|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1993 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1992 : ¥1,400,000 (Direct Cost : ¥1,400,000)
In multi-step tumorigenesis, change in the pattern of gene expression might be an important step, as well as the steps of oncogene activation and/or inactivation of antioncogene. To investigate the possible alteration of the cellular pattern of gene expression during neoplastic transformation, it may be useful to explore tumor maker gene as one of the tools. Form this view point, I have been studying the regulation mechanism of glutathione transferase P (GST-P) gene during chemical hepatocarcinogenesis of the rat. The strong enhancer element, GPEI, and another TRE like sequence located at-65 of the GST-P gene are both activated by Jun and also activated by recently reported oncogene product, Maf. Glucocorticoide is known as an inhibitor of Jun. Both the stimulated expressions of GST-P gene by TPA and that by over-expressed c-Jun were suppressed to the basal level by Dexamethasone(Dex). Basal expression of this gene, however, was not ingibited by Dex. Transgection experiments in the cul
tured cells also show the essentially the same results. These results indicate that the GPEI is activated by Jun but constitutive activity of this enhancer is due to some unknown mechanism other than Jun.
GST-P is specifically expressed in precancerous lesions and in hepatomas induced by chemicalcarcinogens except that by peroxisome proliferator(PP). Moreover, the GST-P expression in pre-neoplastic lesion is suppressed by PP.To determine the molecular mechanism of suppression of the GST-P expression by PP, I have analyzed the effects of PP and their receptor, PPAR on the expression of GST-P.The expression of transfected reporter gene having GST-P 5' flanking sequence was specifically suppressed by PPAR and PP, clofibrate. The responsive element of suppression was the TRE located on -65nt upstream from the cap site. Although AP-1(Jun/Fos) and Maf are bing and activate this element, the expression activated by Jun was specifically inhibited by PPAR and clofibrate. Oppositelly, the expression of transfected CAT gene containing PPAR responsive elements was inhibited by co-transfection of Jun expression plasmid. These results suggest that PPAR and Jun were mutually interact and inhibit both activities, like Jun and glucocorticoide receptor. Less