MTOR-independent translational control of the extrinsic cell death pathway by RalA
MTOR-independent translational control of the extrinsic cell death pathway by RalA
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DOI：
10.1128/mcb.00126-06
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发表时间：
2006-10-01
影响因子：
5.3
通讯作者：
Pieper, Russell O.
中科院分区：
文献类型：
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作者：
Panner, Amith;Nakamura, Jean L.;Pieper, Russell O.
致癌潜力与翻译调控相关，普遍的观点是致癌基因利用 mTOR 依赖性途径上调对转化至关重要的蛋白质的合成。在这项研究中，我们表明 Ras 转化的关键介质 RalA 也与翻译机制有关。然而，这种联系的至少一部分独立于 mTOR，并通过 RaIBP1 发挥作用，抑制 cdc42 介导的 S6 激酶激活和抗凋亡蛋白 FLIP 的翻译。这种作用并没有促进转化，而是开启了一种潜在的肿瘤抑制机制，该机制可以被肿瘤坏死因子相关的凋亡诱导配体激活。这些结果表明，翻译机制与肿瘤抑制以及细胞增殖途径有关，并且通过激活 Ral 致癌程序来重建细胞死亡途径，为选择性治疗靶向 Ral 驱动的恶性肿瘤提供了一种手段。
Oncogenic potential is associated with translational regulation, and the prevailing view is that oncogenes use mTOR-dependent pathways to up-regulate the synthesis of proteins critical for transformation. In this study, we show that RalA, a key mediator of Ras transformation, is also linked to the translational machinery. At least part of this linkage, however, is independent of mTOR and acts through RaIBP1 to suppress cdc42-mediated activation of S6 kinase and the translation of the antiapoptotic protein FLIP,. This action, rather than contributing to transformation, opens a latent tumor-suppressive mechanism that can be activated by tumor necrosis factor-related apoptosis -inducing ligand. These results show that the translational machinery is linked to tumor suppression as well as cell-proliferative pathways and that the reestablishment of cell death pathways by activation of the Ral oncogenic program provides a means for selective therapeutic targeting of Ral-driven malignancies.