文章：

调节p53通路：体外假设，体内事实

Regulating the p53 pathway: in vitro hypotheses, in vivo veritas

原文发布日期：2006-12-01

DOI: 10.1038/nrc2012

类型: Review Article

开放获取: 否

要点：

1. In vitro and transfection studies have suggested a p53 regulation model that emphasizes the importance of phosphorylation to produce structural changes in p53 to enable competition between MDM2 and p300 for binding the N-terminal p53 transactivation domain and inducing competing modifications in the p53 C-terminal regulatory domain. In unstressed cells, MDM2 binding in the N terminus would inhibit p53 activity and the MDM2-mediated ubiquitylation of the C terminus would promote p53 degradation; after stress, the phosphorylation of the p53 N terminus increases p300 binding, and the p300-mediated acetylation of the C terminus stabilizes and activates p53.
2. The above model is not supported by recent in vivo studies, because mouse mutants that express different point mutations in the N terminus and C terminus of p53 do not have the predicted phenotypes. Analysis of mutations found in human tumours also suggest that modifiable serine, threonine and lysine residues in the N-terminal and C-terminal domains do not provide on–off switches for p53.
3. Recent mouse mutants confirm the importance of MDM2 in p53 regulation, and show the separate contribution of the MDM2-related protein, MDM4 (also called MDMX) for p53 regulation: in vivo data now indicate that MDM2 mainly regulates p53 stability, whereas MDM4 contributes significantly to regulating p53 activity. These and other data suggest that a switch from MDM2 degradation of p53 to degradation of itself and MDM4 is responsible for p53 accumulation and activation after stress.
4. These results indicate the importance of developing drugs that antagonize MDM2–p53 and MDM4–p53 interactions. Candidate MDM2 antagonists have been developed, but not MDM4 antagonists.
5. Importantly, MDM2 and MDM4 antagonists could cooperate to activate p53 in two to three million patients diagnosed with cancer each year.
6. As p53, MDM2 and MDM4 interact with many proteins, further analyses of these interactions might also lead to new and broadly useful anticancer strategies.

要点翻译：

1. 体外实验和转染研究曾提出一个p53调控模型，该模型强调磷酸化的重要性——通过引发p53结构变化，使MDM2与p300能够竞争结合p53氨基端转录激活结构域，并在p53羧基端调控域诱导产生相互竞争的修饰。在未应激细胞中，MDM2在氨基端的结合会抑制p53活性，而其介导的羧基端泛素化会促进p53降解；应激后，p53氨基端的磷酸化增强了p300结合，而p300介导的羧基端乙酰化则稳定并激活p53。
2. 这一模型未能获得近期体内实验的支持，因为在p53氨基端和羧基端表达不同点突变的小鼠突变体并未出现预期表型。对人类肿瘤中发现的突变进行分析也表明，氨基端和羧基端结构域中可修饰的丝氨酸、苏氨酸和赖氨酸残基并非p53的开关调节器。
3. 最新小鼠突变体证实了MDM2在p53调控中的重要性，并揭示了MDM2相关蛋白MDM4（亦称MDMX）对p53调控的独立贡献：现有体内数据表明，MDM2主要调控p53稳定性，而MDM4在调控p53活性方面发挥重要作用。这些数据与其他研究共同提示，从MDM2降解p53转向降解自身及MDM4的转换机制，是应激后p53累积与激活的关键。
4. 这些研究结果提示开发MDM2-p53与MDM4-p53相互作用拮抗剂的重要性。目前已有候选MDM2拮抗剂被开发出来，但MDM4拮抗剂仍属空白。
5. 值得注意的是，MDM2与MDM4拮抗剂的协同使用，每年可能为两到三百万确诊癌症患者激活p53。
6. 由于p53、MDM2和MDM4与多种蛋白质存在相互作用，对这些互作网络的进一步解析或将为抗癌策略开辟崭新而广泛的应用前景。

英文摘要：

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.

摘要翻译： 

TP53基因编码的肿瘤抑制因子p53在50%的人类癌症中发生突变，而在其余许多癌症中，其负调控因子MDM2和MDM4（又称MDMX）水平升高会下调p53功能。深入理解p53的调控机制，对于设计基于该通路的广谱抗癌策略至关重要。本综述综合体外研究、人类肿瘤数据及近期小鼠模型结果指出：p53的翻译后修饰仅起调节作用，而MDM2和MDM4对其调控更为关键。尤为重要的是，MDM4可作为独立的药物靶点，因其失活对于完全激活p53必不可少。

原文链接：

Regulating the p53 pathway: in vitro hypotheses, in vivo veritas