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mTOR-Independent Translational Control of the Extrinsic Cell Death Pathway by RalA ^,

Department of Neurological Surgery,¹ The Brain Tumor Research Center,² The UCSF Comprehensive Cancer Center, University of California—San Francisco, 2340 Sutter St., San Francisco, California 94115-0875³

Received 20 January 2006/ Returned for modification 10 March 2006/ Accepted 27 July 2006

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.

Supplemental material for this article may be found at http://mcb.asm.org/.

Published ahead of print on 7 August 2006.

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