A cellular response linking eIF4AI activity to eIF4AII transcription
A cellular response linking eIF4AI activity to eIF4AII transcription
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DOI：
10.1261/rna.033209.112
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发表时间：
2012-07-01
期刊：
影响因子：
4.5
通讯作者：
Pelletier, Jerry
中科院分区：
文献类型：
--
作者：
Galicia-Vazquez, Gabriela;Cencic, Regina;Pelletier, Jerry
核糖体向真核细胞mRNA的募集需要两种原型RNA解旋酶的活性，真核起始因子（eIF）4AI和eIF4AII。eIF4A同种型是高度保守的，被认为是功能上可互换的，并且在翻译起始期间通过其组装成eIF4F（也含有eIF4E帽结合蛋白和eIF4G支架单元的异源三聚体复合物）而针对mRNA的59 m 7GpppN帽结构。在旨在研究eIF4AI和eIF4AII在翻译中各自作用的RNA干扰实验过程中，我们发现了一种细胞反应途径，通过抑制eIF4AI增加eIF4AII基因的转录，导致eIF4AII mRNA和蛋白水平升高。抑制eIF4AI会抑制蛋白质合成，尽管eIF4AII蛋白质水平增加超过足以补偿eIF4AI水平降低的水平，但在eIF4AI抑制后，没有相应的翻译拯救或细胞增殖阻断。这些结果使用小分子eIF4A抑制剂马尿酸进行表型复制。两者合计，我们的研究结果表明，eIF4AI和eIF4AII的表达出现连接，这两种蛋白质亚型表现出功能差异。
The recruitment of ribosomes to eukaryotic cellular mRNAs requires the activity of two prototypic RNA helicases, eukaryotic initiation factor (eIF) 4AI and eIF4AII. The eIF4A isoforms are highly conserved, are thought to be functionally interchangeable, and are directed to the 59 m 7 GpppN cap structure of mRNAs during translation initiation by virtue of their assembly into eIF4F, a heterotrimeric complex that also harbors the eIF4E cap binding protein and eIF4G scaffolding unit. During the course of RNA interference experiments aimed at investigating the respective roles of eIF4AI and eIF4AII in translation, we uncovered a cellular response pathway whereby suppression of eIF4AI increases transcription of the eIF4AII gene, leading to elevated eIF4AII mRNA and protein levels. Inhibition of eIF4AI suppresses protein synthesis, and although eIF4AII protein levels increase above and beyond what should be sufficient to compensate for the decrease in eIF4AI levels, there is no corresponding rescue of translation or of the block on cellular proliferation that occurs upon eIF4AI suppression. These results were phenocopied using the small molecule eIF4A inhibitor hippuristanol. Taken together, our results indicate that eIF4AI and eIF4AII expression appear linked and that the two protein isoforms exhibit functional differences.