Apical localization of ITPK1 enhances its ability to be a modifier gene product in a murine tracheal cell model of cystic fibrosis

Journal of Cell Science
Ling YangS B Shears

Abstract

A new aspect of research into the pathogenesis of cystic fibrosis (CF) is a genetics-based search for ;modifier genes' that may affect the severity of CF lung disease. Using an alternative, cell biological approach, we show that ITPK1 should be considered a modifier gene. ITPK1 synthesizes an intracellular signal, inositol (3,4,5,6)-tetrakisphosphate [Ins(3,4,5,6)P4]. A bio-activatable, cell-permeable analogue of Ins(3,4,5,6)P4 inhibited Ca2+-dependent secretion of Cl- from polarized monolayers of immortalized mouse tracheal epithelial cells (MTEs). Analysis by high-pressure liquid chromatography showed endogenous Ins(3,4,5,6)P4 levels in CF MTEs were approximately 60% below those in wild-type MTEs (P<0.03). This adaptation, which improves purinergic activation of Ca2+-dependent Cl- secretion in CF MTEs, was exceptionally specific; there was no effect upon the cellular levels of all the other inositol phosphate signals. Real-time PCR provided the explanation: the level of ITPK1 expression in wild-type MTEs was twice as high as that in CF MTEs (P<0.002). The biological impact of this differential gene expression is amplified by ITPK1 being concentrated at the apical membrane of MTEs, which we discovered following confocal immuno...Continue Reading

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Citations

Jul 10, 2007·The Journal of Biological Chemistry·Philip P ChamberlainGlen Spraggon
Dec 5, 2013·American Journal of Respiratory Cell and Molecular Biology·Emily A VucicWan L Lam
Jul 11, 2007·Expert Review of Molecular Diagnostics·Isabel Carvalho-OliveiraDeborah Penque
Sep 6, 2012·British Journal of Pharmacology·Yuemin TianKarl Kunzelmann
Oct 28, 2008·Current Biology : CB·Jennifer MitchellStephen B Shears

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