Parthenolide promotes the ubiquitination of MDM2 and activates p53 cellular functions
Parthenolide promotes the ubiquitination of MDM2 and activates p53 cellular functions
复制标题
DOI：
10.1158/1535-7163.mct-08-0661
复制
发表时间：
2009-03-01
影响因子：
5.7
通讯作者：
Van Dyke, Michael W.
中科院分区：
文献类型：
--
作者：
Gopal, Y. N. Vashisht;Chanchorn, Ekkavvit;Van Dyke, Michael W.
MDM2 属于一类含有泛素连接酶的环指结构域，可介导多种蛋白质（包括蛋白质本身）的蛋白酶体降解。可以说，MDM2 最重要的底物是 p53，它控制细胞周期进程和细胞凋亡。 MDM2 和 p53 是反馈调节环路的一部分，其扰动通常存在于癌症中，并且是抗癌药物开发的目标。我们发现天然产物小分子抗炎剂小白菊内酯 (PN) 正在积极研究作为许多人类癌症的潜在治疗方法，它会诱导治疗细胞中 MDM2 泛素化，从而激活 p53 和其他 MDM2 调节的肿瘤抑制蛋白。使用具有功能性基因缺失的细胞和小干扰RNA敲除研究，我们发现这些效应需要DNA损伤传感器共济失调毛细血管扩张突变。 PN 对肿瘤抑制因子激活的影响与 nutlin-3a 相当，nutlin-3a 是一种最近开发的小分子，旨在干扰 MDM2 和 p53 之间的相互作用，但不会促进 MDM2 泛素化。我们的研究阐明了控制 MDM2 和 p53 活性的替代方法，并确定了受 PN 影响的另一个极其重要的癌症途径。 [摩尔癌症疗法 2009； 8（3）：552-62]
MDM2 belongs to a class of ring-finger domain - containing ubiquitin ligases that mediate the proteasomal degradation of numerous proteins, including themselves. Arguably, the most important substrate of MDM2 is p53, which controls cell cycle progression and apoptosis. MDM2 and p53 are parts of a feedback regulatory loop whose perturbations are often present in cancer and are targets for anticancer drug development. We found that the natural product, small-molecule anti-inflammatory agent parthenolide (PN), which is actively being investigated as a potential therapeutic for many human cancers, induces ubiquitination of MDM2 in treated cells, resulting in the activation of p53 and other MDM2-regulated tumor-suppressor proteins. Using cells with functional gene deletions and small interfering RNA knockdown studies, we found that these effects required the DNA damage transducer ataxia telangiectasia mutated. The effects of PN on tumor suppressor activation were comparable with that of nutlin-3a, a recently developed small molecule that was designed to interfere with the interaction between MDM2 and p53 but does not promote MDM2 ubiquitination. Our study illustrates an alternative approach for controlling MDM2 and p53 activities and identifies an additional critically important cancer pathway affected by PN. [Mol Cancer Ther 2009; 8(3):552-62]