Induction of AP-1 (Fos/Jun) by chemical agents mediates activation of glutathione S-transferase and quinone reductase gene expression.
A regulatory element, EpRE, was found to be responsible for the induction of mouse glutathione S-transferase (GST) Ya gene expression by a variety of chemical agents such as planar aromatic hydrocarbons, diphenols, phorbol ester, phenobarbital and electrophilic compounds. The EpRE is composed of two adjacent AP-1-like binding sites and was recently found to be activated by Fos/Jun heterodimeric complex (AP-1). In this report we show that regulatory elements ARE, previously demonstrated to mediate the chemical induction of rat GST Ya and quinone reductase genes, have a similar structure with EpRE and are activated by Fos/Jun complex. The activation of GST Ya and quinone reductase genes by a variety of chemical inducers is found to be associated with an increase in AP-1 binding activity. We present evidence that chemical agents induce expression of c-fos and c-jun proto-oncogenes and an enhanced synthesis of protein components of AP-1 complex. We suggest that the increased synthesis of AP-1 complex followed by an AP-1-mediated transcriptional activation of GST Ya and quinone reductase genes may provide a molecular mechanism for the induction of these drug-metabolizing enzymes by chemical agents.
Bergelson
S
S
Department of Biochemistry, Weizmann Institute of Science, Rehovot, Israel.
Pinkus
R
R
Daniel
V
V
D001149:Arsenates / Q000494:pharmacology; D018053:Arsenites / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D018236:Carcinoma, Embryonal / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002712:Chlorides / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005809:Genes, Regulator / Q000235:genetics; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D006838:Hydrocarbons / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008969:Molecular Sequence Data; D010634:Phenobarbital / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D011808:Quinone Reductases / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured; D017967:Zinc Compounds / Q000494:pharmacology
D001149:Arsenates; D018053:Arsenites; D002712:Chlorides; D006838:Hydrocarbons; D010703:Phorbol Esters; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D017967:Zinc Compounds; C016837:zinc chloride; D003513:Cycloheximide; D006861:Hydrogen Peroxide; D011808:Quinone Reductases; D005982:Glutathione Transferase; D010634:Phenobarbital