradative pathways such as the
proteasome and allowed to mature.
short-circuit current; dimethyl sulfoxide; cystic fibrosis transmembrane conductance regulator; cell differentiation
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