Publication Date:
2008-11-18
Description:
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 Emu-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 Emu-Myc/+ mice. When accurate translational control is re-established in Emu-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880952/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880952/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barna, Maria -- Pusic, Aya -- Zollo, Ornella -- Costa, Maria -- Kondrashov, Nadya -- Rego, Eduardo -- Rao, Pulivarthi H -- Ruggero, Davide -- R01 HL085572/HL/NHLBI NIH HHS/ -- R01 HL085572-03/HL/NHLBI NIH HHS/ -- England -- Nature. 2008 Dec 18;456(7224):971-5. doi: 10.1038/nature07449. Epub 2008 Nov 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry & Biophysics, University of California San Francisco, Rock Hall Room 384C, 1550 Fourth Street, San Francisco, California 94158-2517, USA. maria.barna@ucsf.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19011615" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apoptosis
;
B-Lymphocytes/cytology/metabolism/pathology
;
Cell Division
;
Cell Size
;
Cells, Cultured
;
Cytokinesis
;
Gene Expression Regulation, Neoplastic
;
Genes, myc/*genetics
;
Genomic Instability
;
Heterozygote
;
Lymphoma/genetics/pathology
;
Mice
;
Mice, Inbred C57BL
;
Mitosis
;
Oncogene Protein p55(v-myc)/*genetics/*metabolism
;
Precancerous Conditions/metabolism/pathology
;
*Protein Biosynthesis
;
Protein-Serine-Threonine Kinases/metabolism
;
Ribosomal Proteins/*deficiency/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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