Mechanism of Copper-Activated Transcription: Activation of AP-1, and the JNK/SAPK and p38 Signal Transduction Pathways

Michael D. Mattie, Matthew K. McElwee, Jonathan H. Freedman

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Copper is an essential metal that is able to produce reactive oxygen species and to induce intracellular oxidative stress. Several studies have examined the effects of excessive copper and oxidative stress on various organisms and tissues, but few have addressed the molecular mechanisms by which copper affects transcription. Our results demonstrated that, in COS-7 cells, copper treatment caused an increase in the binding of nuclear proteins to activating protein-1 and antioxidant response elements. The level of copper-inducible nuclear protein binding was modulated by increasing or decreasing the level of intracellular oxidative stress. Copper exposure also led to an increase in the steady-state levels of c-fos, c-jun, and c-myc mRNAs. Exposure to copper resulted in an increase in the levels of phosphorylation and activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 pathways. The activation of these pathways resulted in a concomitant increase in c-Jun phosphorylation. We investigated the hypothesis that copper-induced oxidative stress leads to the formation of stable lipid peroxidation by-products that activate mitogen-activated protein kinase (MAPK) pathways, ultimately affecting transcription. While exposure did result in the production of 4-hydroxynonenal, the timing of the increased levels of proto-oncogene mRNA, phosphorylation of c-jun, and phosphorylation and activation of MAPKs, as well as the inability of the lipophilic antioxidant vitamin E to abrogate MAPK phosphorylation, suggest that the formation of stable lipid peroxidation by-products may not be the primary mechanism by which copper activates MAPKs. These results further elucidate the effects of copper on signal transduction pathways to alter gene expression.

Original languageEnglish (US)
Pages (from-to)1008-1018
Number of pages11
JournalJournal of Molecular Biology
Volume383
Issue number5
DOIs
StatePublished - Nov 28 2008

Bibliographical note

Funding Information:
This work was supported, in part, by National Institute of Environmental Health Sciences grants ES-10356 and 5T32-ES-07031-22, and by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences.

Keywords

  • MAPK
  • copper
  • reactive oxygen species
  • signal transduction
  • transcription

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