1. Department of Biochemistry & Biophysics, University of California San Francisco, Rock Hall Room 384C, 1550 Fourth Street, San Francisco, California 94158-2517, USA
2. School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, Byers Hall Room 308E, 1700 Fourth Street, San Francisco, California 94158-2517, USA
3. Center for Cell Based Therapy, Fundação Hemocentro de Ribeirão Preto, University of Sao Paulo, 14048-900 Brazil
4. Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA
5. These authors contributed equally to this work.

Correspondence to: Maria Barna¹Davide Ruggero² Correspondence and requests for materials should be addressed to M.B. (Email: maria.barna@ucsf.edu) or D.R. (Email: Davide.Ruggero@ucsf.edu).

Abstract

The Myc oncogene regulates the expression of several components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, RNA polymerase III and ribosomal DNA^{1, 2}. Whether and how increasing the cellular protein synthesis capacity affects the multistep process leading to cancer remains to be addressed. Here we use ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in E-Myc/+ transgenic mice to normal levels, and show that the oncogenic potential of Myc in this context is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc-overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Our findings reveal a new mechanism that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation used to regulate the expression of selective messenger RNAs. We show that an aberrant increase in cap-dependent translation downstream of Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation that is required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (also known as Cdc2l and PITSLRE)^{3, 4, 5}, which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in E-Myc/+ mice. When accurate translational control is re-established in E-Myc/+ mice, genome instability is suppressed. Our findings demonstrate how perturbations in translational control provide a highly specific outcome for gene expression, genome stability and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post-genomic level.

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