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首页> 外文期刊>Molecular and Cellular Biology >Transduction of Growth or Mitogenic Signals into Translational Activation of TOP mRNAs Is Fully Reliant on the Phosphatidylinositol 3-Kinase-Mediated Pathway but Requires neither S6K1 nor rpS6 Phosphorylation
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Transduction of Growth or Mitogenic Signals into Translational Activation of TOP mRNAs Is Fully Reliant on the Phosphatidylinositol 3-Kinase-Mediated Pathway but Requires neither S6K1 nor rpS6 Phosphorylation

机译：将生长或有丝分裂信号转化为TOP mRNA的翻译激活完全依赖于磷脂酰肌醇3-激酶介导的途径，但既不需要S6K1也不需要rpS6磷酸化

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Translation of terminal oligopyrimidine tract (TOP) mRNAs, which encode multiple components of the protein synthesis machinery, is known to be controlled by mitogenic stimuli. We now show that the ability of cells to progress through the cell cycle is not a prerequisite for this mode of regulation. TOP mRNAs can be translationally activated when PC12 or embryonic stem (ES) cells are induced to grow (increase their size) by nerve growth factor and retinoic acid, respectively, while remaining mitotically arrested. However, both growth and mitogenic signals converge via the phosphatidylinositol 3-kinase (PI3-kinase)-mediated pathway and are transduced to efficiently translate TOP mRNAs. Translational activation of TOP mRNAs can be abolished by LY294002, a PI3-kinase inhibitor, or by overexpression of PTEN as well as by dominant-negative mutants of PI3-kinase or its effectors, PDK1 and protein kinase Bα (PKBα). Likewise, overexpression of constitutively active PI3-kinase or PKBα can relieve the translational repression of TOP mRNAs in quiescent cells. Both mitogenic and growth signals lead to phosphorylation of ribosomal protein S6 (rpS6), which precedes the translational activation of TOP mRNAs. Nevertheless, neither rpS6 phosphorylation nor its kinase, S6K1, is essential for the translational response of these mRNAs. Thus, TOP mRNAs can be translationally activated by growth or mitogenic stimuli of ES cells, whose rpS6 is constitutively unphosphorylated due to the disruption of both alleles of S6K1. Similarly, complete inhibition of mammalian target of rapamycin (mTOR) and its effector S6K by rapamycin in various cell lines has only a mild repressive effect on the translation of TOP mRNAs. It therefore appears that translation of TOP mRNAs is primarily regulated by growth and mitogenic cues through the PI3-kinase pathway, with a minor role, if any, for the mTOR pathway.
机译：已知编码蛋白质合成机制的多个组成部分的末端寡嘧啶束（TOP）mRNA的翻译受促有丝分裂刺激控制。现在我们表明，细胞通过细胞周期前进的能力不是这种调节模式的先决条件。当PC12或胚胎干（ES）细胞分别被神经生长因子和视黄酸诱导生长（增加其大小），同时保持有丝分裂阻滞时，TOP mRNA可以被翻译激活。但是，生长和有丝分裂信号均通过磷脂酰肌醇3-激酶（PI3-激酶）介导的途径汇聚，并被转导以有效翻译TOP mRNA。可以通过PI3激酶抑制剂LY294002或PTEN的过表达以及PI3激酶或其效应子的显性阴性突变体PDK1和蛋白激酶Bα（PKBα）来消除TOP mRNA的翻译激活。同样，组成型活性PI3-激酶或PKBα的过表达可以减轻静态细胞中TOP mRNA的翻译抑制。有丝分裂和生长信号均导致核糖体蛋白S6（rpS6）的磷酸化，这先于TOP mRNA的翻译激活。尽管如此，rpS6磷酸化或其激酶S6K1都不是这些mRNA的翻译反应所必需的。因此，TOP mRNA可通过ES细胞的生长或促有丝分裂刺激而翻译激活，ES细胞的rpS6由于S6K1的两个等位基因的破坏而在组成上未磷酸化。同样，雷帕霉素在各种细胞系中对哺乳动物雷帕霉素靶标（mTOR）及其效应物S6K的完全抑制仅对TOP mRNA的翻译产生轻微的抑制作用。因此看来，TOP mRNA的翻译主要受PI3激酶途径的生长和有丝分裂线索的调控，而对于mTOR途径的作用则很小。

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