title: Intracellular glutathione levels regulate Fos/Jun induction and activation of glutathione S-transferase gene expression.
abstract: Induction of glutathione S-transferase Ya and NAD(P)H:quinone reductase gene expression by a variety of chemical agents is mediated by regulatory elements, EpRE and ARE, composed of two adjacent AP-1-like binding sites and activated by Fos/Jun heterodimeric complex (AP-1). Recent studies show that chemical induction of glutathione S transferase Ya and quinone reductase gene expression is associated with an induction of c-fos and c-jun gene expression and AP-1 binding activity. In this report we present evidence that the AP-1 binding activity and the expression of chloramphenicol acetyltransferase activity from an EpRE Ya-cat gene construct are induced by an increase in intracellular oxidant levels. We observe that lowering the glutathione levels with buthionine sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, or diamide, a thiol-oxidizing agent, stimulates both basal and chemical-inducible expression of chloramphenicol acetyltransferase activity from EpRE Ya-cat and the AP-1 binding activity. Furthermore, we observe that the induction of these activities by a variety of chemical agents is inhibited by thiol compounds N-acetylcysteine and glutathione. These findings suggest that diverse chemicals that induce the AP-1 complex, leading to the AP-1-mediated transcriptional activation of glutathione S-transferase Ya gene expression, may act through a common mechanism involving the production of reactive oxygen species and depletion of reduced glutathione.
authors.affiliation: Department of Biochemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Bergelson
authors.forename: R
authors.initials: R
authors.lastname: Pinkus
authors.forename: V
authors.initials: V
authors.lastname: Daniel
mesh_terms: D019328:Buthionine Sulfoximine; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism*; D003958:Diamide / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D016762:Genes, fos / Q000502:physiology; D016758:Genes, jun / Q000502:physiology; D005978:Glutathione / Q000502:physiology*; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D003958:Diamide; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D015500:Chloramphenicol O-Acetyltransferase; D005982:Glutathione Transferase; D005978:Glutathione