Proud C G, Denton R M
Department of Biosciences, University of Kent, Canterbury, Kent, CT2 7NJ, U.K.
Biochem J. 1997 Dec 1;328 ( Pt 2)(Pt 2):329-41. doi: 10.1042/bj3280329.
Insulin acutely stimulates protein synthesis in mammalian cells, and this involves activation of the process of mRNA translation. mRNA translation is a complex multi-step process mediated by proteins termed translation factors. Several translation factors are regulated in response to insulin, often as a consequence of changes in their states of phosphorylation. The initiation factor eIF4E binds to the cap structure at the 5'-end of the mRNA and mediates assembly of an initiation-factor complex termed eIF4F. Assembly of this complex can be regulated by eIF4E-binding proteins (4E-BPs), which inhibit eIF4F complex assembly. Insulin induces phosphorylation of the 4E-BPs, resulting in alleviation of the inhibition. This regulatory mechanism is likely to be especially important for the control of the translation of specific mRNAs whose 5'-untranslated regions (5'-UTRs) are rich in secondary structure. Translation of another class of mRNAs, those with 5'-UTRs containing polypyrimidine tracts is also activated by insulin and this, like phosphorylation of the 4E-BPs, appears to involve the rapamycin-sensitive signalling pathway which leads to activation of the 70 kDa ribosomal protein S6 kinase (p70 S6 kinase) and the phosphorylation of the ribosomal protein S6. Overall stimulation of translation may involve activation of initiation factor eIF2B, which is required for all initiation events. This effect is dependent upon phosphatidylinositol 3-kinase and may involve the inactivation of glycogen synthase kinase-3 and consequent dephosphorylation of eIF2B, leading to its activation. Peptide-chain elongation can also be activated by insulin, and this is associated with the dephosphorylation and activation of elongation factor eEF2, probably as a consequence of the insulin-induced reduction in eEF2 kinase activity. Thus multiple signalling pathways acting on different steps in translation are involved in the activation of this process by insulin and lead both to general activation of translation and to the selective regulation of specific mRNAs.
胰岛素可急性刺激哺乳动物细胞中的蛋白质合成，这涉及mRNA翻译过程的激活。mRNA翻译是一个由称为翻译因子的蛋白质介导的复杂多步骤过程。几种翻译因子会响应胰岛素而受到调节，这通常是其磷酸化状态变化的结果。起始因子eIF4E与mRNA 5'端的帽结构结合，并介导一种称为eIF4F的起始因子复合物的组装。这种复合物的组装可由eIF4E结合蛋白（4E-BPs）调节，4E-BPs会抑制eIF4F复合物的组装。胰岛素诱导4E-BPs的磷酸化，从而减轻这种抑制作用。这种调节机制可能对于控制5'-非翻译区（5'-UTRs）富含二级结构的特定mRNA的翻译尤为重要。另一类mRNA，即5'-UTRs含有多嘧啶序列的mRNA的翻译也会被胰岛素激活，这与4E-BPs的磷酸化一样，似乎涉及雷帕霉素敏感信号通路，该通路会导致70 kDa核糖体蛋白S6激酶（p70 S6激酶）的激活以及核糖体蛋白S6的磷酸化。翻译的总体刺激可能涉及起始因子eIF2B的激活，这是所有起始事件所必需的。这种作用依赖于磷脂酰肌醇3-激酶，可能涉及糖原合酶激酶-3的失活以及随后eIF2B的去磷酸化，从而导致其激活。肽链延伸也可被胰岛素激活，这与延伸因子eEF2的去磷酸化和激活有关，这可能是胰岛素诱导eEF2激酶活性降低的结果。因此，作用于翻译不同步骤的多种信号通路参与了胰岛素对这一过程的激活，并导致翻译的全面激活以及特定mRNA的选择性调节。
