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/或抗胃gog烯的癌变的步骤。为了研究肿瘤转化过程中基因表达的细胞表达的可能改变，探索肿瘤制造子基因作为工具之一可能是有用的。形成这个观点，我一直在研究大鼠化学肝癌发生期间谷胱甘肽转移酶P（GST-P）基因的调节机制。强大的增强子元件GPEI和另一个位于GST-P基因AT-65的TRE序列都被JUN激活，并且也被最近报道的致癌基因MAF激活。糖皮质激素被称为Jun的抑制剂。TPA刺激的GST-P基因表达式，而被过表达的C-JUN均被去塞米松（DEX）抑制至基础水平。然而，该基因的基础表达并未被DEX摄入。在CUL中进行的转介实验……更具染色的细胞也显示出基本相同的结果。这些结果表明，GPEI被JUN激活，但该增强子的本质活性是由于Jun.G.S-P以外的某些未知机制引起的。GST-P在预癌病变中特异性表达，在化学上粘剂诱导的肝瘤中，除非过氧化物体增生剂（PP）。此外，pp抑制了肿瘤前病变中的GST-P表达，以确定PP通过PP抑制GST-P表达的分子机制，我已经分析了PP及其受体对GST-P的影响。PPAR对GST-P的表达对GST-P的表达。该表达的表达是由GST-P 5'侧面P 5'FARK PARENCER抑制的报告基因的表达。抑制的响应元素是位于-65nt上的TRE，尽管AP -1（JUN/FOS）和MAF是BING并激活该元素，但JUN激活的表达式被PPAR和Clofibrate特别抑制。对立，通过共转染Jun表达质粒的共转染抑制了含有PPAR响应元件的翻译CAT基因的表达。这些结果表明，PPAR和JUN相互相互作用并抑制JUN和糖皮质苯基受体等两种活性。较少的