SILENCER BINDING-PROTEINS FUNCTION ON MULTIPLE CIS-ELEMENTS IN THE GLUTATHIONE TRANSFERASE-P GENE

The glutathione transferase P (GST-P) gene is specifically expressed during chemical hepatocarcinogenesis of the rat, whereas mRNA of this gene is virtually undetectable in normal liver. We have previously identified a stretch of DNA, that acted negatively in transcription, at 400 bp upstream from the cap site of the rat GST-P gene. Further characterization has revealed that this negative fragment functions in an orientation and position independent manner, suggesting that it is acting as a silencer. This silencer consists of multiple negative elements to which nuclear factors bind. This silencer is active not only in rat nonhepatoma and hepatoma cells but also in human and mouse cell lines, suggesting that these elements function as general regulators of basal gene expression. At least two proteins bind to this silencer fragment, one of which, designated SF-A (Silencer Factor A), has been partially purified. SF-A binds to several regions in this silencer, and likely plays an important role on negative regulation of this gene.