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

Barbara Benassi, Maurizio Fanciulli, Francesco Fiorentino, Alessandro Porrello, Giovanna Chiorino, Massimo Loda, Gabriella Zupi, Annamaria Biroccio

Research output: Contribution to journalArticle

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 γ-glutamyl-cysteine synthetase (γ-GCS), the rate-limiting enzyme catalyzing GSH biosynthesis. Indeed, c-Myc transcriptionally regulates γ-GCS by binding and activating the promoters of both γ-GCS heavy and light subunits. Exposure to H2O 2 enhances c-Myc recruitment to γ-GCS regulatory regions through ERK-dependent phosphorylation. Phosphorylation at Ser-62 is required for c-Myc recruitment to γ-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.

Original languageEnglish
Pages (from-to)509-519
Number of pages11
JournalMolecular Cell
Volume21
Issue number4
DOIs
Publication statusPublished - Feb 17 2006

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ASJC Scopus subject areas

  • Molecular Biology

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