Fang Yan
Last active: 4/11/2016

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells.

Hobbs SS, Goettel JA, Liang D, Yan F, Edelblum KL, Frey MR, Mullane MT, Polk DB
Am J Physiol Gastrointest Liver Physiol. 2011 301 (2): G220-9

PMID: 21566012 · PMCID: PMC3154604 · DOI:10.1152/ajpgi.00383.2010

TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2(-/-) mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1(-/-) cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR(-/-) and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFR(wa2) and EGFR(wa5), mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.

MeSH Terms (22)

Animals Cell Line Cell Survival Colon Cyclooxygenase 2 Epithelial Cells ErbB Receptors Gastric Mucosa Gene Expression Regulation Mice Mice, Inbred C57BL Mice, Knockout p38 Mitogen-Activated Protein Kinases Receptors, Tumor Necrosis Factor, Type I RNA, Messenger RNA, Small Interfering Signal Transduction src-Family Kinases Stomach Transcriptional Activation Transfection Tumor Necrosis Factor-alpha

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