Roles of mitogen-activated protein kinase signal-integrating kinases 1 and 2 in oxidant-mediated eIF4E phosphorylation

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• 作者：Jeffrey S. Shenberger ; Lianqin Zhang ; Mariah K. Hughlock ; Takeshi Ueda ; Rie Watanabe-Fukunaga ; Rikiro Fukunaga
• 关键词：Translation ; Oxidant stress ; Signal transduction ; Mitogen-activate protein kinase signal-integrating kinase ; eIF4E
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2007
• 期刊代码：127_13572725
• 类别：med
• 出版时间：2007
• 卷：39
• 期：10
• 页码：1828-1842
• 文件大小：1153 K

摘要

Oxidative stress alters cellular metabolic processes including protein synthesis. The eukaryotic initiation factor, eIF4E, acts in the rate-limiting steps of initiation and promotes nuclear export. Phosphorylation of eIF4E by mitogen activated protein kinase signal-integrating kinases 1 and 2 (Mnk) influences the affinity of eIF4E for the 5′-mRNA cap and fosters nuclear export activity. Although phosphorylation of eIF4E on Ser²⁰⁹ is observed following oxidant exposure, the contribution of Mnk isoforms and the significance of phosphorylation remain elusive. Using a Mnk inhibitor and fibroblasts derived from Mnk knockout mice, we demonstrate that that H₂O₂ enhances eIF4E phosphorylation in cells containing Mnk1. In contrast, cells containing only Mnk2 show little change or a decrease in eIF4E phosphorylation in response to H₂O₂. H₂O₂ also shifted eIF4GI protein from the nucleus to the cytoplasm suggesting that the increases in eIF4E phosphorylation may reflect enhanced substrate availability to cytoplasmic Mnk1. In Mnk1^+/+ cells, H₂O₂ also enhanced eIF4E phosphorylation in the nucleus to a greater degree than in the cytoplasm, an effect not observed in cells containing Mnk2. In response to H₂O₂, all MEFs showed increased eIF4E:4E-BP1 and 4E-BP2:eIF4E binding and reduced eIF4E:eIF4GI binding. We also observed a dramatic increase in the amount of Mnk1 associated with eIF4E following affinity chromatography. These changes coincided with a smaller reduction in global protein synthesis in response to H₂O₂ in the DKO cells. These findings suggest that changes in eIF4GI distribution may enhance eIF4E phosphorylation and that the presence of either Mnk1 or 2 or any degree of eIF4E phosphorylation negatively regulates global protein synthesis in response to oxidant stress.