Induction of cellular antioxidative stress genes through heterodimeric transcription factor Nrf2/small Maf by antirheumatic gold(I) compounds.
Gold(I)-containing compounds have long been used in the treatment of rheumatoid arthritis (RA), but the molecular mechanism of their action has remained largely unknown. In this paper we have demonstrated that gold(I) drugs selectively activate the DNA binding of a heterodimer consisting of the basic-leucine zipper transcription factors Nrf2 and small Maf. Once bound to its recognition DNA sequence termed antioxidant-responsive element or Maf-recognition element, Nrf2/small Maf induces a set of antioxidative stress genes, including heme oxygenase-1 and gamma-glutamylcysteine synthetase, whose products have been demonstrated to contribute to the scavenging of reactive oxygen species and to exhibit anti-inflammatory effects. Our findings suggest that stimulation of antioxidative stress response through activation of Nrf2/small Maf may be a pharmacologically important part of the actions of gold(I) drugs for the treatment of rheumatoid arthritis. Alternatively, activation of Nrf2/small Maf may be a protective response of cells against toxic effects of the drugs.
Kataoka
K
K
Frontier Collaborative Research Center, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, 226-8503 Yokohama, Japan. kkataoka@bio.titech.ac.jp
Handa
H
H
Nishizawa
M
M
D018501:Antirheumatic Agents / Q000494:pharmacology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D006046:Gold / Q000378:metabolism*; D006367:HeLa Cells; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D019169:Jurkat Cells; D016350:Leucine Zippers; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D051267:NF-E2-Related Factor 2; D018384:Oxidative Stress; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D020298:U937 Cells
D018501:Antirheumatic Agents; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D012313:RNA; D006046:Gold; D008156:Luciferases; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase