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Received for publication July 20, 2004.
Revised October 25, 2004.
Accepted for publication October 25, 2004.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to have chemopreventive activity but the mechanisms involved are not clearly understood. Although NSAIDs inhibit cyclooxygenase activity, they also increase the expression of a divergent member of the transforming growth factor-
superfamily, termed NSAID activated gene (NAG-1), a protein with an anti-tumorigenic and pro-apoptotic activity that could in part be linked to the chemoprevention activity of NSAIDs. NAG-1 is induced by some NSAIDs but the mechanisms responsible are not clear. In this report, we have identified a cis-acting element responsive to NSAIDs located within the -73 to -51 region of the NAG-1 promoter. This region contains overlapping EGR-1 and Sp1 binding sites and mutations in this region suggest that the transacription factors have an important role in NSAID-induced NAG-1 expression. EGR-1 was found to play a critical role in the induction of NAG-1 by sulindac sulfide and other NSAIDs.NSAIDs increase EGR-1 protein expression that occurs prior to the induction of NAG-1 expression supporting the hypothesis that EGR-1 is necessary for NSAID-induced NAG-1 expression. Thus, NSAIDs induce the expression of EGR-1, a tumor suppressor gene, providing a novel mechanism to explain, in part, the anti-tumorigenic properties of some NSAIDs. NAG-1 appears to be an important down stream target protein of this transcription factor, EGR-1 and may mediate the chemopreventive activity of some NSAIDs.
Key words:
Cyclooxygenases, Transcription targets, Tumor suppressors
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