Regulation mechamism of gene expression on the early stage of carcinogenesis.

在多步骤肿瘤发生中，基因表达模式的改变可能是重要的一步，癌基因激活和/或抑癌基因失活也可能是重要的一步。为了研究肿瘤转化过程中基因表达的细胞模式的可能变化，探索肿瘤标志物基因作为工具之一可能是有用的。从这个角度出发，我一直在研究谷胱甘肽转移酶P(GST-P)基因在大鼠化学性肝癌发生过程中的调控机制。位于GST-P基因-65位的强增强子元件GPEI和另一个类似Tre的序列既被Jun激活，也被最近报道的癌基因产物Maf激活。糖皮质激素是一种JUN的抑制剂，地塞米松(Dex)可将TPA和c-Jun刺激的GST-P基因表达抑制到基础水平。然而，该基因的基础表达不受地塞米松的抑制。CUL…中的转基因实验更多的培养细胞也显示出本质上相同的结果。这些结果表明，GPEI被Jun激活，但该增强子的构成活性是由于Jun以外的其他未知机制所致。GST-P在癌前病变和除过氧化体增殖物(PP)以外的化学致癌物诱导的肝癌中特异表达。为了探讨PP抑制GST-P表达的分子机制，我们分析了PP及其受体PPAR对GST-P表达的影响。PPAR和PP、氯贝特能特异性地抑制带有GST-P 5‘侧翼序列的报告基因表达。抑制的反应元件是位于帽区上游-65nt的TrE。虽然AP-1(Jun/Fos)和Maf是结合并激活该元件，但PPAR和氯贝特特异性地抑制了Jun激活的表达。反之，Jun表达载体共转染可抑制含有PPAR反应元件的CAT基因的表达。这些结果表明，PPAR和JUN与JUN和糖皮质激素受体一样，相互作用并抑制两者的活性。较少

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 … More 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