CDC20, a potential cancer therapeutic target, is negatively regulated by p53
CDC20, a potential cancer therapeutic target, is negatively regulated by p53
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DOI：
10.1038/sj.onc.1210799
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发表时间：
2008-03-06
期刊：
影响因子：
8
通讯作者：
Matsuda, K.
中科院分区：
文献类型：
--
作者：
Kidokoro, T.;Tanikawa, C.;Matsuda, K.
P53蛋白通过直接和间接调节许多与细胞周期、细胞凋亡和细胞衰老相关的基因的转录来抑制恶性转化。P53诱导的一些基因已经得到了很好的描述，但被P53抑制表达的基因的生物学意义仍然很大程度上是未知的。为了阐明抑癌基因在肿瘤发生中的作用，我们分析了两个全基因组表达谱数据集，一个是外源导入野生型p53的细胞，另一个是大量临床癌症组织。在这里，我们确定了CDC20，它在许多类型的恶性肿瘤中频繁上调，并通过异位引入P53而显著抑制。基因毒性应激通过CDC20启动子中的CDE-CHR元件以p53和p21依赖的方式抑制CDC20的表达。此外，小干扰RNA(SiRNA)介导的p53沉默诱导了正常人皮肤中CDC20的表达。成鳞状细胞。正如我们所预期的那样，用针对CDC20的siRNA处理癌细胞，导致G(2)/M期停滞，并抑制细胞生长。我们的结果表明，P53通过CDC20的间接调控抑制肿瘤细胞的生长，CDC20可能是一个很好的潜在的治疗靶点，广泛的人类癌症。
The p53 protein inhibits malignant transformation through direct and indirect regulation of transcription of many genes related to cell cycle, apoptosis and cellular senescence. A number of genes induced by p53 have been well characterized, but biological significance of genes whose expression was suppressed by p53 is still largely undisclosed. To clarify the roles of p53-suppressive genes in carcinogenesis, we analysed two data sets of whole-genome expression profiles, one for cells in which wildtype p53 was exogenously introduced and the other for a large number of clinical cancer tissues. Here, we identified CDC20 that was frequently upregulated in many types of malignancies and remarkably suppressed by ectopic introduction of p53. CDC20 expression was suppressed by genotoxic stresses in p53- and p21-dependent manners through CDE-CHR elements in the CDC20 promoter. Furthermore, small interference RNA (siRNA)-mediated silencing of p53 induced CDC20 expression in normal human dermal. broblast cells. As we expected, treatment of cancer cells with siRNA against CDC20 induced G(2)/M arrest and suppressed cell growth. Our results indicate that p53 inhibits tumor cell growth through the indirect regulation of CDC20 and that CDC20 might be a good potential therapeutic target for a broad spectrum of human cancer.