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

癌变早期基因表达的调控机制。

基本信息

批准号：
04670156
负责人：
SAKAI Masaharu
金额：
$ 1.34万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

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

在多步骤肿瘤发生中，基因表达模式的变化可能是一个重要的步骤，以及癌基因激活和/或抑癌基因失活的步骤。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。强增强子元件 GPEI 和位于 GST-P 基因 65 处的另一个 TRE 样序列均被 Jun 激活，也被最近报道的致癌基因产物 Maf 激活，糖皮质激素被称为 Jun 的抑制剂。这两种刺激的表达都被激活。 TPA 和过表达的 c-Jun 的 GST-P 基因的表达均被地塞米松 (Dex) 抑制至基础水平，但该基因的基础表达并未被抑制。在培养细胞中进行的转染实验也显示出基本相同的结果，这些结果表明 GPEI 是由 Jun 激活的，但该增强子的组成性活性是由于 Jun.GST-P 之外的一些未知机制所致。 GST-P在癌前病变和除过氧化物酶体增殖物(PP)以外的化学致癌物诱导的肝癌中特异表达。此外，癌前病变中GST-P的表达受到抑制。为了明确PP抑制GST-P表达的分子机制，我分析了PP及其受体PPAR对GST-P表达的影响。转染的GST-P报告基因的表达5 ' 侧翼序列被 PPAR 和 PP 特异性抑制，但抑制的响应元件是位于帽位点上游 -65nt 的 TRE。 Jun 激活的表达被 PPAR 和安妥明特异性抑制，相反，转染的含有 PPAR 反应元件的 CAT 基因的表达被 Jun 表达质粒的共转染所抑制。相互相互作用并抑制这两种活性，如 Jun 和糖皮质激素受体。