Signalling to eIF4E in cancer.
Signalling to eIF4E in cancer.
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DOI：
10.1042/bst20150126
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发表时间：
2015-10
影响因子：
3.9
通讯作者：
Sonenberg N
中科院分区：
文献类型：
--
作者：
Siddiqui N;Sonenberg N
翻译调控在真核生物基因表达调控中起着至关重要的作用，影响着许多重要的细胞过程，包括增殖、凋亡和分化。在大多数情况下，翻译控制发生在核糖体被招募到mRNA的起始步骤。真核生物翻译起始因子4E （eIF4E）作为eIF4F复合体的一部分，首先与mRNA相互作用，促进40S核糖体亚基的募集。eIF4E的活性在许多水平上受到调节，最深刻的是通过两种主要信号通路：PI3K（磷酸肌肽3-激酶）/Akt（也称为蛋白激酶B， PKB）/mTOR（雷帕霉素的机制/哺乳动物靶点）和Ras（大鼠肉瘤）/MAPK（丝裂原活化蛋白激酶）/Mnk （MAPK相互作用激酶）。mTOR直接磷酸化eIF4E的抑制剂4e - bp （eIF4E结合蛋白）来缓解翻译抑制，而Mnk磷酸化eIF4E来刺激翻译。这些通路的过度激活发生在大多数癌症中，导致eIF4E活性增加。因此，通过eIF4E进行的翻译控制作为过度活跃的信号通路的汇聚点，促进肿瘤发生。因此，最近的工作旨在针对这些途径，并最终为癌症治疗的翻译机制。
Translational control plays a critical role in the regulation of gene expression in eukaryotes and affects many essential cellular processes, including proliferation, apoptosis and differentiation. Under most circumstances, translational control occurs at the initiation step at which the ribosome is recruited to the mRNA. The eukaryotic translation initiation factor 4E (eIF4E), as part of the eIF4F complex, interacts first with the mRNA and facilitates the recruitment of the 40S ribosomal subunit. The activity of eIF4E is regulated at many levels, most profoundly by two major signalling pathways: PI3K (phosphoinositide 3-kinase)/Akt (also known and Protein Kinase B, PKB)/mTOR (mechanistic/mammalian target of rapamycin) and Ras (rat sarcoma)/MAPK (mitogen-activated protein kinase)/Mnk (MAPK-interacting kinases). mTOR directly phosphorylates the 4E-BPs (eIF4E-binding proteins), which are inhibitors of eIF4E, to relieve translational suppression, whereas Mnk phosphorylates eIF4E to stimulate translation. Hyperactivation of these pathways occurs in the majority of cancers, which results in increased eIF4E activity. Thus, translational control via eIF4E acts as a convergence point for hyperactive signalling pathways to promote tumorigenesis. Consequently, recent works have aimed to target these pathways and ultimately the translational machinery for cancer therapy.