Deregulated expression and function of CFTR and Cl- secretion after activation of the Ras and Src/PyMT pathways in Caco-2 cells

Biochemical and Biophysical Research Communications
S E DavenportS E Gabriel

Abstract

We evaluated the role of the activated Ras and Src/PyMT (Polyoma Middle T) signaling pathways on the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in human colonic Caco-2 cell lines. Control vector-transfected Caco-2 cell monolayer preparations (Caco-2-H) responded to forskolin with an increase in short circuit current (Isc) mediated by CFTR. Furthermore, Caco-2-H cells responded to ATP, a reported stimulator of intracellular Ca2+ (Cai2+), and a potential source of adenosine-mediated elevation of cAMP. In contrast, Caco-2 cells transfected with PyMT (Caco-2-MT), expressing high levels of PKC, showed no sustained Isc response to forskolin or ATP. Pretreatment of Caco-2-MT cells with 2.5 microM phorbol 12-myristate 13-acetate (PMA) for 24 hr. effectively down-regulated PKC activity and restored expression of CFTR mRNA but failed to re-establish functional CFTR. These data suggest that, stable up-regulation of PKC alpha, consequent to activation of the Ras or Src/PyMT pathways, leads to an absence of CFTR expression and Cl- secretion mediated by either cAMP or Cai2+. Moreover, Cl- secretion in the colonic Caco-2 epithelial cell line is mediated primarily by CFTR and an alternate Cai(2+)-activated Cl-...Continue Reading

Citations

Feb 28, 2004·American Journal of Physiology. Gastrointestinal and Liver Physiology·Matthew E LoewenSherif E Gabriel
Jan 29, 1999·Physiological Reviews·B R Grubb, R C Boucher
May 9, 2000·American Journal of Physiology. Gastrointestinal and Liver Physiology·S UmarA P Morris
Jan 14, 1999·The American Journal of Physiology·S E GabrielE J Rozhon

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