Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins
Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins
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DOI：
10.1038/sj.emboj.7600279
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发表时间：
2004-07-21
期刊：
影响因子：
11.4
通讯作者：
Eilers, M
中科院分区：
文献类型：
--
作者：
Bouchard, C;Marquardt, J;Eilers, M
Myc 在细胞转化中与 Ras 和 PI3 激酶发挥协同作用，但人们对这种行为的分子基础知之甚少。我们现在表明，Myc 将 TFIIH、P-TEFb 和 Mediator 募集到细胞周期蛋白 D2 和其他目标启动子，而 PI3 激酶途径控制前起始复合物的形成和 RNA 聚合酶 II 的加载。 PI3 激酶途径涉及 Akt 介导的 FoxO 转录因子磷酸化。在非磷酸化状态下，FoxO 因子抑制多个 Myc 靶基因的诱导、Myc 诱导的细胞增殖以及 Myc 和 Ras 的转化。 FoxO功能的废除使Myc能够在缺乏PI3激酶活性的情况下激活靶基因，并在缺乏致癌Ras的情况下诱导原代细胞中的灶形成。我们认为 Myc 和 Ras 之间的协同性至少部分是由于 Myc 和 FoxO 蛋白控制一组重叠的关键靶基因激活中的不同步骤。
Myc synergizes with Ras and PI3-kinase in cell transformation, yet the molecular basis for this behavior is poorly understood. We now show that Myc recruits TFIIH, P-TEFb and Mediator to the cyclin D2 and other target promoters, while the PI3-kinase pathway controls formation of the preinitiation complex and loading of RNA polymerase II. The PI3-kinase pathway involves Akt-mediated phosphorylation of FoxO transcription factors. In a nonphosphorylated state, FoxO factors inhibit induction of multiple Myc target genes, Myc-induced cell proliferation and transformation by Myc and Ras. Abrogation of FoxO function enables Myc to activate target genes in the absence of PI3-kinase activity and to induce foci formation in primary cells in the absence of oncogenic Ras. We suggest that the cooperativity between Myc and Ras is at least in part due to the fact that Myc and FoxO proteins control distinct steps in the activation of an overlapping set of critical target genes.