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

Abstract

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.

• Authors: Fang Yan, Sutha K John, Guinn Wilson, David S Jones, M Kay Washington, D Brent Polk
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 114 Issue 9 Pg. 1272-80 (Nov 2004) ISSN: 0021-9738 [Print] United States
• PMID: 15520859 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytokines
• Platelet Endothelial Cell Adhesion Molecule-1
• Proto-Oncogene Proteins
• Protein Kinases
• KSR-1 protein kinase
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Casp3 protein, mouse
• Caspase 3
• Caspases

Topics

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