Parant J, Chavez-Reyes A, Little N A, Yan W, Reinke V, Jochemsen A G, Lozano G
The University of Texas M. D. Anderson Cancer Center, Department of Molecular Genetics, Section of Cancer Genetics, Box 11, 1515 Holcombe Blvd., Houston, Texas, USA.
Nat Genet. 2001 Sep;29(1):92-5. doi: 10.1038/ng714.
The p53 protein can inhibit cell cycling or induce apoptosis, and is thus a critical regulator of tumorigenesis. This protein is negatively regulated by a physical interaction with MDM2, an E3 ubiquitin ligase. This interaction is critical for cell viability; loss of Mdm2 causes cell death in vitro and in vivo in a p53-dependent manner. The recently discovered MDM2-related protein MDM4 (also known as MDMX) has some of the same properties as MDM2. MDM4 binds and inhibits p53 transcriptional activity in vitro. Unlike MDM2, however, MDM4 does not cause nuclear export or degradation of p53 (refs. 9,10). To study MDM4 function in vivo, we deleted Mdm4 in mice. Mdm4-null mice died at 7.5-8.5 dpc, owing to loss of cell proliferation and not induction of apoptosis. To assess the importance of p53 in the death of Mdm4-/- embryos, we crossed in the Trp53-null allele. The loss of Trp53 completely rescued the Mdm4-/- embryonic lethality. Thus, MDM2 and MDM4 are nonoverlapping critical regulators of p53 in vivo. These data define a new pathway of p53 regulation and raise the possibility that increased MDM4 levels and the resulting inactivation of p53 contribute to the development of human tumors.
p53蛋白可抑制细胞周期或诱导细胞凋亡，因此是肿瘤发生的关键调节因子。该蛋白通过与E3泛素连接酶MDM2的物理相互作用受到负调控。这种相互作用对细胞活力至关重要；Mdm2的缺失会以p53依赖的方式导致体外和体内细胞死亡。最近发现的与MDM2相关的蛋白MDM4（也称为MDMX）具有一些与MDM2相同的特性。MDM4在体外结合并抑制p53的转录活性。然而，与MDM2不同的是，MDM4不会导致p53的核输出或降解（参考文献9,10）。为了研究MDM4在体内的功能，我们在小鼠中删除了Mdm4。Mdm4基因敲除小鼠在胚胎发育7.5 - 8.5天时死亡，原因是细胞增殖丧失而非细胞凋亡诱导。为了评估p53在Mdm4 - / - 胚胎死亡中的重要性，我们引入了Trp53基因敲除等位基因。Trp53的缺失完全挽救了Mdm4 - / - 胚胎的致死性。因此，MDM2和MDM4在体内是p53的非重叠关键调节因子。这些数据定义了一种新的p53调节途径，并增加了MDM4水平升高及由此导致的p53失活促成人类肿瘤发生的可能性。
