Regulation of glutathione transferase P (GST-P) gene expression during chemical hepatocarcinogenesis.

Glutathione transferase P gene becomes highly and constitutively expressed in the course of chemical hepatocarcinogenesis of the rat. To understand the mechanism of this specific gene activation and also to obtain an insight into the general mechanism of tumor marker expression, we have been studying the regulation of a cloned gene of this enzyme. Analysis of the GST-P cDNA clone revealed that this enzyme consists of 209 amino acid residues and that homologies with other isozymes, Ya and Yc, were both about 32%. The rat GST-P gene consists of seven exons and six introns. Multiple regulatory elements were found in the 5' flanking region including two TPA responsive elements (TRE), a GC box, viral enhancer, core-like elements, and a silencer. This gene was activated by a tumor promoter TPA in certain cell lines. The rat cDNA clone or a TRE binding protein, c-jun oncogene, was isolated and characterized. Analysis of the tissue distribution and expression during chemical hepatocarcinogenesis of the c-jun mRNA suggests that the GST-P gene is regulated, at least in part, by the c-jun product. Further investigation of the mechanism of expression of GST-P, particularly in terms of the interaction with c-jun products, is now underway.