CCAAT/enhancer-binding proteins alpha and beta interact with the silencer element in the promoter of glutathione S-transferase P gene during hepatocarcinogenesis.
We have previously identified a silencer in the glutathione S-transferase P (GST-P) gene which is strongly and specifically expressed during chemical hepatocarcinogenesis. At least three trans-acting factors bind to multiple cis-elements in the silencer. One of them, Silencer Factor-B (SF-B), is identical with CCAAT/enhancer-binding protein beta (C/EBP beta) and binds to GST-P Silencer 1 (GPS1). Many C/EBP beta binding sites are recognized by each of the C/EBP isoforms. Western blot analyses of C/EBP isoforms during chemical hepatocarcinogenesis revealed a decrease of C/EBP alpha expression. However, there was no change in C/EBP beta level. In the nuclear extracts from normal liver, C/EBP alpha was the dominant form that bound to GPS1, whereas both C/EBP alpha and C/EBP beta bound to GPS1 in the nuclear extracts from carcinogenic liver. Furthermore, transfection assays showed that C/EBP alpha not only repressed the GST-P promoter activity but also attenuated the transcriptional stimulation by C/EBP beta. These observations strongly suggest that the ratio of C/EBP alpha to C/EBP beta is one of the important factors for the GST-P silencer activity, and the decrease of this ratio during hepatocarcinogenesis reduces the silencer activity and, consequently, increases the GST-P expression.
Department of Environmental Biochemistry, Faculty of Pharmaceutical Sciences, Osaka University, Japan.
S
S
Osada
K
K
Takano
T
T
Nishihara
T
T
Suzuki
M
M
Muramatsu
M
M
Imagawa
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D002273:Carcinogens; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004052:Diethylnitrosamine; D005982:Glutathione Transferase / Q000235:genetics*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; D002273:Carcinogens; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D014157:Transcription Factors; D004052:Diethylnitrosamine; D005982:Glutathione Transferase