Regulation of the p53 Tumor Suppressor Pathway: The Problems and Promises of Studying Mdm2's E3 Ligase Function
Regulation of the p53 Tumor Suppressor Pathway: The Problems and Promises of Studying Mdm2's E3 Ligase Function
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DOI：
10.1615/critreveukargeneexpr.v20.i1.60
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发表时间：
2010-01-01
影响因子：
1.6
通讯作者：
Zhang, Yanping
中科院分区：
文献类型：
--
作者：
Clegg, Hilary V.;Zhang, Yanping
Mdm 2是肿瘤抑制因子p53的主要负调节因子，长期以来一直被认为以两种方式抑制p53：通过遍在化p53以发出其降解信号，以及通过结合p53，掩盖其反式激活结构域。mdm 2也被认为是通过自动代谢来控制其自身水平。尽管这些假设被广泛接受，但支持数据主要来自体外和异位表达研究，当在敲入或敲除小鼠模型的生理学相关环境中进行测试时，这些数据并不总是得到证实。最近，产生了一种小鼠模型，其中Mdm 2的RING结构域中的单点突变（C462 A）废除了Mdm 2的E3活性，同时保持Mdm 2-p53结合完整。这项研究质疑了关于Mdm 2的两个主要教条，即当内源性表达时，（1）Mdm 2不能通过结合而不泛素化来充分抑制p53，（2）Mdm 2可能不受autoubiquitination的调节。两年后，我们仍然没有确切的答案，为什么这些结果与以前的发现相冲突，但我们从随后的研究中获得了新的见解。在这里，我们讨论了Mdm 2功能差异的潜在原因，以及如何解决这些问题，同时考虑到该领域的新研究。
Mdm2 is a major negative regulator of the tumor suppressor p53 and has long been thought to inhibit p53 in two ways: by ubiquitinating p53 to signal for its degradation, and by binding to p53, masking its transactivation domain. Mdm2 is also believed to control its own levels by autoubiquitination. Despite the widespread acceptance of these hypotheses, the supporting data were drawn primarily from in vitro and ectopic expression studies, which have not always been corroborated when tested in the more physiologically relevant setting of a knock-in or knock-out mouse model. Recently, a mouse model was generated in which a single point mutation (C462A) in Mdm2's RING domain abrogated Mdm2's E3 activity while leaving Mdm2-p53 binding intact. This study called into question two major dogmas about Mdm2 by suggesting that when endogenously expressed, (1) Mdm2 cannot inhibit p53 sufficiently by binding without ubiquitination, and (2) Mdm2 may not be regulated by autoubiquitination. Two years later, we are still without definitive answers for why these results conflict with previous findings, but we have gained new insights from subsequent studies. Here, we discuss potential reasons for the discrepancies concerning Mdm2's functions and how they might be resolved, taking into account new research in the field.