The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase

EMBO J. 1996 Nov 15;15(22):6269-79.

Abstract

Trivalent arsenic (As3+) is highly carcinogenic, but devoid of known mutagenic activity. Therefore, it is likely to act as a tumor promoter. To understand the molecular basis for the tumor-promoting activity of As3+, we examined its effect on transcription factor AP-1, whose activity is stimulated by several other tumor promoters. We found that As3+, but not As5+, which is toxic but not carcinogenic, is a potent stimulator of AP-1 transcriptional activity and an efficient inducer of c-fos and c-jun gene expression. Induction of c-jun and c-fos transcription by As3+ correlates with activation of Jun kinases (JNKs) and p38/Mpk2, which phosphorylate transcription factors that activate these immediate early genes. No effect on ERK activity was observed. As5+, on the other hand, had a negligible effect on JNK or p38/Mpk2 activity. Biochemical analysis and co-transfection experiments strongly suggest that the primary mechanism by which As3+ stimulates JNK activity involves the inhibition of a constitutive dual-specificity JNK phosphatase. This phosphatase activity appears to be responsible for maintaining low basal JNK activity in non-stimulated cells and its inhibition may lead to tumor promotion through induction of proto-oncogenes such as c-jun and c-fos, and stimulation of AP-1 activity. The same phosphatase may also regulate p38/Mpk2 activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arsenites / pharmacology*
  • Blotting, Northern
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Carcinogens / pharmacology*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation / genetics
  • Genes, Reporter / genetics
  • HeLa Cells
  • Humans
  • Mitogen-Activated Protein Kinases*
  • Phosphoprotein Phosphatases / metabolism
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Sulfhydryl Compounds / pharmacology
  • Transcription Factor AP-1 / drug effects*
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects
  • Transfection / genetics
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Arsenites
  • Carcinogens
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-jun
  • Sulfhydryl Compounds
  • Transcription Factor AP-1
  • Transcription Factors
  • Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Phosphoprotein Phosphatases
  • arsenite