Westbrook Thomas F, Martin Eric S, Schlabach Michael R, Leng Yumei, Liang Anthony C, Feng Bin, Zhao Jean J, Roberts Thomas M, Mandel Gail, Hannon Gregory J, Depinho Ronald A, Chin Lynda, Elledge Stephen J
Howard Hughes Medical Institute, Department of Genetics, Harvard Partners Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Cell. 2005 Jun 17;121(6):837-48. doi: 10.1016/j.cell.2005.03.033.
Tumorigenesis is a multistep process characterized by a myriad of genetic and epigenetic alterations. Identifying the causal perturbations that confer malignant transformation is a central goal in cancer biology. Here we report an RNAi-based genetic screen for genes that suppress transformation of human mammary epithelial cells. We identified genes previously implicated in proliferative control and epithelial cell function including two established tumor suppressors, TGFBR2 and PTEN. In addition, we uncovered a previously unrecognized tumor suppressor role for REST/NRSF, a transcriptional repressor of neuronal gene expression. Array-CGH analysis identified REST as a frequent target of deletion in colorectal cancer. Furthermore, we detect a frameshift mutation of the REST gene in colorectal cancer cells that encodes a dominantly acting truncation capable of transforming epithelial cells. Cells lacking REST exhibit increased PI(3)K signaling and are dependent upon this pathway for their transformed phenotype. These results implicate REST as a human tumor suppressor and provide a novel approach to identifying candidate genes that suppress the development of human cancer.
肿瘤发生是一个多步骤过程，其特征是存在大量的基因和表观遗传改变。确定导致恶性转化的因果扰动是癌症生物学的核心目标。在此，我们报告了一项基于RNA干扰的基因筛选，以寻找抑制人乳腺上皮细胞转化的基因。我们鉴定出了先前与增殖控制和上皮细胞功能相关的基因，包括两个已确定的肿瘤抑制因子TGFBR2和PTEN。此外，我们还发现了神经元基因表达的转录抑制因子REST/NRSF此前未被认识到的肿瘤抑制作用。阵列比较基因组杂交（Array-CGH）分析确定REST是结直肠癌中常见的缺失靶点。此外，我们在结直肠癌细胞中检测到REST基因的一个移码突变，该突变编码一种具有显性作用的截短形式，能够转化上皮细胞。缺乏REST的细胞表现出PI(3)K信号增强，并依赖于该信号通路来维持其转化表型。这些结果表明REST是一种人类肿瘤抑制因子，并为鉴定抑制人类癌症发展所需的候选基因提供了一种新方法。
