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一个重要步骤，也可能是癌基因激活和/或抑癌基因失活的步骤。为了研究肿瘤转化过程中基因表达的细胞模式的可能改变，探索肿瘤标志物基因可能是有用的工具之一。本课题从这个角度出发，研究了谷胱甘肽转移酶P（GST-P）基因在大鼠化学性肝癌发生过程中的调控机制。强增强子元件GPEI和位于GST-P基因-65的另一个TRE样序列都被Jun激活，也被最近报道的癌基因产物Maf激活。糖皮质激素被认为是Jun的抑制剂，地塞米松（Dex）可将TPA刺激的GST-P基因表达和过表达的c-Jun基因表达抑制至基础水平。然而，该基因的基础表达不受Dex的抑制。Cul中的转染实验 关于我们 被捕获的细胞也显示出基本上相同的结果。这些结果表明，GPEI是由Jun激活的，但这种增强子的组成性活性是由于Jun以外的一些未知机制所致。GST-P在癌前病变和化学致癌物诱导的肝癌中特异性表达，但过氧化物酶体增殖物（PP）除外。此外，PP还能抑制癌前病变中GST-P的表达，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，发现PP和PP、氯贝特均能特异性抑制GST-P 5'侧翼序列的报告基因的表达。抑制的反应元件是位于帽位点上游-65nt的TRE。虽然AP-1（Jun/Fos）和Maf结合并激活该元件，但Jun激活的表达被PPAR和氯贝特特异性抑制。而Jun表达质粒的共转染则抑制了含有PPAR反应元件的CAT基因的表达。这些结果表明，PPAR和Jun相互作用，抑制两种活性，如Jun和糖皮质激素受体。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