TUMOR SUPPRESSOR ACTIVITIES OF ETS1 GENE PRODUCTS

ETS1基因产物的肿瘤抑制活性

• 批准号: 5201556
• 负责人: J LAUTENBERGER
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5201556
• 关键词: DNA binding protein; breast neoplasms; carcinogenesis inhibitor; colon neoplasms; gene expression; human tissue; molecular oncology; mutant; neoplasm /cancer genetics; neoplastic cell; prostate neoplasms; protein structure function; protooncogene; tissue /cell culture; transcription factor; transfection; tumor suppressor genes

We have ectopically expressed transcription factor ETS! in two different highly tumorigenic human colon cancer cell lines, DLD-1 and HCT116, that do not express endogenous ETS1 protein and have obtained several independent clones. The expression of wild-type ETS1 protein in these colon cancer cells reverses the transformed phenotype and tumorigenicity in a dose-dependent manner. By contrast, expression in DLD-1 cells of a variant form of ETS1, lacking transcriptional activity, did not alter the tumorigenic properties of the cells, suggesting that the reduction in tumorigenicity in these clones was specific for the wild-type ETS1 gene products. DLD-1 wild-type ETS1 transfectants grow much slower in serum-free media than DLD-1 cells expressing mutant ETS1 proteins lacking transcriptional activities. Furthermore, DLD-1 wild-type ETS1 transfectants remain longer in G0/G1 stage of the cell cycle than DLD-1 mutant ETS1 transfectants. These results suggest that ETS1 protein under appropriate conditions may interfere with growth of colon cancer cells. To identify functional domains of ETS1 involved in tumor suppressor function, we have generated variant forms of ETS1 lacking either transcriptional activities or DNA binding activities. Experiments are in progress to express mutant ETS1 proteins in colon, breast and prostate cancer cells as well as to identify "minimum region of ETS1" responsible for suppression of tumorigenicity of colon cancer cells.

我们异位表达了转录因子ETS！在两个不同 高致瘤性人结肠癌细胞系DLD-1和HCT 116， 不表达内源性ETS 1蛋白，并获得了几个 独立克隆人 野生型ETS 1蛋白在这些细胞中的表达， 结肠癌细胞逆转转化表型和致瘤性 剂量依赖性 相反，在DLD-1细胞中， 缺乏转录活性的ETS 1变异体， 细胞的致瘤特性，这表明， 在这些克隆的致瘤性中， 基因产物 DLD-1野生型ETS 1转染子在大肠杆菌中生长缓慢得多。 与表达缺乏突变ETS 1蛋白的DLD-1细胞相比， 转录活性。 此外，DLD-1野生型ETS 1 与DLD-1相比，转染子在细胞周期的G 0/G1期停留的时间更长 突变型ETS 1转染子。 这些结果表明，ETS 1蛋白在 适当的条件可以干扰结肠癌细胞的生长。 鉴定肿瘤抑制因子ETS 1的功能域， 函数，我们已经生成了ETS 1的变体形式， 转录活性或DNA结合活性。 实验 在结肠、乳腺和前列腺中表达突变ETS 1蛋白的进展 癌细胞以及确定负责的“ETS 1的最小区域” 用于抑制结肠癌细胞的致瘤性。