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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Rapamycin Differentially Inhibits S6ks And 4e-bp1 To Mediate Cell-type-specific Repression Of Mrna Translation
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Rapamycin Differentially Inhibits S6ks And 4e-bp1 To Mediate Cell-type-specific Repression Of Mrna Translation

机译：雷帕霉素差异抑制S6ks和4e-bp1介导Mrna翻译的细胞类型特异性抑制。

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摘要

The mammalian translational initiation machinery is a tightly controlled system that is composed of eukaryotic initiation factors, and which controls the recruitment of ribosomes to mediate cap-dependent translation. Accordingly, the mTORC1 complex functionally controls this cap-dependent translation machinery through the phosphorylation of its downstream substrates 4E-BPs and S6Ks. It is generally accepted that rapamycin, a specific inhibitor of mTORC1, is a potent translational repressor. Here we report the unexpected discovery that rapamycin's ability to regulate cap-dependent translation varies significantly among cell types. We show that this effect is mechanistically caused by rapamycin's differential effect on 4E-BP1 versus S6Ks. While rapamycin potently inhibits S6K activity throughout the duration of treatment, 4E-BP1 recovers in phosphorylation within 6 h despite initial inhibition (1-3 h). This reemerged 4E-BP1 phosphorylation is rapamycin-resistant but still requires mTOR, Raptor, and mTORC1's activity. Therefore, these results explain how cap-dependent translation can be maintained in the presence of rapamycin. In addition, we have also defined the condition by which rapamycin can control cap-dependent translation in various cell types. Finally, we show that mTOR catalytic inhibitors are effective inhibitors of the rapamycin-resistant phenotype.
机译：哺乳动物的翻译起始机制是由真核起始因子组成的严格控制的系统，该系统控制核糖体的募集以介导帽依赖性翻译。因此，mTORC1复合物通过其下游底物4E-BPs和S6Ks的磷酸化在功能上控制这种依赖于帽的翻译机制。公认的雷帕霉素是mTORC1的特异性抑制剂，是一种有效的翻译阻遏物。在这里，我们报告了一个出乎意料的发现，即雷帕霉素调节帽依赖性翻译的能力在细胞类型之间显着不同。我们表明，这种作用是由雷帕霉素对4E-BP1与S6Ks的差异作用引起的。尽管雷帕霉素在整个治疗过程中均有效抑制S6K活性，但尽管有最初的抑制作用（1-3小时），但4E-BP1在6小时内仍能恢复磷酸化。重新出现的4E-BP1磷酸化具有雷帕霉素抗性，但仍需要mTOR，Raptor和mTORC1的活性。因此，这些结果解释了在雷帕霉素存在下如何维持帽依赖性翻译。此外，我们还定义了雷帕霉素可以控制各种细胞类型中帽依赖性翻译的条件。最后，我们表明mTOR催化抑制剂是雷帕霉素抗性表型的有效抑制剂。

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