Glutathione S-Transferases: Gene Structure and Regulation of Expression

The current knowledge about the structure of GST genes and the molecular mechanisms involved in regulation of their expression are reviewed. Information derived from the study of rat and mouse GST Alpha-class, Ya genes, and a rat GST Pi-class gene seems to indicate that a single cis-regulatory element, composed of two adjacent AP-1-like binding sites in the 5'-flanking region of these GST genes, is responsible for their basal and xenobiotic-inducible activity. The identification of Fos/Jun (AP-1) complex as the trans-acting factor that binds to this element and mediates the basal and inducible expression of GST genes offers a basis for an understanding of the molecular processes involved in GST regulation. The induction of expression of Fos and Jun transcriptional regulatory proteins by a variety of extracellular stimuli is known to mediate the activation of target genes via the AP-1 binding sites. The modulation of the AP-1 activity may account for the changes induced by growth factors, hormones, chemical carcinogens, transforming oncogenes, and cellular stress-inducing agents in the pattern of GST expression. Recent observations implying reactive oxygen as the transduction signal that mediates activation of c-fos and c-jun genes are presently considered to provide an explanation for the induction of GST gene expression by chemical agents of diverse structure. The possibility that these agents may all induce conditions of oxidative stress by various pathways to activate expression of GST genes that are regulated by the AP-1 complex is discussed.