文章：

MDM2， MDMX和p53在肿瘤发生和癌症治疗中的作用

MDM2, MDMX and p53 in oncogenesis and cancer therapy

原文发布日期：2013-01-10

DOI: 10.1038/nrc3430

类型: Review Article

开放获取: 否

要点：

1. MDM2 and MDMX are RING domain proteins that exert their oncogenic effects primarily by inhibiting the p53 tumour suppressor protein.
2. Each protein is overexpressed in diverse tumour types by mechanisms including gene amplification and post-translational stabilization; this is generally more frequent in tumours with a wild-type TP53 allele.
3. Despite their similar structures, only MDM2 has intrinsic E3 ubiquitin ligase activity. Although MDM2 alone can inhibit p53, its RING-dependent heterodimerization with MDMX has an important role in p53 inhibition.
4. Both MDM2 and MDMX interact with multiple other partners. Aberrant interactions with these partners may also affect gene expression and genome stability.
5. Structure-based drug design has yielded several MDM antagonists that block MDM–p53 interactions, leading to p53 activation. At least one agent has progressed to clinical trials.
6. Systems biology studies are providing the rationale for using MDM protein antagonists in combination with both approved and experimental pathway-targeted anticancer drugs.

要点翻译：

1. MDM2和MDMX是RING结构域蛋白，主要通过抑制p53肿瘤 suppressor蛋白发挥其致癌作用。
2. 这两种蛋白在多种肿瘤类型中通过基因扩增和翻译后稳定等机制过表达，这在携带野生型TP53等位基因的肿瘤中通常更为常见。
3. 尽管结构相似，但只有MDM2具有内在的E3泛素连接酶活性。虽然MDM2单独即可抑制p53，但其通过RING结构域与MDMX形成的异源二聚体在p53抑制中具有重要作用。
4. MDM2和MDMX均与多种其他蛋白相互作用，与这些伙伴蛋白的异常相互作用也可能影响基因表达和基因组稳定性。
5. 基于结构的药物设计已开发出多种可阻断MDM-p53相互作用的MDM拮抗剂，从而激活p53功能。
6. 至少有一种药物已进入临床试验阶段。系统生物学研究为将MDM蛋白拮抗剂与已获批及实验性的通路靶向抗癌药物联合使用提供了理论依据。

英文摘要：

The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor. However, the MDM proteins modulate and respond to many other signalling networks in which they are embedded. Recent mechanistic studies and animal models have demonstrated how functional interactions in these networks are crucial for maintaining normal tissue homeostasis, and for determining responses to oncogenic and therapeutic challenges. This Review highlights the progress made and pitfalls encountered as the field continues to search for MDM-targeted antitumour agents.

摘要翻译： 

MDM2和MDMX（也称为HDMX和MDM4）蛋白在许多人类癌症中发生失调，主要通过抑制p53肿瘤抑制因子发挥其致癌活性。然而，MDM蛋白还会调节并响应其所嵌入的其他许多信号网络。近期的机制研究和动物模型已表明，这些网络中的功能相互作用对于维持正常组织稳态以及决定对致癌和治疗挑战的反应至关重要。本综述重点介绍了该领域在继续寻找靶向MDM的抗肿瘤药物时所取得的进展和遇到的陷阱。

原文链接：

MDM2, MDMX and p53 in oncogenesis and cancer therapy