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Nitric oxide upregulates the cyclooxygenase-2 expression through the cAMP-response element in its promoter in several cancer cell lines
Cited 46 time in
Web of Science
Cited 47 time in Scopus
- Authors
- Issue Date
- 2005-07-12
- Publisher
- Nature Publishing Group
- Citation
- Oncogene. 2005 Oct 6;24(44):6689-98.
- Keywords
- Activating Transcription Factor 2 ; Base Sequence ; Cell Line, Tumor ; Cyclic AMP Response Element-Binding Protein/physiology ; Cyclic GMP/physiology ; Cyclooxygenase 2 ; DNA Primers ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Membrane Proteins ; Nitric Oxide/*physiology ; Nitric Oxide Synthase/antagonists & inhibitors ; Prostaglandin-Endoperoxide Synthases/*genetics ; Proto-Oncogene Proteins c-jun/drug effects/physiology ; Transcription Factors/drug effects/*physiology ; Up-Regulation/*physiology ; p38 Mitogen-Activated Protein Kinases/metabolism ; Promoter Regions, Genetic
- Abstract
- We previously showed that nitric oxide (NO) induces overexpression of cyclooxygenase-2 (COX-2) and production of prostaglandin E(2) in cancer cells. Here, we investigated the mechanisms by which NO induces COX-2 expression in cancer cells. We found that the cAMP-response element (CRE) is a critical factor in NO-induced COX-2 expression in all cells tested. We found that in cancer cells, three transcription factors (TFs) - cAMP response element-binding protein (CREB), activating transcription factor-2 (ATF-2) and c-jun, bound the CRE in the COX-2 promoter, and their activities were increased by addition of the NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP). NO-induced activation of soluble guanylate cyclase (sGC), p38 and c-Jun NH(2)-terminal kinase (JNK) upregulated the three TFs, leading to COX-2 overexpression. Addition of dibutyryl-cGMP (db-cGMP) induced COX-2 expression in a manner similar to SNAP; this induction was blocked by a p38 inhibitor (SB202190), but not by a JNK inhibitor (SP600125). NO-induced cGMP was found to activate CREB and ATF-2 in a p38, but not c-jun-dependent manner, while NO induced JNK in a cGMP-independent manner, leading to subsequent activation of c-jun and ATF-2. These results suggest that the low concentrations of endogenous NO present in cancer cell may induce the expression of many genes, including COX-2, which promotes the growth and survival of tumor cells.
- ISSN
- 0950-9232 (Print)
- Language
- English
- URI
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16007171
https://hdl.handle.net/10371/15998
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