期刊
GASTROENTEROLOGY
卷 135, 期 2, 页码 539-551出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2008.04.025
关键词
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资金
- Intramural NIH HHS [Z01 DK056008] Funding Source: Medline
- NCI NIH HHS [CA68485, P30 CA068485] Funding Source: Medline
- NEI NIH HHS [P30 EY008126, EY08126] Funding Source: Medline
- NICHD NIH HHS [P30 HD015052, HD15052] Funding Source: Medline
- NIDDK NIH HHS [DK20593, DK66176, DK58404, DK59637, P30 DK020593, R01 DK054993-05, R01 DK066176, U24 DK059637, P30 DK058404-06, R01 DK066176-04, R01 DK056008-09, R01 DK056008, R01 DK054993, P30 DK058404, P60 DK020593] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008554, T32GM008554] Funding Source: Medline
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-kappa B 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-kappa B 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.
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