Yamada T, Takaoka A S, Naishiro Y, Hayashi R, Maruyama K, Maesawa C, Ochiai A, Hirohashi S
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
Cancer Res. 2000 Sep 1;60(17):4761-6.
The mutational inactivation of a tumor suppressor gene, adenomatous polyposis coli (APC), results in the accumulation of cytoplasmic beta-catenin protein and the activation of T-cell factor (TCF)/lymphoid enhancer factor transcriptional factors. A colorectal carcinoma cell line, DLD-1, was engineered to suppress transactivation by the TCF4/beta-catenin complex in a dominant-negative manner under the strict control of the tetracycline regulatory system. A large-scale comparison of the expression profiles, using two-color fluorescence hybridization of cDNA microarray, led to the identification of MDR1 as a target gene of the TCF4/beta-catenin complex. Luciferase reporter and gel retardation assays revealed the TCF4/beta-catenin responsive elements in the promoter of the human MDR1 gene. Corresponding to the accumulation of beta-catenin, expression of the MDR1 gene product was steadily up-regulated in adenomas and adenocarcinomas of 10 patients with familial adenomatous polyposis. In combination with cell proliferative activities of c-myc and cyclin D1, MDR1 may initiate colorectal tumorigenesis by suppressing cell death pathways programmed in intestinal epithelial cells.
肿瘤抑制基因腺瘤性息肉病基因（APC）的突变失活会导致细胞质β-连环蛋白的积累以及T细胞因子（TCF）/淋巴样增强因子转录因子的激活。利用四环素调控系统的严格控制，构建了一种结肠癌细胞系DLD-1，以显性负性方式抑制TCF4/β-连环蛋白复合物的反式激活。通过cDNA微阵列的双色荧光杂交对表达谱进行大规模比较，从而鉴定出MDR1是TCF4/β-连环蛋白复合物的一个靶基因。荧光素酶报告基因和凝胶阻滞分析揭示了人类MDR1基因启动子中的TCF4/β-连环蛋白反应元件。与β-连环蛋白的积累相对应，在10例家族性腺瘤性息肉病患者的腺瘤和腺癌中，MDR1基因产物的表达稳步上调。与c-myc和细胞周期蛋白D1的细胞增殖活性相结合，MDR1可能通过抑制肠上皮细胞中程序性细胞死亡途径来启动结直肠癌的发生。
