Suppression of rat glutathione transferase P expression by peroxisome proliferators: interaction between Jun and peroxisome proliferator-activated receptor alpha.

Abstract

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.