Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency

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. Whether and how increasing the cellular protein synthesis capacity affects the multistep process...

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Bibliographic Details
Published in:Nature 2008-12, Vol.456 (7224), p.971-975
Main Authors: Barna, Maria, Ruggero, Davide, Pusic, Aya, Zollo, Ornella, Costa, Maria, Kondrashov, Nadya, Rego, Eduardo, Rao, Pulivarthi H
Format: Article
Language:English
Subjects:
Animal tumors. Experimental tumors
Animals
Apoptosis
B-Lymphocytes - cytology
B-Lymphocytes - metabolism
B-Lymphocytes - pathology
Biological and medical sciences
Cancer
Cell cycle
Cell death
Cell Division
Cell growth
Cell Size
Cells, Cultured
Chemical properties
Cytokinesis
Experimental malignant blood diseases
Gene Expression Regulation, Neoplastic
Genes, myc - genetics
Genomes
Genomic Instability
Health aspects
Heterozygote
Lymphoma
Lymphoma - genetics
Lymphoma - pathology
Medical sciences
Mice
Mice, Inbred C57BL
Mitosis
Oncogene Protein p55(v-myc) - genetics
Oncogene Protein p55(v-myc) - metabolism
Oncogenes
Precancerous Conditions - metabolism
Precancerous Conditions - pathology
Protein Biosynthesis
Protein synthesis
Protein-Serine-Threonine Kinases - metabolism
Proteins
Ribosomal proteins
Ribosomal Proteins - deficiency
Ribosomal Proteins - genetics
RNA polymerase
Transgenic animals
Tumors
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Summary: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. 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), 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.
ISSN:0028-0836
1476-4687
1476-4679
DOI:10.1038/nature07449