Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11995-2000. doi: 10.1073/pnas.1102241108. Epub 2011 Jul 5.
Mdm2 and Mdm4 are homologous RING domain-containing proteins that negatively regulate the tumor suppressor p53 under physiological and stress conditions. The RING domain of Mdm2 encodes an E3-ubiquitin ligase that promotes p53 degradation. In addition, Mdm2 and Mdm4 interact through their respective RING domains. The in vivo significance of Mdm2-Mdm4 heterodimerization in regulation of p53 function is unknown. In this study, we generated an Mdm4 conditional allele lacking the RING domain to investigate its role in Mdm2 and p53 regulation. Our results demonstrate that homozygous deletion of the Mdm4 RING domain results in prenatal lethality. Mechanistically, Mdm2-Mdm4 heterodimerization is critical for inhibiting lethal p53 activation during early embryogenesis. However, Mdm2-Mdm4 interaction is dispensable for regulating p53 activity as well as the stability of Mdm2 and p53 at later stages of development. We propose that Mdm4 is a key cofactor of Mdm2 that inhibits p53 activity primarily during early embryogenesis but is dispensable for regulating p53 and Mdm2 stability in the adult mouse.
Mdm2 和 Mdm4 是同源的 RING 结构域蛋白，它们在生理和应激条件下负调控肿瘤抑制因子 p53。Mdm2 的 RING 结构域编码一种 E3 泛素连接酶，促进 p53 降解。此外，Mdm2 和 Mdm4 通过其各自的 RING 结构域相互作用。Mdm2-Mdm4 异二聚体在调节 p53 功能中的体内意义尚不清楚。在这项研究中，我们生成了一个缺乏 RING 结构域的 Mdm4 条件性等位基因，以研究其在 Mdm2 和 p53 调节中的作用。我们的结果表明，Mdm4 RING 结构域的纯合缺失导致产前致死。从机制上讲，Mdm2-Mdm4 异二聚体对于抑制早期胚胎发生过程中致死性 p53 激活至关重要。然而，Mdm2-Mdm4 相互作用对于调节 p53 活性以及 Mdm2 和 p53 在发育后期的稳定性是可有可无的。我们提出，Mdm4 是 Mdm2 的关键辅助因子，它主要在早期胚胎发生过程中抑制 p53 活性，但在成年小鼠中调节 p53 和 Mdm2 稳定性时则是可有可无的。
