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. 1996 Aug 15;318(Pt 1):325–331. doi: 10.1042/bj3180325

Down-regulation of cytokine-induced cyclo-oxygenase-2 transcript isoforms by dexamethasone: evidence for post-transcriptional regulation.

A Ristimäki 1, K Narko 1, T Hla 1
PMCID: PMC1217625  PMID: 8761489

Abstract

The immediate-early cyclo-oxygenase-2 (Cox-2) gene encodes an inducible prostaglandin synthase enzyme that has been implicated in inflammatory and proliferative diseases. We have shown that the inflammatory cytokine interleukin-1 (IL-1) induces the Cox-2 gene in a sustained manner and that post-transcriptional mRNA stabilization is an important even [Ristimäki, Garfinkel, Wessendorf, Maciag and Hla (1994) J. Biol. Chem. 269, 11769-11775]. The anti-inflammatory glucocorticoid dexamethasone potently down-regulates IL-1-induced Cox-2 mRNA expression. Kinetic studies suggest that antagonism of IL-1-induced mRNA stabilization is, at least in part, responsible for the suppression of Cox-2 mRNA. The Cox-2 gene produces two major transcript isoforms, namely Cox-2(4.6) (4.6 kb) and Cox-2(2.8) (2.8 kb), which are derived by alternative polyadenylation in the 3'-untranslated region (UTR). In response to dexamethasone, the short Cox-2(2.8) transcript isoform, which lacks a highly conserved AU-rich region, decays with a longer half-life than the Cox-2(4.6) isoform. Furthermore, heterologous expression of the hybrid Cox-1 open reading frame and the Cox-2 3'-UTR results in the accumulation of high levels of the short isoform and lower levels of the long isoform. These data suggest that multiple elements in the 3'-UTR of the Cox-2 gene are involved in the determination of the differential mRNA stabilities of Cox-2 transcript isoforms. Because dexamethasone destabilizes the Cox-2 transcript, and because the decay of Cox-2 transcript isoforms induced by dexamethasone occurs with different half-lives, post-transcriptional mRNA destabilization may be an important mechanism in the action of anti-inflammatory glucocorticoids.

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Selected References

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