eIF2α kinases GCN2 and PERK modulate transcription and translation of distinct sets of mRNAs in mouse liver
eIF2α kinases GCN2 and PERK modulate transcription and translation of distinct sets of mRNAs in mouse liver
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DOI：
10.1152/physiolgenomics.90396.2008
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发表时间：
2009-08-01
影响因子：
4.6
通讯作者：
Jefferson, Leonard S.
中科院分区：
文献类型：
--
作者：
Do, An N. Dang;Kimball, Scot R.;Jefferson, Leonard S.
首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容EIF2α激酶GCN2和PERK调节小鼠肝脏中不同组mRNAs的转录和翻译。PhysIOL基因组学38：328-341,2009。2009年6月9日首次发表；DOI：10.1152/Physiolgenomics.90396.2008.-在真核生物中，通过改变逆境暴露后上游开放阅读框架(UORF)或内部核糖体进入位点(IRES)调节基序的改变来选择性地去抑制mR NA翻译，在起始阶段通过真核细胞起始因子2在其阿尔法亚单位(eIF2α)上增加磷酸化来调节。虽然酵母中只有一种已知的eIF2α激酶，即一般控制的不可降压2(GCN2)，但哺乳动物已经进化成至少表达四种：GCN2，血红素调节的抑制因子激酶(HRI)，双链RNA激活的蛋白激酶(PKR)和PKR样内质网驻留蛋白激酶(PERK)。到目前为止，这四种激酶之间已知的主要区别是它们对不同的急性应激源的反应被激活。在本研究中，我们使用原位灌流小鼠肝脏模型和杂交阵列分析来评估GCN2和PERK这两种激酶对应激的一般翻译反应，并区分激活GCN2和PERK的下游效应。结果数据显示，至少2.5%的小鼠肝脏mRNAs在应激后受到去抑制的翻译。此外，数据表明，eIF2α激酶GCN2和PERK对mRNA的转录和翻译起着不同的调节作用，在后者的情况下，eIF2α磷酸化的增加不足以抑制翻译的下调。这些发现为未来更有针对性地研究编码早期细胞应激反应蛋白的mRNAs组开辟了一条途径。
Do AND, Kimball SR, Cavener DR, Jefferson LS. eIF2 alpha kinases GCN2 and PERK modulate transcription and translation of distinct sets of mRNAs in mouse liver. Physiol Genomics 38: 328-341, 2009. First published June 9, 2009; doi: 10.1152/physiolgenomics.90396.2008.-In eukaryotes, selective derepression of mRNA translation through altered utilization of upstream open reading frames (uORF) or internal ribosomal entry sites (IRES) regulatory motifs following exposure to stress is regulated at the initiation stage through the increased phosphorylation of eukaryotic initiation factor 2 on its alpha-subunit (eIF2 alpha). While there is only one known eIF2 alpha kinase in yeast, general control nonderepressible 2 (GCN2), mammals have evolved to express at least four: GCN2, heme-regulated inhibitor kinase (HRI), double-stranded RNA-activated protein kinase (PKR), and PKR-like endoplasmic reticulum-resident kinase (PERK). So far, the main known distinction among these four kinases is their activation in response to different acute stressors. In the present study, we used the in situ perfused mouse liver model and hybridization array analyses to assess the general translational response to stress regulated by two of these kinases, GCN2 and PERK, and to differentiate between the downstream effects of activating GCN2 versus PERK. The resulting data showed that at least 2.5% of mouse liver mRNAs are subject to derepressed translation following stress. In addition, the data demonstrated that eIF2 alpha kinases GCN2 and PERK differentially regulate mRNA transcription and translation, which in the latter case suggests that increased eIF2 alpha phosphorylation is not sufficient for derepression of translation. These findings open an avenue for more focused future research toward groups of mRNAs that code for the early cellular stress response proteins.