title: Kinase suppressor of Ras determines survival of intestinal epithelial cells exposed to tumor necrosis factor.
abstract: The single layer of epithelial cells lining the intestine that serves as an important physical and functional barrier regulating the uptake of nutrients and the exclusion of various environmental antigens is disrupted in inflammatory bowel diseases. A central cytokine in the pathogenesis of inflammatory bowel disease is tumor necrosis factor (TNF), which increases apoptosis in a number of cell types. However, details determining the fate of intestinal cells exposed to high levels of TNF are lacking. Our laboratory reported that kinase suppressor of Ras (KSR) regulates TNF activation of the Raf/mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase/ERK signaling cassette by threonine phosphorylation of Raf-1, regulating proliferation and differentiation pathways. In the present study, we expressed a dominant-negative kinase-inactive KSR and determined the survival of young adult mouse colon cells exposed to TNF. Our data show that inhibition of KSR signaling decreases survival and increases apoptosis of TNF-treated cells. Antiapoptotic pathways including nuclear factor kappa B activation and one of its transcriptional targets, cIAP2 (c inhibitor of apoptosis protein 2) gene expression, and ERK/MAP kinase activation are all inhibited in TNF-treated kinase-inactive KSR-expressing young adult mouse colon cells. These antiapoptotic pathways are also inhibited by antisense-mediated down-regulation of KSR. However, TNF activation of p38 or stress-activated protein kinase/c-Jun NH(2)-terminal kinase is not inhibited by disruption of KSR signaling. Furthermore, inhibitors of both ERK and nuclear factor kappa B activation synergistically enhance apoptosis of cells treated with TNF. These findings demonstrate that KSR plays a novel regulatory role in intestinal epithelial cells exposed to TNF by activating cell survival pathways.
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: F
authors.initials: F
authors.lastname: Yan
authors.forename: S K
authors.initials: SK
authors.lastname: John
authors.forename: D B
authors.initials: DB
authors.lastname: Polk
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020672:I-kappa B Proteins; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases