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

Publication Type:

Journal Article

Source:

Cell cycle (Georgetown, Tex.), Volume 7, Issue 8, p.1054-66 (2008)

Keywords:

2008, Analysis of Variance, Animals, cell cycle, Cell Line, Cell Proliferation, Clinical Research Division, Gene Expression Profiling, Glycolysis, Membrane Potential, Mitochondrial, Metabolic Networks and Pathways, Microarray Analysis, mitochondria, Oxidative Phosphorylation, Proto-Oncogene Proteins c-myc, Rats, Reactive Oxygen Species

Abstract:

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.