Ristimäki A, Narko K, Hla T
Department of Molecular Biology, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
Biochem J. 1996 Aug 15;318 ( Pt 1)(Pt 1):325-31. doi: 10.1042/bj3180325.
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.
即刻早期环氧化酶-2（Cox-2）基因编码一种诱导性前列腺素合酶，该酶与炎症和增殖性疾病有关。我们已经表明，炎性细胞因子白细胞介素-1（IL-1）以持续的方式诱导Cox-2基因，并且转录后mRNA稳定化是一个重要事件[里斯蒂马基、加芬克尔、韦森多夫、马西亚格和赫拉（1994年）《生物化学杂志》269卷，第11769 - 11775页]。抗炎糖皮质激素地塞米松能有效下调IL-1诱导的Cox-2 mRNA表达。动力学研究表明，IL-1诱导的mRNA稳定化的拮抗作用至少部分地导致了Cox-2 mRNA的抑制。Cox-2基因产生两种主要的转录异构体，即Cox-2(4.6)（4.6 kb）和Cox-2(2.8)（2.8 kb），它们是通过3' - 非翻译区（UTR）中的可变聚腺苷酸化产生的。对地塞米松的反应中，缺乏高度保守的富含AU区域的短Cox-2(2.8)转录异构体的半衰期比Cox-2(4.6)异构体更长。此外，杂交的Cox-1开放阅读框和Cox-2 3' - UTR的异源表达导致高水平的短异构体和低水平的长异构体的积累。这些数据表明，Cox-2基因3' - UTR中的多个元件参与了Cox-2转录异构体不同mRNA稳定性的决定。由于地塞米松使Cox-2转录本不稳定，并且由于地塞米松诱导的Cox-2转录异构体的降解以不同的半衰期发生，转录后mRNA不稳定化可能是抗炎糖皮质激素作用的一个重要机制。
