Mdm2 E3 连接酶功能对 p53 的调节在胚胎发生和发育中是可有可无的，但在应对 DNA 损伤时却是必不可少的。
Regulation of p53 by Mdm2 E3 ligase function is dispensable in embryogenesis and development, but essential in response to DNA damage.
机构信息
Department of Radiation Oncology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7512, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7512, USA; Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7512, USA.
Department of Radiation Oncology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7512, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7512, USA.
出版信息
Cancer Cell. 2014 Aug 11;26(2):235-47. doi: 10.1016/j.ccr.2014.06.006.
Mdm2 E3 ubiquitin ligase-mediated p53 degradation is generally accepted as the major mechanism for p53 regulation; nevertheless, the in vivo significance of this function has not been unequivocally established. Here, we have generated an Mdm2(Y487A) knockin mouse; Mdm2(Y487A) mutation inactivates Mdm2 E3 ligase function without affecting its ability to bind its homolog MdmX. Unexpectedly, Mdm2(Y487A/Y487A) mice were viable and developed normally into adulthood. While disruption of Mdm2 E3 ligase function resulted in p53 accumulation, p53 transcriptional activity remained low; however, exposure to sublethal stress resulted in hyperactive p53 and p53-dependent mortality in Mdm2(Y487A/Y487A) mice. These findings reveal a potentially dispensable nature for Mdm2 E3 ligase function in p53 regulation, providing insight that may affect how this pathway is targeted therapeutically.
Mdm2 E3 泛素连接酶介导的 p53 降解通常被认为是 p53 调节的主要机制；然而，这种功能在体内的重要性尚未得到明确证实。在这里，我们生成了一种 Mdm2(Y487A) 敲入小鼠；Mdm2(Y487A) 突变使 Mdm2 E3 连接酶失活，而不影响其与同源物 MdmX 结合的能力。出乎意料的是，Mdm2(Y487A/Y487A) 小鼠是有活力的，并正常发育到成年。虽然破坏 Mdm2 E3 连接酶功能导致 p53 积累，但 p53 转录活性仍然很低；然而，暴露于亚致死应激会导致 Mdm2(Y487A/Y487A) 小鼠中 p53 过度活跃和 p53 依赖性死亡。这些发现揭示了 Mdm2 E3 连接酶功能在 p53 调节中可能具有潜在的非必需性质，为靶向治疗该途径提供了新的认识。
Zotero 插件