Involvement of Erks activation in cadmium-induced AP-1 transactivation in vitro and in vivo

Mol Cell Biochem. 2001 Jun;222(1-2):141-7. doi: 10.1023/a:1017953927347.

Abstract

Cadmium is a potent and effective carcinogen in rodents and has recently been accepted by IARC (International Agency for Research on Cancer) as a category I carcinogen. Cadmium-induced up-regulation of intracellular signaling pathways leading to increased mitogenesis is thought to be a major mechanism for the carcinogenic activity following chronic cadmium exposure. In the present study, we found that exposure of cells to cadmium induced significant activation of AP-1 and all three members of the MAP kinase family in mouse epidermal JB6 cells. The induction of AP-1 activity by cadmium appears to involve activation of Erks, since the induction of AP-1 activity by cadmium was blocked by pretreatment of cells with PD98058. Interestingly, the induction of AP-1 by cadmium was greatly enhanced by the chemical tumor promoter, TPA and the growth factor EGF, but not by ultraviolet C radiation. In vivo studies demonstrated that cadmium could also induce transactivation of AP-1 in AP-1-luciferase report transgenic mice. Considering the role of AP-1 activation in tumor promotion, the results presented in this study provide a possible molecular mechanism for cadmium-induced carcinogenesis.

MeSH terms

  • Animals
  • Cadmium / toxicity*
  • Carcinogens / toxicity
  • Cell Line
  • Drug Synergism
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Epidermal Cells
  • Epidermal Growth Factor / pharmacology
  • Epidermis / drug effects
  • Flavonoids / pharmacology
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / metabolism*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor AP-1 / genetics*
  • Transcription Factor AP-1 / radiation effects
  • Transcriptional Activation / drug effects*
  • Ultraviolet Rays
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Carcinogens
  • Enzyme Inhibitors
  • Flavonoids
  • Transcription Factor AP-1
  • Cadmium
  • Epidermal Growth Factor
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one