化学抑制剂使 HuR 与 TNF-α mRNA 的 AU 富含元件的结合不稳定。
Chemical inhibitors destabilize HuR binding to the AU-rich element of TNF-alpha mRNA.
机构信息
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
出版信息
Exp Mol Med. 2009 Nov 30;41(11):824-31. doi: 10.3858/emm.2009.41.11.088.
Abstract
Hu protein R (HuR) binds to the AU-rich element (ARE) in the 3UTR to stabilize TNF-alpha mRNA. Here, we identified chemical inhibitors of the interaction between HuR and the ARE of TNF-alpha mRNA using RNA electrophoretic mobility gel shift assay (EMSA) and filter binding assay. Of 179 chemicals screened, we identified three with a half-maximal inhibitory concentration (IC(50)) below 10 microM. The IC(50) of quercetin, b-40, and b-41 were 1.4, 0.38, and 6.21 microM, respectively, for binding of HuR protein to TNF-alpha mRNA. Quercetin and b-40 did not inhibit binding of tristetraprolin to the ARE of TNF-alpha mRNA. When LPS-treated RAW264.7 cells were treated with quercetin and b-40, we observed decreased stability of TNF-alpha mRNA and decreased levels of secreted TNF-alpha. From these results, we could find inhibitors for the TNF-alpha mRNA stability, which might be used advantageously for both the study for post-transcriptional regulation and the discovery of new anti-inflammation drugs.
摘要
Hu 蛋白 R（HuR）与 TNF-α mRNA 的 3'UTR 中的 AU 丰富元件（ARE）结合以稳定 TNF-α mRNA。在这里，我们使用 RNA 电泳迁移率凝胶阻滞 assay（EMSA）和过滤结合 assay 鉴定了 HuR 和 TNF-α mRNA 的 ARE 之间相互作用的化学抑制剂。在筛选的 179 种化学物质中，我们鉴定出三种的半最大抑制浓度（IC（50））低于 10 microM。槲皮素、b-40 和 b-41 与 HuR 蛋白结合到 TNF-α mRNA 的 IC（50）分别为 1.4、0.38 和 6.21 microM。槲皮素和 b-40 不抑制 tristetraprolin 与 TNF-α mRNA 的 ARE 的结合。当用 LPS 处理的 RAW264.7 细胞用槲皮素和 b-40 处理时，我们观察到 TNF-α mRNA 的稳定性降低，分泌的 TNF-α 水平降低。从这些结果中，我们可以找到 TNF-α mRNA 稳定性的抑制剂，这可能有利于研究转录后调节和发现新的抗炎药物。
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