Karolinska Institutet, Stockholm, Sweden.
Cell Cycle. 2011 May 15;10(10):1590-8. doi: 10.4161/cc.10.10.15519.
Recent advances in the field of pharmacological activation of the p53 tumor suppressor are beginning to be translated into the clinic. In addition, small molecules that activate p53 through established mechanisms of action are proving invaluable tools for basic research. Here we analyze and compare the effects of nutlin-3, tenovin-6 and low doses of actinomycin-D on p53 and its main negative regulator, mdm2. We reveal striking differences in the speed at which these compounds increase p53 protein levels, with nutlin-3 having a substantial impact within minutes. We also show that nutlin-3 is very effective at increasing the synthesis of mdm2 mRNA, mdm2 being not only a modulator of p53 but also a transcriptional target. In addition, we show that nutlin-3 stabilizes mdm2's conformation and protects mdm2 from degradation. These strong effects of nutlin-3 on mdm2 correlate with a remarkable rate of recovery of p53 levels upon removal of the compound. We discuss the potential application of our results as molecular signatures to assess the on-target effects of small-molecule mdm2 inhibitors. To conclude, we discuss the implications of our observations for using small-molecule p53 activators to reduce the growth of tumors retaining wild-type p53 or to protect normal tissues against the undesired side effects of conventional chemotherapy.
近年来，p53 肿瘤抑制因子的药理学激活领域的进展开始转化为临床应用。此外，通过已确立的作用机制激活 p53 的小分子已被证明是基础研究的宝贵工具。在这里，我们分析和比较了 nutlin-3、tenovin-6 和低剂量放线菌素 D 对 p53 及其主要负调节因子 mdm2 的影响。我们揭示了这些化合物提高 p53 蛋白水平的速度存在惊人的差异，nutlin-3 在数分钟内就产生了实质性的影响。我们还表明，nutlin-3 非常有效地增加 mdm2 mRNA 的合成，mdm2 不仅是 p53 的调节剂，也是转录靶标。此外，我们表明 nutlin-3 稳定了 mdm2 的构象并保护 mdm2 免受降解。nutlin-3 对 mdm2 的这些强烈影响与化合物去除后 p53 水平恢复的显著速度相关。我们讨论了将我们的结果作为分子特征应用于评估小分子 mdm2 抑制剂的靶标效应的潜力。最后，我们讨论了使用小分子 p53 激活剂来减少保留野生型 p53 的肿瘤的生长或保护正常组织免受常规化疗的不良副作用的观察结果的意义。
