CASK Deletion in Intestinal Epithelia Causes Mislocalization of LIN7C and the DLG1/Scrib Polarity Complex without Affecting Cell Polarity

CASK is the mammalian ortholog of LIN2, a component of the LIN2/7/10 protein complex that targets epidermal growth factor receptor (EGFR) to basolateral membranes in Caenorhabditis elegans. A member of the MAGUK family of scaffolding proteins, CASK resides at basolateral membranes in polarized epithelia. Its interaction with LIN7 is evolutionarily conserved. In addition, CASK forms a complex with another MAGUK, the DLG1 tumor suppressor. Although complete knockout of CASK is lethal, the gene is X-linked, enabling us to generate heterozygous female adults that are mosaic for its expression. We also generated intestine-specific CASK knockout mice. Immunofluorescence analysis revealed that in intestine, CASK is not required for epithelial polarity or differentiation but is necessary for the basolateral localization of DLG1 and LIN7C. However, the subcellular distributions of DLG1 and LIN7C are independent of CASK in the stomach. Moreover, CASK and LIN7C show normal localization in dlg1^−/− intestine. Despite the disappearance of basolateral LIN7C in CASK-deficient intestinal crypts, this epithelium retains normal localization of LIN7A/B, EGFR and ErbB-2. Finally, crypt-to-villus migration rates are unchanged in CASK-deficient intestinal epithelium. Thus, CASK expression and the appropriate localization of DLG1 are not essential for either epithelial polarity or intestinal homeostasis in vivo.     

A Prospective Study of Alcohol Consumption and Smoking and the Risk of Major Gastrointestinal Bleeding in Men

MethodsWe prospectively studied 48,000 men in the Health Professional follow-up Study (HPFS) who were aged 40–75 years at baseline in 1986. We identified men with major GIB requiring hospitalization and/or blood transfusion via biennial questionnaires and chart review.ResultsWe documented 305 episodes of major GIB during 26 years of follow-up. Men who consumed >30 g/day of alcohol had a multivariable relative risk (RR) of 1.43 (95% confidence interval (CI), 0.88–2.35; P for trend 0.006) for major GIB when compared with nondrinkers. Alcohol consumption appeared to be primarily related to upper GIB (multivariable RR for >30 g/day vs. nondrinkers was 1.35; 95% CI, 0.66–2.77; P for trend 0.02). Men who consumed ≥ 5 drinks/week vs. < 1 drink/month of liquor had a multivariable RR of 1.72 (95% CI, 1.26–2.35, P for trend <0.001). Wine and beer were not significantly associated with major GIB. The risk of GIB associated with NSAIDs/aspirin use increased with greater alcohol consumption (multivariable RR 1.37; 95% CI, 0.85–2.19 for 1-14g/day of alcohol, RR 1.75; 95% CI, 1.07–2.88 for ≥ 15g/day compared to nondrinkers). Smoking was not significantly associated with GIB.ConclusionsAlcohol consumption, but not smoking, was associated with an increased risk of major GIB. Associations were most notable for upper GIB associated with liquor intake. Alcohol appeared to potentiate the risk of NSAID-associated GIB.