Unlocking the Mdm2-p53 loop - Ubiquitin is the key
Unlocking the Mdm2-p53 loop - Ubiquitin is the key
复制标题
DOI：
10.4161/cc.7.3.5358
复制
发表时间：
2008-02-01
期刊：
影响因子：
4.3
通讯作者：
Zhang, Yanping
中科院分区：
文献类型：
--
作者：
Clegg, Hilary V.;Itahana, Koji;Zhang, Yanping
十多年来，Mdm2一直被认为主要通过两种机制来调节p53：通过掩蔽p53对转录机制的访问，以及通过泛素化p53，以它为目标进行蛋白酶体降解。这一教条最近受到敲入小鼠产生的数据的挑战，其中 Mdm2 的 RING E3 泛素连接酶活性因单点突变而被消除。 RING突变体Mdm2完全能够与p53结合，但不能抑制p53活性，这表明Mdm2不能通过单独结合而无需泛素化来阻断p53。来自 RING 敲入小鼠的数据还表明，内源性 Mdm2 并不像之前认为的那样通过自身泛素化调节自身稳定性。在这篇综述中，我们讨论了这些发现及其与该领域的相关性，包括先前数据与我们的敲入小鼠产生的数据之间差异的潜在原因，以及针对癌症中 Mdm2 的 E3 泛素连接酶活性的可行性。我们还讨论了可以使用我们的小鼠模型解决的其他研究问题。
For more than a decade, Mdm2 has been believed to regulate p53 primarily through two mechanisms: by masking p53' s access to transcriptional machinery, and by ubiquitinating p53, targeting it for proteasomal degradation. This dogma was recently challenged by data generated from knockin mice in which Mdm2' s RING E3 ubiquitin ligase activity was abrogated by a single point mutation. The RING mutant Mdm2 is fully capable of binding with p53, yet cannot suppress p53 activity, suggesting that Mdm2 cannot block p53 by binding alone without ubiquitination. Data from the RING knockin mice also revealed that endogenous Mdm2 does not, as previously thought, regulate its own stability by self-ubiquitination. In this review, we discuss these findings and their relevance to the field, including potential reasons for the discrepancies between previous data and that generated by our knockin mice, as well as the feasibility of targeting Mdm2' s E3 ubiquitin ligase activity in cancer. We also discuss additional research questions that may be addressed using our mouse model.