Title | c-Myc phosphorylation is required for cellular response to oxidative stress. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Benassi B, Fanciulli M, Fiorentino F, Porrello A, Chiorino G, Loda M, Zupi G, Biroccio A |
Journal | Mol Cell |
Volume | 21 |
Issue | 4 |
Pagination | 509-19 |
Date Published | 2006 Feb 17 |
ISSN | 1097-2765 |
Keywords | Animals, Cell Survival, Cells, Cultured, Enzyme Inhibitors, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Enzymologic, Glutamate-Cysteine Ligase, Glutathione, Humans, Hydrogen Peroxide, Mice, Oxidants, Oxidation-Reduction, Oxidative Stress, Phosphorylation, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc, Serine, Signal Transduction, Transcription, Genetic |
Abstract | 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. |
DOI | 10.1016/j.molcel.2006.01.009 |
Alternate Journal | Mol Cell |
PubMed ID | 16483932 |
Related Faculty:
Massimo Loda, M.D.