Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Apoptosis Regulatory Proteins / metabolism
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Astrocytes / cytology
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Astrocytes / metabolism
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Cell Death
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Cell Line
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Gene Expression Regulation
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism
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Membrane Glycoproteins / metabolism
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Mice
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Phosphorylation
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Protein Binding
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Protein Biosynthesis*
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Ribosomal Protein S6 Kinases / genetics
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Ribosomal Protein S6 Kinases / metabolism
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Signal Transduction
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TNF-Related Apoptosis-Inducing Ligand
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TOR Serine-Threonine Kinases
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Tumor Necrosis Factor-alpha / metabolism
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cdc42 GTP-Binding Protein / genetics
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cdc42 GTP-Binding Protein / metabolism
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ral GTP-Binding Proteins / genetics
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ral GTP-Binding Proteins / metabolism*
Substances
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ATP-Binding Cassette Transporters
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Cflar protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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Ribosomal Protein S6 Kinases
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TOR Serine-Threonine Kinases
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cdc42 GTP-Binding Protein
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ral GTP-Binding Proteins