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The oncogene c-Myc coordinates regulation of metabolic networks to enable rapid cell cycle entry.

Morrish, Fionnuala and Neretti, Nicola and Sedivy, John, M. and Hockenbery, David M. (2008) The oncogene c-Myc coordinates regulation of metabolic networks to enable rapid cell cycle entry. Cell Cycle, 7 (8). pp. 1054-1066. ISSN 1538-4101 (Unpublished)

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The c-myc proto-oncogene is rapidly activated by serum and regulates genes involved in metabolism and cell cycle progression. This gene is thereby uniquely poised to coordinate both the metabolic and cell cycle regulatory events required for cell cycle entry. However, this function of Myc has not been evaluated. Using a rat fibroblast model of isogenic cell lines, myc(-/-), myc(+/-), myc(+/+) and myc(-/-) cells with an inducible c-myc transgene (mycER), we show that the Myc protein programs cells to utilize both oxidative phosphorylation and glycolysis to drive cell cycle progression. We demonstrate this coordinate regulation of metabolic networks is essential, as specific inhibitors of these pathways block Myc-induced proliferation. Metabolic events temporally correlated with cell cycle entry include increased oxygen consumption, mitochondrial function, pyruvate and lactate production, and ATP generation. Treatment of normal cells with inhibitors of oxidative phosphorylation recapitulates the myc(-/-) phenotype, resulting in impaired cell cycle entry and reduced metabolism. Combined with a kinetic expression profiling analysis of genes linked to mitochondrial function, our study indicates that Myc's ability to coordinately regulate the mitochondrial metabolic network transcriptome is required for rapid cell cycle entry. This function of Myc may underlie the pervasive presence of Myc in many human cancers.

Item Type: Article or Abstract
Additional Information: This article is available to subscribers only via the URL above for the first 12 months post-publication.
DOI: 10.4161/cc.7.8.5739
PubMed ID: 18414044
PMCID: PMC2518168
Grant Numbers: R01 CA106650-02, R01 GM041690-18, K25 AG028753-01A1
Keywords or MeSH Headings: Analysis of Variance; Animals; Cell Cycle/*physiology; Cell Line; Cell Proliferation; Gene Expression Profiling; Glycolysis/physiology; Membrane Potential, Mitochondrial; Metabolic Networks and Pathways/*physiology; Microarray Analysis; Mitochondria/*metabolism; Oxidative Phosphorylation; Proto-Oncogene Proteins c-myc/genetics/*metabolism; Rats; Reactive Oxygen Species/metabolism
Subjects: Molecules > Genes > Oncogenes
Cellular and Organismal Processes > Cell Physiology > Cell cycle
Depositing User: Library Staff
Date Deposited: 03 Apr 2009 18:25
Last Modified: 11 Oct 2011 00:52

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