MDM2 E3 ligase activity is essential for p53 regulation and cell cycle integrity.
MDM2 E3 ligase activity is essential for p53 regulation and cell cycle integrity.
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DOI：
10.1371/journal.pgen.1010171
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发表时间：
2022-05
期刊：
影响因子：
4.5
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中科院分区：
文献类型：
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MDM2和MDM4是p53的关键调控因子，在异常表达时作为癌基因发挥作用。MDM2和MDM4合作抑制p53的转录反激活，并使p53多泛素化降解。关于MDM2 e3连接酶介导的p53调控的重要性仍然存在争议。为了解决这个问题，我们产生了Mdm2 L466A突变的小鼠，该突变特异性地破坏了E2相互作用，破坏了Mdm2 E3连接酶的活性，同时保留了其结合MDM4和抑制p53转激活的能力。Mdm2L466A/L466A小鼠表现出p53依赖性胚胎致死性，表明MDM2 E3连接酶活性对体内p53调控至关重要。出乎意料的是，即使在缺乏p53的情况下，表达Mdm2L466A的细胞也表现出细胞周期G2-M过渡缺陷和非整倍性增加，这表明MDM2 E3连接酶在细胞周期调节和基因组完整性中发挥了p53独立的作用。此外，携带E3-dead MDM2突变体的细胞在DNA损伤时表现出异常的细胞周期调节。本研究揭示了MDM2的E3连接酶活性在细胞周期中除了在体内调节p53稳定性的重要作用之外的一个未被描述的作用。人类癌症中最常见的突变蛋白p53肿瘤抑制蛋白受到潜在致癌蛋白MDM2和MDM4的负调控。MDM2/MDM4通过两种机制调控p53， MDM2 E3泛素连接酶活性标志着p53的降解，MDM2/MDM4可以结合p53抑制其促进RNA转录的能力。这些机制是否有助于体内正常的p53调控仍然存在争议。使用一种新开发的小鼠模型，将这两种机制遗传分离，我们发现表达MDM2特异性缺乏E3泛素连接酶活性的小鼠不能在胚胎发育中存活，因为不受调节的p53是致命的。与先前的报道相反，MDM2 E3泛素连接酶活性是胚胎发育过程中p53调控所必需的。此外，无论p53状态如何，缺乏MDM2 E3泛素连接酶活性的细胞都存在细胞周期缺陷，揭示了MDM2在调节细胞周期中的作用与p53无关。通过阻断与MDM2/MDM4的物理相互作用来激活p53是目前研究的一种癌症治疗方法，但这种方法并不能解释独立于p53的MDM2/MDM4的促癌活性。本文报道的研究结果表明，直接靶向MDM2 E3连接酶活性可能是有利的，因为它可以抑制p53依赖性和p53非依赖性的致癌机制。
MDM2 and MDM4 are key regulators of p53 and function as oncogenes when aberrantly expressed. MDM2 and MDM4 partner to suppress p53 transcriptional transactivation and polyubiquitinate p53 for degradation. The importance of MDM2 E3-ligase-mediated p53 regulation remains controversial. To resolve this, we generated mice with an Mdm2 L466A mutation that specifically compromises E2 interaction, abolishing MDM2 E3 ligase activity while preserving its ability to bind MDM4 and suppress p53 transactivation. Mdm2L466A/L466A mice exhibit p53-dependent embryonic lethality, demonstrating MDM2 E3 ligase activity is essential for p53 regulation in vivo. Unexpectedly, cells expressing Mdm2L466A manifest cell cycle G2-M transition defects and increased aneuploidy even in the absence of p53, suggesting MDM2 E3 ligase plays a p53-independent role in cell cycle regulation and genome integrity. Furthermore, cells bearing the E3-dead MDM2 mutant show aberrant cell cycle regulation in response to DNA damage. This study uncovers an uncharacterized role for MDM2’s E3 ligase activity in cell cycle beyond its essential role in regulating p53’s stability in vivo. The most frequently mutated protein in human cancer, the p53 tumor suppressor protein, is negatively regulated by the potentially oncogenic proteins MDM2 and MDM4. MDM2/MDM4 regulates p53 through two mechanisms, MDM2 E3 ubiquitin ligase activity marks p53 for degradation while MDM2/MDM4 can bind p53 to inhibit its ability to promote RNA transcription. Whether these mechanisms contribute to normal p53 regulation in vivo remains controversial. Using a newly developed mouse model that genetically separates these two mechanisms, we find that mice expressing MDM2 deficient specifically for E3 ubiquitin ligase activity do not survive embryonic development because unregulated p53 is lethal. In contrast to prior reports, MDM2 E3 ubiquitin ligase activity is thus required for p53 regulation during embryonic development. In addition, cells lacking MDM2 E3 ubiquitin ligase activity have cell cycle defects regardless of p53 status, uncovering a p53-independent function for MDM2 in regulating the cell cycle. Activating p53 by blocking physical interaction with MDM2/MDM4 is one currently pursued approach for cancer therapy, but this approach does not account for cancer-promoting activities of MDM2/MDM4 independent of p53. Findings reported here suggest targeting MDM2 E3 ligase activity directly may be advantageous as it would inhibit both p53-dependent and p53-independent oncogenic mechanisms.
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DOI：
10.4161/15384101.2015.945831
发表时间：
2014
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Müllers E;Silva Cascales H;Jaiswal H;Saurin AT;Lindqvist A
通讯作者：
Lindqvist A
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
p53 抑制剂 MDM2/MDMX 复合物是控制体内 p53 活性所必需的
DOI：
10.1073/pnas.1102309108
发表时间：
2011-07-19
影响因子：
11.1
作者：
Huang, Lei;Yan, Zheng;Yuan, Zhi-Min
通讯作者：
Yuan, Zhi-Min
DOI：
10.1126/science.1232033
发表时间：
2013-02-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Mali P;Yang L;Esvelt KM;Aach J;Guell M;DiCarlo JE;Norville JE;Church GM
通讯作者：
Church GM
影响因子：
6.6
作者：
Aylon Y;Oren M
通讯作者：
Oren M