Provincil Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu, 221002, China.
Curr Cancer Drug Targets. 2011 Oct;11(8):987-94. doi: 10.2174/156800911797264789.
The p53 tumor suppressor has been pursued as a cancer therapeutic target based on its ability to induce cell cycle arrest and apoptosis. Reactivation of p53 in the approximately 50% of tumors that retain a functional p53 has served as potential approach in the development of cancer drug therapy. Mdm2 is a major negative regulator of p53 and has long been thought to inhibit p53 in two ways: through ubiquitination of p53, signaling for its degradation by the proteasome, and through directly binding to p53, masking its transactivation domain. Research on Mdm2 E3 function and regulation has important implications for the feasibility of targeting Mdm2 in cancer treatment. By targeting Mdm2 in cancers, especially those harboring wild-type p53, it may be possible to restore p53 function to control tumor growth. Several inhibitors for Mdm2 have been developed and have shown promise in restoring p53 function. This review will summarize the current progress of targeting Mdm2 in cancer treatment with a focus on regulating Mdm2 E3 ubiquitin ligase activity via a number of small Mdm2 binding proteins and the post-translational modification of Mdm2 itself. The potential of inhibitors of Mdm2 E3 ligase as a new novel class of anticancer drugs will also be discussed.
p53 肿瘤抑制因子能够诱导细胞周期停滞和细胞凋亡，因此被作为癌症治疗的靶点。在大约 50%保留有功能 p53 的肿瘤中重新激活 p53，可以作为癌症药物治疗开发的潜在方法。Mdm2 是 p53 的主要负调控因子，长期以来一直被认为通过两种方式抑制 p53：通过泛素化 p53，信号使其被蛋白酶体降解，以及通过直接与 p53 结合，掩盖其转录激活结构域。对 Mdm2 E3 功能和调节的研究对靶向 Mdm2 治疗癌症的可行性具有重要意义。通过在癌症中靶向 Mdm2，特别是那些具有野生型 p53 的癌症，可能恢复 p53 功能以控制肿瘤生长。已经开发了几种 Mdm2 抑制剂，并在恢复 p53 功能方面显示出前景。这篇综述将总结目前靶向 Mdm2 治疗癌症的进展，重点是通过多种与 Mdm2 结合的小分子蛋白调节 Mdm2 E3 泛素连接酶活性，以及 Mdm2 自身的翻译后修饰。Mdm2 E3 连接酶抑制剂作为一类新型抗癌药物的潜力也将进行讨论。
