Raf protects against colitis by promoting mouse colon epithelial cell survival through NF-kappaB.

Edelblum KL, Washington MK, Koyama T, Robine S, Baccarini M, Polk DB
Gastroenterology. 2008 135 (2): 539-51

PMID: 18598699 · PMCID: PMC2640938 · DOI:10.1053/j.gastro.2008.04.025

BACKGROUND & AIMS - Raf-1 kinase is a key regulator of a number of cellular processes, which promote the maintenance of a healthy colon epithelium. This study addresses the role of Raf in epithelial cell survival in response to dextran sulfate sodium (DSS)-induced injury and inflammation.

METHODS - Inducible intestinal epithelium-specific Raf knockout mice were generated and subjected to acute colitis followed by a short recovery period. Colon sections were analyzed by in situ oligo ligation or immunostaining for Ki67, phospho-extracellular signal regulated kinase, and nuclear factor-kappaB p65. Western blot analysis and terminal deoxynucleotidyl transferase nick-end labeling assays were performed on Raf small interfering RNA-transfected young adult mouse colon cells following DSS treatment.

RESULTS - We report that Raf protects against epithelial injury and inflammation and promotes recovery from acute DSS-induced colitis by both MAPK/ERK kinase (MEK)-dependent and -independent pathways. Furthermore, we demonstrate that Raf induces novel cell survival responses through activating nuclear factor-kappaB in a MEK-independent manner.

CONCLUSIONS - These novel findings indicate a protective role for Raf in colon epithelium following ulcerative damage through inhibiting cell apoptosis and promoting proliferation with important implications for responses such as inflammation-associated carcinogenesis.

MeSH Terms (27)

Animals Apoptosis Blotting, Western Cell Proliferation Cells, Cultured Cell Survival Colitis Colon Dextran Sulfate Disease Models, Animal Extracellular Signal-Regulated MAP Kinases Immunohistochemistry In Situ Nick-End Labeling Intestinal Mucosa Ki-67 Antigen Mice Mice, Inbred C57BL Mice, Knockout NF-kappa B Phosphorylation raf Kinases Regeneration RNA Interference Signal Transduction Time Factors Transcription Factor RelA Transfection

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