Li Jing, Zhang Shuyong, Gao Linghuan, Chen Ying, Xie Xin
Stake Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
J Biomol Screen. 2011 Apr;16(4):450-6. doi: 10.1177/1087057111399191.
The p53 tumor suppressor is a potent transcription factor that regulates cell growth inhibition and apoptosis. The oncoprotein MDM2 suppresses p53 activity by direct inhibition of its transcriptional activity and enhances the degradation of p53 via the ubiquitin-proteosome pathway. Overexpression of MDM2, found in many human tumors, impairs p53-mediated cell death effectively. Inhibition of the p53-MDM2 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. To search for new inhibitors of the p53-MDM2 interaction, the authors developed a cell-based high-throughput assay system based on mammalian two-hybrid technology. They also used a dual-luciferase reporter system to rule out false- positive hits due to the cytotoxic effect of compounds. Using this assay, they screened a library consisting of 3840 compounds and identified one compound that activates p53 pathway and induces growth arrest in tumor cells.
p53肿瘤抑制因子是一种强大的转录因子，可调节细胞生长抑制和细胞凋亡。癌蛋白MDM2通过直接抑制p53的转录活性来抑制其活性，并通过泛素-蛋白酶体途径增强p53的降解。在许多人类肿瘤中发现的MDM2过表达有效地损害了p53介导的细胞死亡。抑制p53-MDM2相互作用可以使p53稳定，并可能为癌症治疗提供一种新策略。为了寻找p53-MDM2相互作用的新抑制剂，作者基于哺乳动物双杂交技术开发了一种基于细胞的高通量检测系统。他们还使用双荧光素酶报告系统来排除由于化合物的细胞毒性作用导致的假阳性结果。利用该检测方法，他们筛选了一个由3840种化合物组成的文库，并鉴定出一种能激活p53途径并诱导肿瘤细胞生长停滞的化合物。
