Kinase suppressor of Ras-1 protects intestinal epithelium from cytokine-mediated apoptosis during inflammation.

Yan F, John SK, Wilson G, Jones DS, Washington MK, Polk DB
J Clin Invest. 2004 114 (9): 1272-80

PMID: 15520859 · PMCID: PMC524224 · DOI:10.1172/JCI21022

TNF plays a pathogenic role in inflammatory bowel diseases (IBDs), which are characterized by altered cytokine production and increased intestinal epithelial cell apoptosis. In vitro studies suggest that kinase suppressor of Ras-1 (KSR1) is an essential regulatory kinase for TNF-stimulated survival pathways in intestinal epithelial cell lines. Here we use a KSR1-deficient mouse model to study the role of KSR1 in regulating intestinal cell fate during cytokine-mediated inflammation. We show that KSR1 and its target signaling pathways are activated in inflamed colon mucosa. Loss of KSR1 increases susceptibility to chronic colitis and TNF-induced apoptosis in the intestinal epithelial cell. Furthermore, disruption of KSR1 expression enhances TNF-induced apoptosis in mouse colon epithelial cells and is associated with a failure to activate antiapoptotic signals including Raf-1/MEK/ERK, NF-kappaB, and Akt/protein kinase B. These effects are reversed by WT, but not kinase-inactive, KSR1. We conclude that KSR1 has an essential protective role in the intestinal epithelial cell during inflammation through activation of cell survival pathways.

MeSH Terms (28)

Animals Apoptosis Blotting, Western Caspase 3 Caspases Cell Line, Tumor Cell Nucleus Cell Survival Colon Cytokines Epithelial Cells Genetic Predisposition to Disease Immunohistochemistry Immunoprecipitation Inflammation In Situ Nick-End Labeling Intestinal Mucosa Intestines Mice Mice, Inbred BALB C Mice, Transgenic Platelet Endothelial Cell Adhesion Molecule-1 Protein-Serine-Threonine Kinases Protein Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt Signal Transduction Time Factors

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