Panner Amith, Nakamura Jean L, Parsa Andrew T, Rodriguez-Viciana Pablo, Berger Mitchel S, Stokoe David, Pieper Russell O
UCSF Cancer Center, 2340 Sutter St., Rm N219, San Francisco, CA 94115-0875, USA.
Mol Cell Biol. 2006 Oct;26(20):7345-57. doi: 10.1128/MCB.00126-06. Epub 2006 Aug 7.
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 RalBP1 to suppress cdc42-mediated activation of S6 kinase and the translation of the antiapoptotic protein FLIP(S). 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.
致癌潜能与翻译调控相关，目前普遍的观点是癌基因利用mTOR依赖性途径上调对细胞转化至关重要的蛋白质的合成。在本研究中，我们发现RalA（Ras转化的关键介质）也与翻译机制相关。然而，这种联系至少部分独立于mTOR，并通过RalBP1发挥作用，以抑制cdc42介导的S6激酶激活和抗凋亡蛋白FLIP(S)的翻译。这种作用并非促进细胞转化，而是开启了一种潜在的肿瘤抑制机制，该机制可被肿瘤坏死因子相关凋亡诱导配体激活。这些结果表明，翻译机制与肿瘤抑制以及细胞增殖途径相关，并且通过激活Ral致癌程序重建细胞死亡途径为选择性治疗Ral驱动的恶性肿瘤提供了一种手段。
