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Molecular mechanism of endometrial cancer and its application to gene diagnosis

子宫内膜癌的分子机制及其在基因诊断中的应用

基本信息

批准号：
09470362
负责人：
WAKE Norio
金额：
$ 9.86万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470362/
关键词：
endometrial cancer a tumor suppressor gene on 1q cell senescence Ras ER DPC4 DOC cyclin G tumor supppressor gene on 1q 癌抑制遺伝子子宮体癌 1番染色体微小核融合変異型K-Ras エストロゲンリセプター形質転換変異型K・Ras

项目摘要

1. Identification of an endometrial cancer suppressor gene locus : The gene located chromosome 1q has an ability to induce senescence in endometrial cancer cells. By introducing a del 1q chromosome that has incurred an interstitial deletion of approximately 63 cM or subchromosomal transferable fragments derived from the 1q into the endometrial cancer cells, we identified the localization of a target gene within 1q31-ter. In addition, we analyzed LOH on 1q using 60 sample of endometrial cancers and narrowed down the localization with 1q42.2. Contribution of ER to Ras mediated transformation. Mutant K-ras protein had an ability to induce expression of ER protein (3-fold) that functioned as a transcription factor. Reconstituted cells that had enhanced ER activities were tumorigenic but the cells with lower ER activities were nontumorigenic. Suppression of ER activities resulted in the loss of tumorigenicity in the cells transformed by mutant k-ras.3. Both DPC4 and DOC genes targeted by 18q LOH in endometrial cancers. : 18qLOH is frequent in endometrial cancers. By making a detailed deletions map on 18q, we found that deletions targeted both DPC4 and DOC genes. Mutations of the DPC4 promoter regions in the remaining allele resulted in the suppression of DPC4 gene activities. In turn, transfection of DOC cDNA resulted in the suppression of tumorigenicity or the induction of apoptosis in endometrial cancer cells. A DOC gene functions as a tumor suppressor gene by inducing apoptosis of endometrial cells.4. Function of p53-dependent cyclin G : Dox treatment induced p53 accumulation, p21 and cyclin G transcription, that resulted in G2/M arrest of cells. In turn, NaB induced p53 accumulation and p21 transcription but not cyclin G transcription, that resulted in G1 arrest of cells. Suppression of cyclin G expression corresponded to the release of cells from G2/M. Overexpression of cyclin G reverted the cell susceptible to apoptosis.

1.子宫内膜癌抑制基因位点的鉴定：该基因位于染色体1 q，具有诱导子宫内膜癌细胞衰老的能力。通过引入一个del 1 q染色体，该染色体已引起约63 cM的间质缺失或来自1 q的亚染色体可转移片段到子宫内膜癌细胞中，我们确定了1 q31-ter内的靶基因的定位。此外，我们还对60例子宫内膜癌进行了1 q的洛缺失分析，并将1q42.2的定位范围缩小。ER对Ras介导的转化的贡献。突变的K-ras蛋白具有诱导作为转录因子的ER蛋白（3倍）表达的能力。ER活性增强的重组细胞具有致瘤性，但ER活性较低的细胞无致瘤性。ER活性的抑制导致突变型k-ras转化细胞的致瘤性丧失。DPC 4和DOC基因在子宫内膜癌中的18洛靶向：18 qLOH在子宫内膜癌中是常见的。通过在18 q上制作详细的缺失图谱，我们发现缺失针对DPC 4和DOC基因。其余等位基因中DPC 4启动子区域的突变导致DPC 4基因活性的抑制。反过来，DOC cDNA的转染导致在子宫内膜癌细胞的致瘤性抑制或诱导凋亡。DOC基因作为抑癌基因通过诱导子宫内膜细胞凋亡发挥作用. p53依赖性细胞周期蛋白G的功能：Dox处理诱导p53积累，p21和细胞周期蛋白G转录，导致细胞G2/M期阻滞。反过来，NaB诱导p53的积累和p21的转录，但不是细胞周期蛋白G的转录，导致G1期阻滞的细胞。细胞周期蛋白G表达的抑制对应于细胞从G2/M期的释放。细胞周期蛋白G的过表达使细胞恢复对凋亡的敏感性。