Coping with stress: eIF2 kinases and translational control
Coping with stress: eIF2 kinases and translational control
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DOI：
10.1042/bst0340007
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发表时间：
2006-02-01
影响因子：
3.9
通讯作者：
Anthony, TG
中科院分区：
文献类型：
--
作者：
Wek, RC;Jiang, HY;Anthony, TG
为了应对环境胁迫，一个蛋白激酶家族磷酸化eIF2（真核起始因子2）以减轻细胞损伤或诱导细胞凋亡。eIF2的磷酸化减少了全局翻译，允许细胞保存资源并启动基因表达的重新配置，以有效地管理应激条件。伴随着这种一般的蛋白质合成控制，eIF2磷酸化诱导了特定mrna的翻译，例如编码bZIP（碱性亮氨酸拉链）转录调节因子ATF4（激活转录因子4）的mrna。ATF4还增强了其他转录因子ATF3和CHOP （CCAAT/增强子结合蛋白同源蛋白）/GADD153（生长阻滞和dna损伤诱导蛋白）的表达，这些转录因子有助于调节参与代谢、细胞氧化还原状态和凋亡的基因。eIF2磷酸化减少翻译还可以通过降低短寿命调节蛋白如I kappa B （NF-kappa B抑制剂）的稳态水平，导致与应激相关的转录因子，如NF-kappa B（核因子kappa B）的激活。虽然eIF2磷酸化诱导的许多基因在不同的环境胁迫之间是共享的，但eIF2激酶与其他应激反应途径（如由丝裂原激活的蛋白激酶调节的途径）一起起作用，以引发针对特定应激条件量身定制的基因表达程序。eIF2激酶途径的缺失可能对健康产生重要影响。缺乏eIF2激酶GCN2[一般对照非去抑制-2或EIF2AK4 (eIF2 α激酶4)]的小鼠对营养缺乏和异常饮食行为敏感，PEK[胰腺eIF2 α激酶或PERK （rna依赖蛋白激酶样内质网激酶）或EIF2AK3]的缺失导致新生儿胰岛素依赖型糖尿病、骺端发育不良和肝肾并发症。
In response to environmental stresses, a family of protein kinases phosphorylate eIF2 (eukaryotic initiation factor 2) to alleviate cellular injury or alternatively induce apoptosis. Phosphorylation of eIF2 reduces global translation, allowing cells to conserve resources and to initiate a reconfiguration of gene expression to effectively manage stress conditions. Accompanying this general protein synthesis control, eIF2 phosphorylation induces translation of specific mRNAs, such as that encoding the bZIP (basic leucine zipper) transcriptional regulator ATF4 (activating transcription factor 4). ATF4 also enhances the expression of additional transcription factors, ATF3 and CHOP (CCAAT/enhancer-binding protein homologous protein)/GADD153 (growth arrest and DNA-damage-inducible protein), that assist in the regulation of genes involved in metabolism, the redox status of the cells and apoptosis. Reduced translation by eIF2 phosphorylation can also lead to activation of stress-related transcription factors, such as NF-kappa B (nuclear factor kappa B), by lowering the steady-state levels of short-lived regulatory proteins such as I kappa B (inhibitor of NF-kappa B). While many of the genes induced by eIF2 phosphorylation are shared between different environmental stresses, eIF2 kinases function in conjunction with other stress-response pathways, such as those regulated by mitogen-activated protein kinases, to elicit gene expression programmes that are tailored for the specific stress condition. Loss of eIF2 kinase pathways can have important health consequences. Mice devoid of the eIF2 kinase GCN2 [general control non-derepressible-2 or EIF2AK4 (eIF2 alpha kinase 4)] show sensitivity to nutritional deficiencies and aberrant eating behaviours, and deletion of PEK [pancreatic eIF2 alpha kinase or PERK (RNA-dependent protein kinase-like endoplasmic reticulum kinase) or EIF2AK3] leads to neonatal insulin-dependent diabetes, epiphyseal dysplasia and hepatic and renal complications.