Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage.
Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage.
复制标题
RNA结合蛋白CUGBP2和环氧合酶2介导的前列腺素E2在辐射损伤中的动态拮抗作用。
DOI：
10.1073/pnas.0406066101
复制
发表时间：
2004
影响因子：
11.1
通讯作者：
Anant,Shrikant
中科院分区：
文献类型：
--
作者：
Murmu,Nabendu;Jung,Jesse;Mukhopadhyay,Debnath;Houchen,CourtneyW;Riehl,TerrenceE;Stenson,WilliamF;Morrison,AubreyR;Arumugam,Thiruvengadam;Dieckgraefe,BrianK;Anant,Shrikant
肠上皮损伤限制了电离辐射（IR）在癌症治疗中的应用。前列腺素（Prostaglandins，PGs）是通过环氧合酶-1（cyclooxygenase-1，考克斯-1）和考克斯-2的作用而产生的，具有保护肠干细胞免受IR的作用。在这里，我们证明了CUGBP 2和考克斯-2之间的动态拮抗关系。IR后小鼠肠腺上皮细胞中CUGBP 2和考克斯-2均被迅速诱导，但CUGBP 2蛋白表达立即观察到，而考克斯-2蛋白表达延迟。与此相反，细菌脂多糖的管理诱导考克斯-2的表达和PGE 2，导致CUGBP 2表达的抑制和肠道的辐射保护。这些作用被考克斯-2特异性抑制剂NS 398逆转，表明脂多糖介导的CUGBP 2抑制是PG依赖性机制。此外，在基础条件下，COX-1-/-和COX-2-/-小鼠的CUGBP 2表达高于野生型对照，IR后进一步增加。
Damage to intestinal epithelium limits the use of ionizing radiation (IR) in cancer therapy. Prostaglandins (PGs), generated through the action of cyclooxygenase-1 (COX-1) and COX-2 protect the intestinal stem cells from IR. In previous studies, we demonstrated that the RNA-binding protein CUGBP2 regulates the stability and translation of COX-2 mRNA by interacting with AU-rich sequences in 3′ UTR. Here, we demonstrate a dynamic antagonistic relationship between CUGBP2 and COX-2. Both CUGBP2 and COX-2 are rapidly induced after IR in intestinal crypt epithelial cells in mice, but CUGBP2 protein expression is observed immediately and COX-2 protein expression is delayed. In contrast, administration of bacterial lipopolysaccharide induced COX-2 expression and PGE2, resulting in the inhibition of CUGBP2 expression and radioprotection of the intestine. These effects were reversed by NS398, a COX-2-specific inhibitor, suggesting that lipopolysaccharide-mediated inhibition of CUGBP2 is a PG-dependent mechanism. Furthermore, CUGBP2 expression is higher inCOX-1–/–andCOX-2–/–mice than wild-type controls at basal conditions, which is further increased after IR.