c-Myc phosphorylation is required for cellular response to oxidative stress

Mol Cell. 2006 Feb 17;21(4):509-19. doi: 10.1016/j.molcel.2006.01.009.


Aside from the well-established roles of c-Myc in the regulation of cell cycle, differentiation, and apoptosis, a recent picture is beginning to emerge linking c-Myc to the regulation of metabolic pathways. Here, we define a further function for c-Myc in determining cellular redox balance, identifying glutathione (GSH) as the leading molecule mediating this process. The link between c-Myc and GSH is gamma-glutamyl-cysteine synthetase (gamma-GCS), the rate-limiting enzyme catalyzing GSH biosynthesis. Indeed, c-Myc transcriptionally regulates gamma-GCS by binding and activating the promoters of both gamma-GCS heavy and light subunits. Exposure to H2O2 enhances c-Myc recruitment to gamma-GCS regulatory regions through ERK-dependent phosphorylation. Phosphorylation at Ser-62 is required for c-Myc recruitment to gamma-GCS promoters and determines the cellular response to oxidative stress induced by different stimuli. Thus, the c-Myc phosphorylation-dependent activation of the GSH-directed survival pathway can contribute to oxidative stress resistance in tumor cells, which generally exhibit deregulated c-Myc expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival
  • Cells, Cultured
  • Enzyme Inhibitors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Enzymologic*
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / metabolism*
  • Humans
  • Hydrogen Peroxide / metabolism
  • Mice
  • Oxidants / metabolism
  • Oxidation-Reduction
  • Oxidative Stress*
  • Phosphorylation
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Serine / metabolism
  • Signal Transduction / physiology*
  • Transcription, Genetic


  • Enzyme Inhibitors
  • Oxidants
  • Proto-Oncogene Proteins c-myc
  • Serine
  • Hydrogen Peroxide
  • Extracellular Signal-Regulated MAP Kinases
  • Glutamate-Cysteine Ligase
  • Glutathione