Kinase suppressor of Ras-1 protects intestinal epithelium from cytokine-mediated apoptosis during inflammation.
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.
Yan
Fang
F
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2576, USA.
John
Sutha K
SK
Wilson
Guinn
G
Jones
David S
DS
Washington
M Kay
MK
Polk
D Brent
DB
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology*; D007413:Intestinal Mucosa / Q000473:pathology*; D007422:Intestines / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D013997:Time Factors
D016207:Cytokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases