Mazroui Rachid, Di Marco Sergio, Kaufman Randal J, Gallouzi Imed-Eddine
McGill University, Department of Biochemistry, Montreal, Quebec, Canada.
Mol Biol Cell. 2007 Jul;18(7):2603-18. doi: 10.1091/mbc.e06-12-1079. Epub 2007 May 2.
The inhibition of the ubiquitin-dependent proteasome system (UPS) via specific drugs is one type of approach used to combat cancer. Although it has been suggested that UPS inhibition prevents the rapid decay of AU-rich element (ARE)-containing messages, very little is known about the cellular mechanisms leading to this effect. Here we establish a link between the inhibition of UPS activity, the formation of cytoplasmic stress granules (SGs), and mRNA metabolism. The assembly of the SGs requires the phosphorylation of the translation initiation factor eIF2alpha by a mechanism involving the stress kinase GCN2. On prolonged UPS inhibition and despite the maintenance of eIF2alpha phosphorylation, SGs disassemble and translation recovers in an Hsp72 protein-dependent manner. The formation of these SGs coincides with the disassembly of processing bodies (PBs), known as mRNA decay entities. As soon as the SGs assemble, they recruit ARE-containing messages such as p21(cip1) mRNA, which are stabilized under these conditions. Hence, our findings suggest that SGs could be considered as one of the players that mediate the early response of the cell to proteasome inhibitors by interfering temporarily with mRNA decay pathways.
通过特定药物抑制泛素依赖性蛋白酶体系统（UPS）是对抗癌症的一种方法。尽管有人提出UPS抑制可防止富含AU元件（ARE）的信息快速降解，但对于导致这种效应的细胞机制却知之甚少。在这里，我们建立了UPS活性抑制、细胞质应激颗粒（SGs）形成与mRNA代谢之间的联系。SGs的组装需要应激激酶GCN2参与的机制使翻译起始因子eIF2α磷酸化。在长时间UPS抑制后，尽管eIF2α磷酸化得以维持，但SGs会解体，翻译以依赖Hsp72蛋白的方式恢复。这些SGs的形成与被称为mRNA降解实体的加工小体（PBs）的解体同时发生。一旦SGs组装，它们就会募集诸如p21（cip1）mRNA等含ARE的信息，这些信息在这些条件下会被稳定下来。因此，我们的研究结果表明，SGs可被视为通过暂时干扰mRNA降解途径介导细胞对蛋白酶体抑制剂早期反应的因素之一。
