Abstract
Overexpression of cyclooxygenase-2 (COX-2), an inducible enzyme regulating prostaglandin release, is mechanistically linked to the development, growth, and spread of gastrointestinal (GI) cancers. GI peptide bombesin (BBS) was reported to stimulate COX-2 gene expression. Here we show that TGF-beta1 dramatically enhances the BBS-induced expression of COX-2 mRNA and protein, and the release of PGE2 in the model rat intestinal epithelial cell (RIE-1) line. The synergistic increase in COX-2 levels results from a combination of enhanced COX-2 transcription and reduced mRNA degradation. BBS, but not TGF-beta1, stimulated COX-2 promoter activity, and TGF-beta1 enhanced COX-2 mRNA stability through a p38(MAPK)-dependent pathway. The synergistic regulation of COX-2 expression by TGF-beta1 and BBS may contribute to the upregulation of COX-2 in GI cancers.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Bombesin / metabolism*
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Cell Line
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Cyclooxygenase 2 / biosynthesis*
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Cyclooxygenase 2 / genetics
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Dinoprostone / metabolism
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Enzyme Induction
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Imidazoles / pharmacology
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / enzymology*
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Promoter Regions, Genetic
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Protein Kinase Inhibitors / pharmacology
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Pyridines / pharmacology
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RNA Interference
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RNA Stability
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RNA, Messenger / biosynthesis
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Rats
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Signal Transduction* / drug effects
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Time Factors
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Transcription, Genetic
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Transfection
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Transforming Growth Factor beta1 / metabolism*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Imidazoles
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Protein Kinase Inhibitors
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Pyridines
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RNA, Messenger
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Transforming Growth Factor beta1
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Cyclooxygenase 2
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Ptgs2 protein, rat
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p38 Mitogen-Activated Protein Kinases
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Dinoprostone
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SB 203580
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Bombesin