Toledo Franck, Wahl Geoffrey M
Institut Curie, Centre de Recherche, UMR CNRS 7147, 26 rue d'Ulm, 75728 Paris Cedex 05, France.
Int J Biochem Cell Biol. 2007;39(7-8):1476-82. doi: 10.1016/j.biocel.2007.03.022. Epub 2007 Apr 8.
The gene TP53, encoding transcription factor p53, is mutated or deleted in half of human cancers, demonstrating the crucial role of p53 in tumor suppression. Importantly, p53 inactivation in cancers can also result from the amplification/overexpression of its specific inhibitors MDM2 and MDM4 (also known as MDMX). The presence of wild-type p53 in those tumors with MDM2 or MDM4 overexpression stimulates the search for new therapeutic agents to selectively reactivate it. This short survey highlights recent insights into MDM2 and MDM4 regulatory functions and their implications for the design of future p53-based anticancer strategies. We now know that MDM2 and MDM4 inhibit p53 in distinct and complementary ways: MDM4 regulates p53 activity, while MDM2 mainly regulates p53 stability. Upon DNA damage, MDM2-dependent degradation of itself and MDM4 contribute significantly to p53 stabilization and activation. These and other data imply that the combined use of MDM2 and MDM4 antagonists in cancer cells expressing wild-type p53 should activate p53 more significantly than agents that only antagonize MDM2, resulting in more effective anti-tumor activity.
编码转录因子p53的TP53基因在一半的人类癌症中发生突变或缺失，这表明p53在肿瘤抑制中起着关键作用。重要的是，癌症中p53的失活也可能是由于其特异性抑制剂MDM2和MDM4（也称为MDMX）的扩增/过表达所致。在那些MDM2或MDM4过表达的肿瘤中存在野生型p53，这促使人们寻找新的治疗药物来选择性地重新激活它。本简短综述重点介绍了对MDM2和MDM4调控功能的最新见解及其对未来基于p53的抗癌策略设计的影响。我们现在知道，MDM2和MDM4以不同且互补的方式抑制p53：MDM4调节p53活性，而MDM2主要调节p53稳定性。在DNA损伤时，MDM2依赖性的自身降解和MDM4降解对p53的稳定和激活有显著贡献。这些以及其他数据表明，在表达野生型p53的癌细胞中联合使用MDM2和MDM4拮抗剂应该比仅拮抗MDM2的药物更显著地激活p53，从而产生更有效的抗肿瘤活性。
