Journal
LABORATORY INVESTIGATION
Volume 90, Issue 10, Pages 1415-1424Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/labinvest.2010.117
Keywords
cell survival; colon epithelial cells; cyclooxygenase-2; ErbB4; inflammatory bowel diseases; receptor tyrosine kinases
Categories
Funding
- NCI NIH HHS [P30 CA068485, P30 CA68485] Funding Source: Medline
- NIDDK NIH HHS [P30DK058404, K01 DK077956, R03 DK090295, P30 DK058404, K01DK077956, K01 DK077956-03, R01DK056008, DK058404, R01 DK056008, K01 DK077956-03S1] Funding Source: Medline
Ask authors/readers for more resources
The ErbB4 receptor tyrosine kinase is expressed at high levels in human and mouse colitis, and inhibits colon epithelial cell apoptosis in the presence of proinflammatory cytokines. In this study, we investigated the molecular mechanisms responsible for ErbB4-induced cell survival. In cultured mouse colon epithelial cells, ErbB4 overexpression resulted in increased levels of cyclooxygenase-2 (COX-2) mRNA and protein; in contrast, ErbB4 knockdown with siRNA blocked COX-2 accumulation in response to tumor necrosis factor. Although ErbB4 is expressed as up to four isoforms in epithelial tissues, its ability to promote COX-2 expression was isoform independent. ErbB4-stimulated COX-2 induction was associated with an increase in mRNA half-life and was blocked by inhibition of Src, phosphatidylinositol (PI) 3-kinase, or epidermal growth factor receptor (EGFR). Furthermore, ErbB4 expression promoted EGFR phosphorylation in the presence of heregulin, implicating ErbB4-EGFR heterodimerization in these responses. As to the cellular responses to ErbB4 activation, increased survival of ErbB4-expressing cells in the presence of proinflammatory cytokines was sensitive to the COX-2 inhibitor celecoxib. Furthermore, ErbB4-overexpressing cells acquired the ability to form colonies in soft agar, indicative of cellular transformation, also in a celecoxib-sensitive manner. Together our data indicate that ErbB4 is a key regulator of COX-2 expression and cellular survival in colon epithelial cells, acting in concert with EGFR through a Src- and PI 3-kinase-dependent mechanism. These results suggest that chronic overexpression of ErbB4 in the context of inflammation could contribute to colitis-associated tumorigenesis by inhibiting colonocyte apoptosis. Laboratory Investigation (2010) 90, 1415-1424; doi: 10.1038/labinvest.2010.117; published online 28 June 2010
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available