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Molecular and Cellular Biology, October 2006, p. 7345-7357, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00126-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

mTOR-Independent Translational Control of the Extrinsic Cell Death Pathway by RalA {triangledown},{dagger}

Amith Panner,1,2,3 Jean L. Nakamura,3 Andrew T. Parsa,1,2,3 Pablo Rodriguez-Viciana,3 Mitchel S. Berger,1,2,3 David Stokoe,1,2,3 and Russell O. Pieper1,2,3*

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 FLIPS. 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.

* Corresponding author. Mailing address: UCSF Cancer Center, 2340 Sutter St., Rm N219, San Francisco, CA 94115-0875. Phone: (415) 502-7132. Fax: (415) 502-6779. E-mail: rpieper{at}cc.ucsf.edu.

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

{triangledown} Published ahead of print on 7 August 2006.

Molecular and Cellular Biology, October 2006, p. 7345-7357, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00126-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Singhal, S. S., Singhal, J., Yadav, S., Sahu, M., Awasthi, Y. C., Awasthi, S. (2009). RLIP76: A Target for Kidney Cancer Therapy. Cancer Res. 69: 4244-4251 [Abstract] [Full Text]  
  • Panner, A., Murray, J. C., Berger, M. S., Pieper, R. O. (2007). Heat Shock Protein 90{alpha} Recruits FLIPS to the Death-Inducing Signaling Complex and Contributes to TRAIL Resistance in Human Glioma. Cancer Res. 67: 9482-9489 [Abstract] [Full Text]  


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