Activator Protein-1 Transcription Factor Mediates Bombesin-stimulated Cyclooxygenase-2 Expression in Intestinal Epithelial Cells

Yan Shi Guo, Mark R. Hellmich, Xiao Dong Wen, Courtney M. Townsend

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

Colorectal carcinogenesis is a complex, multistep process involving genetic alterations and progressive changes in signaling pathways regulating intestinal epithelial cell proliferation, differentiation, and apoptosis. Although cyclooxygenase-2 (COX-2), gastrin-releasing peptide (GRP), and its receptor, GRP-R, are not normally expressed by the epithelial cells lining the human colon, the levels of all three proteins are aberrantly overexpressed in premalignant adenomatous polyps and colorectal carcinomas of humans. Overexpression of these proteins is associated with altered epithelial cell growth, adhesion, and tumor cell invasiveness, both in vitro and in vivo; however, a mechanistic link between GRP-R-mediated signaling pathways and increased COX-2 overexpression has not been established. We report that bombesin, a homolog of GRP, potently stimulates the expression of COX-2 mRNA and protein as well as the release of prostaglandin E2 from a rat intestinal epithelial cell line engineered to express GRP-R. Bombesin stimulation of COX-2 expression requires an increase in [Ca2+] i, activation of extracellular signal-regulated kinase (ERK)-1 and -2 and p38MAPK, and increased activation and expression of the transcription factors Elk-1, ATF-2, c-Fos, and c-Jun. These data suggest that the expression of GRP-R in intestinal epithelial cells may play a role in carcinogenesis by stimulating COX-2 overexpression through an activator protein-1-dependent pathway.

Original languageEnglish (US)
Pages (from-to)22941-22947
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number25
DOIs
StatePublished - Jun 22 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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