c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry.
Cell proliferation requires the coordinated activity of cytosolic and mitochondrial metabolic pathways to provide ATP and building blocks for DNA, RNA, and protein synthesis. Many metabolic pathway genes are targets of the c-myc oncogene and cell cycle regulator. However, the contribution of c-Myc to the activation of cytosolic and mitochondrial metabolic networks during cell cycle entry is unknown. Here, we report the metabolic fates of [U-13C] glucose in serum-stimulated myc-/- and myc+/+ fibroblasts by 13C isotopomer NMR analysis. We demonstrate that endogenous c-myc increased 13C-labeling of ribose sugars, purines, and amino acids, indicating partitioning of glucose carbons into C1/folate and pentose phosphate pathways, and increased tricarboxylic acid cycle turnover at the expense of anaplerotic flux. Myc expression also increased global O-linked GlcNAc protein modification, and inhibition of hexosamine biosynthesis selectively reduced growth of Myc-expressing cells, suggesting its importance in Myc-induced proliferation. These data reveal a central organizing role for the Myc oncogene in the metabolism of cycling cells. The pervasive deregulation of this oncogene in human cancers may be explained by its role in directing metabolic networks required for cell proliferation.
- Research Organization:
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC05-76RL01830
- OSTI ID:
- 965998
- Report Number(s):
- PNNL-SA-64106; 25606; KP1704020; TRN: US200921%%568
- Journal Information:
- Oncogene, 28(27):2485-2491, Vol. 28, Issue 27
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
98 NUCLEAR DISARMAMENT, SAFEGUARDS, AND PHYSICAL PROTECTION
AMINO ACIDS
BIOLOGICAL PATHWAYS
BIOSYNTHESIS
CELL CYCLE
CELL PROLIFERATION
DNA
FIBROBLASTS
GENES
GLUCOSE
HEXOSAMINES
ONCOGENES
PENTOSES
PHOSPHATES
PROLIFERATION
PROTEINS
PURINES
RIBOSE
RNA
SACCHARIDES
SUBSTRATES
SYNTHESIS
Environmental Molecular Sciences Laboratory