Toledo Franck, Wahl Geoffrey M
Institut Curie, Centre de Recherche, UMR CNRS 7147, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Nat Rev Cancer. 2006 Dec;6(12):909-23. doi: 10.1038/nrc2012.
Mutations in TP53, the gene that encodes the tumour suppressor p53, are found in 50% of human cancers, and increased levels of its negative regulators MDM2 and MDM4 (also known as MDMX) downregulate p53 function in many of the rest. Understanding p53 regulation remains a crucial goal to design broadly applicable anticancer strategies based on this pathway. This Review of in vitro studies, human tumour data and recent mouse models shows that p53 post-translational modifications have modulatory roles, and MDM2 and MDM4 have more profound roles for regulating p53. Importantly, MDM4 emerges as an independent target for drug development, as its inactivation is crucial for full p53 activation.
编码肿瘤抑制因子p53的TP53基因发生的突变在50%的人类癌症中都有发现，而其负调控因子MDM2和MDM4（也称为MDMX）水平的升高在其余许多癌症中下调了p53的功能。了解p53的调控仍然是基于该途径设计广泛适用的抗癌策略的关键目标。这篇对体外研究、人类肿瘤数据和近期小鼠模型的综述表明，p53的翻译后修饰具有调节作用，而MDM2和MDM4在调控p53方面具有更深远的作用。重要的是，MDM4成为药物开发的一个独立靶点，因为其失活对于p53的完全激活至关重要。
