Integrative Genomics revealed RAI3 is a cell growth-promoting gene and a novel p53 transcriptional target
Integrative Genomics revealed RAI3 is a cell growth-promoting gene and a novel p53 transcriptional target
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DOI：
10.1074/jbc.m409901200
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发表时间：
2005-04-01
影响因子：
4.8
通讯作者：
Liu, SX
中科院分区：
文献类型：
--
作者：
Wu, Q;Ding, W;Liu, SX
在这项研究中，使用Incyte GeneAlbum 1-6研究了正常人乳腺上皮细胞与其恶性对应细胞（8个成熟的乳腺癌细胞系）之间的差异基因表达，其中包含代表33，515个单个基因的65，873个cDNA克隆。与正常人乳腺上皮细胞相比，3，152个cDNA在至少一种人乳腺癌细胞系中显示≥ 3.0倍的表达水平变化。整合乳腺肿瘤基因表达数据与肿瘤抑制基因p53信号通路中的基因，产生了128个基因，其表达在乳腺肿瘤细胞系中改变，并响应于p53表达。对128个基因的层次聚类分析显示，相当一部分基因表现出相反的表达模式，即p53激活的基因在乳腺肿瘤细胞系中下调，而p53抑制的基因上调。这些基因中的大多数参与细胞周期调节和/或凋亡，与p53的肿瘤抑制功能一致。对一个基因RAI 3的后续研究表明，p53与RAI 3的启动子相互作用，并在凋亡开始时抑制其表达。RAI 3的表达在大多数表达突变型p53的肿瘤细胞系中升高，而RAI 3 mRNA在表达野生型p53的肿瘤细胞系中相对被抑制。此外，RAI 3在293细胞中的异位表达促进锚定非依赖性生长，并且小干扰RNA介导的AsPc-1胰腺肿瘤细胞中RAI 3的耗竭诱导细胞形态学改变。总之，这些数据表明RAI 3在肿瘤生长中的作用，并证明了整合基因组学的预测能力。
In this study, differential gene expression between normal human mammary epithelial cells and their malignant counterparts (eight well established breast cancer cell lines) was studied using Incyte GeneAlbum 1-6, which contains 65,873 cDNA clones representing 33,515 individual genes. 3,152 cDNAs showed a >= 3.0- fold expression level change in at least one of the human breast cancer cell lines as compared with normal human mammary epithelial cells. Integration of breast tumor gene expression data with the genes in the tumor suppressor p53 signaling pathway yielded 128 genes whose expression is altered in breast tumor cell lines and in response to p53 expression. A hierarchical cluster analysis of the 128 genes revealed that a significant portion of genes demonstrate an opposing expression pattern, i.e. p53-activated genes are down-regulated in the breast tumor lines, whereas p53-repressed genes are up-regulated. Most of these genes are involved in cell cycle regulation and/or apoptosis, consistent with the tumor suppressor function of p53. Follow-up studies on one gene, RAI3, suggested that p53 interacts with the promoter of RAI3 and repressed its expression at the onset of apoptosis. The expression of RAI3 is elevated in most tumor cell lines expressing mutant p53, whereas RAI3 mRNA is relatively repressed in the tumor cell lines expressing wild-type p53. Furthermore, ectopic expression of RAI3 in 293 cells promotes anchorage-independent growth and small interfering RNA-mediated depletion of RAI3 in AsPc-1 pancreatic tumor cells induces cell morphological change. Taken together, these data suggest a role for RAI3 in tumor growth and demonstrate the predictive power of integrative genomics.