Suppression of rat glutathione transferase P expression by peroxisome proliferators: interaction between Jun and peroxisome proliferator-activated receptor alpha.
Glutathione transferase-P (GST-P) in rats is specifically expressed in precancerous lesions and in hepatomas induced by carcinogens or spontaneously arising hepatomas. GST-P expression in preneoplastic lesions is suppressed by peroxisome proliferators. To determine the mechanism of suppression of GST-P expression by peroxisome proliferators on a molecular level, we have analyzed the effects of peroxisome proliferators and their receptor (peroxisome proliferator-activated receptor alpha, PPAR alpha) on GST-P expression. GST-P gene expression linked to a reporter gene was specifically suppressed by cotransfection with a PPAR alpha expression plasmid in the presence of the peroxisome proliferator, clofibrate. The target element of the suppression was a 12-O-tetradecanoylphorbol-13-acetate-responsive element located 61 nucleotides upstream from the cap site, which is also internal to a Maf consensus binding sequence. Both Jun and Maf bind to this element and activate the gene having this element, but only Jun-activated expression was specifically inhibited by PPAR alpha. Expression of a transfected reporter gene linked to a PPAR-responsive element was inhibited by cotransfection with a Jun expression plasmid. These results suggest that PPAR alpha and Jun interact and share inhibitory activities, similar to Jun and the glucocorticoid receptor.
Sakai
M
M
Department of Biochemistry, Hokkaido University School of Medicine, Sapporo, Japan.
Matsushima-Hibiya
Y
Y
Nishizawa
M
M
Nishi
S
S
D000818:Animals; D001483:Base Sequence; D002994:Clofibrate / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005982:Glutathione Transferase / Q000235:genetics*; D008113:Liver Neoplasms / Q000201:enzymology; D008830:Microbodies / Q000187:drug effects*; D008969:Molecular Sequence Data; D051256:Oncogene Protein v-maf; D009856:Oncogene Proteins, Viral / Q000502:physiology; D011230:Precancerous Conditions / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins
D004268:DNA-Binding Proteins; D051256:Oncogene Protein v-maf; D009856:Oncogene Proteins, Viral; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014764:Viral Proteins; D005982:Glutathione Transferase; D002994:Clofibrate