Phosphorylation of initiation factor-2α is required for activation of internal translation initiation during cell differentiation
Phosphorylation of initiation factor-2α is required for activation of internal translation initiation during cell differentiation
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DOI：
10.1046/j.1432-1033.2002.02974.x
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发表时间：
2002-06-01
期刊：
影响因子：
--
通讯作者：
Elroy-Stein, O
中科院分区：
文献类型：
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作者：
Gerlitz, G;Jagus, R;Elroy-Stein, O
许多编码参与细胞生长和分化的调节蛋白的基因的长uORF负载的5 'UTR含有内部核糖体进入位点（IRES）元件。在以前的研究中，我们表明，利用血小板衍生生长因子（PDGF 2）的弱IRES在巨核细胞分化过程中被激活。在分化过程中IRES介导的翻译的许可条件的建立已被我们证实的增强活性的血管内皮生长因子，c-Myc和脑心肌炎病毒IRES元素在这些条件下，虽然他们的mRNA在分化的K562细胞中不自然表达。与IRES介导的蛋白质合成在分化过程中的增强相反，整体蛋白质合成减少，如通过多聚体概况和放射性标记的氨基酸掺入率所判断的。蛋白质合成速率的降低与翻译起始因子eIF 2 α的磷酸化增加相关。此外，IRES的使用通过eIF 2 α激酶、PKR、牛痘病毒K3 L基因或eIF 2 α-S51 A变体的显性阴性形式的过度表达而减少，这导致eIF 2 α磷酸化减少。这些数据表明eIF 2 α磷酸化和细胞IRES元件激活之间的联系。这表明，磷酸化eIF 2 α，已知是重要的帽依赖性transaltional控制，用于微调不同的mRNA亚群的翻译效率在分化过程中，并有可能调节表达的IRES-含有mRNA在一系列的生理环境下。
The long uORF-burdened 5'UTRs of many genes encoding regulatory proteins involved in cell growth and differentiation contain internal ribosomal entry site (IRES) elements. In a previous study we showed that utilization of the weak IRES of platelet-derived growth factor (PDGF2) is activated during megakaryocytic differentiation. The establishment of permissive conditions for IRES-mediated translation during differentiation has been confirmed by our demonstration of the enhanced activity of vascular endothelial growth factor, c-Myc and encephalomyocarditis virus IRES elements under these conditions, although their mRNAs are not naturally expressed in differentiated K562 cells. In contrast with the enhancement of IRES-mediated protein synthesis during differentiation, global protein synthesis is reduced, as judged by polysomal profiles and radiolabelled amino acid incorporation rate. The reduction in protein synthesis rate correlates with increased phosphorylation of the translation initiation factor eIF2alpha. Furthermore, IRES use is decreased by over-expression of the dominant-negative form of the eIF2alpha kinase, PKR, the vaccinia virus K3L gene, or the eIF2alpha-S51A variant which result in decreased eIF2alpha phosphorylation. These data demonstrate a connection between eIF2alpha phosphorylation and activation of cellular IRES elements. It suggests that phosphorylation of eIF2alpha, known to be important for cap-dependent transaltional control, serves to fine-tune the translation efficiency of different mRNA subsets during the course of differentiation and has the potential to regulate expression of IRES-containing mRNAs under a range of physiological circumstances.