title: Activation of glutathione transferase P gene by lead requires glutathione transferase P enhancer I.
abstract: Glutathione transferase P (GST-P) is specifically induced in rat liver and kidney by lead cation. The increase of GST-P mRNA after lead administration is blocked by actinomycin D, suggesting that GST-P production by lead is regulated at the transcriptional level. To further determine which part of the flanking region of the GST-P gene has the lead-responsive cis-element in vivo, we utilized transgenic rats with five different constructs having GST-P and/or chloramphenicol acetyl-transferase coding sequence. We studied the effect of lead on these transgenic rats and on transfected NRK (normal rat kidney) cells and found that GST-P induction by lead is indeed regulated at the transcriptional level and that the GST-P enhancer I (GPEI) enhancer is an essential cis-element required for the activation of the GST-P gene by lead. GPEI consists of two AP-1 (c-Jun/c-Fos heterodimer) site-like sequences that are palindromically arranged and can bind AP-1, c-jun mRNA in the liver increased after lead administration and GST-P, and c-Jun had patchy expression in the same hepatocytes 24 h after lead exposure. These results suggest that activation of the GST-P gene by lead is mediated in major part by enhancer GPEI and that AP-1 may be involved at least partially. GPEI has been shown to have essential sequence information for the trans-activation of the GST-P gene during chemical hepatocarcinogenesis of the rat (Morimura, S., Suzuki, T., Hochi, S., Yuki, A., Nomura, K., Kitagawa, T., Nagatsu, I., Imagawa, M., and Muramatsu, M. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 2065-2068; Suzuki, T., Imagawa, M., Hirabayashi, M., Yuki, A., Hisatake, K., Nomura, K., Kitagawa, T., and Muramatsu, M. (1995) Cancer Res. 55, 2651-2655). The present study establishes that the same enhancer element does operate in the activation of the GST-P gene by lead regardless of the trans-activators involved.
authors.affiliation: Department of Biochemistry, Saitama Medical School, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: S
authors.initials: S
authors.lastname: Morimura
authors.forename: M B
authors.initials: MB
authors.lastname: Diccianni
authors.forename: R
authors.initials: R
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Hochi
authors.forename: M
authors.initials: M
authors.lastname: Hirabayashi
authors.forename: A
authors.initials: A
authors.lastname: Yuki
authors.forename: K
authors.initials: K
authors.lastname: Nomura
authors.forename: T
authors.initials: T
authors.lastname: Kitagawa
authors.forename: M
authors.initials: M
authors.lastname: Imagawa
authors.forename: M
authors.initials: M
authors.lastname: Muramatsu
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D015153:Blotting, Western; D002413:Cations, Divalent / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D004742:Enhancer Elements, Genetic; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D007668:Kidney / Q000201:enzymology; D007854:Lead / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009566:Nitrates / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D002413:Cations, Divalent; D007527:Isoenzymes; D009566:Nitrates; D009942:Organometallic Compounds; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D007854:Lead; C017461:lead nitrate; D015500:Chloramphenicol O-Acetyltransferase; D005982:Glutathione Transferase; C008261:lead acetate