H2O2 mediates oxidative stress-induced epidermal growth factor receptor phosphorylation

Alexander Meves, Sibylle N. Stock, Astrid Beyerle, Mark R. Pittelkow, Dominik Peus

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

We used a well-established thiol-alkylating agent, N-ethylmaleimide (NEM), to oxidatively stress human keratinocytes. Time course studies revealed that NEM rapidly depleted keratinocytes of reduced glutathione (GSH), which was followed by rapidly increasing levels of intracellular reactive oxygen species (ROS) and subsequently by phosphorylation of epidermal growth factor receptor (EGFR). Pretreatment with antioxidants or enhanced catalase activity in keratinocytes inhibited ROS/H2O2 accumulation and EGFR phosphorylation, demonstrating that H2O2 production is a mediator required for EGFR phosphorylation. Collectively, these results suggest a sequence of events leading to EGFR phosphorylation which is likely shared by oxidative stress-inducing agents, namely: (1) GSH depletion; (2) H2O2 accumulation; and (3) EGFR phosphorylation. We propose that depletion of GSH and accumulation of H2O2 are upstream events and critical mediators required for ligand-independent phosphorylation of growth factor receptors in response to oxidative stress.

Original languageEnglish (US)
Pages (from-to)205-214
Number of pages10
JournalToxicology Letters
Volume122
Issue number3
DOIs
StatePublished - Jul 6 2001

Keywords

  • Cell surface receptors
  • Cellular physiology
  • Glutathione depletion
  • Receptor tyrosine kinases

ASJC Scopus subject areas

  • Toxicology

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