Stommel Jayne M, Wahl Geoffrey M
Department of Biology, University of California, San Diego, CA, USA.
EMBO J. 2004 Apr 7;23(7):1547-56. doi: 10.1038/sj.emboj.7600145. Epub 2004 Mar 18.
p53 activation prevents the proliferation of genetically unstable cells. Conversely, p53 antagonism by its transcriptional target, the E3 ubiquitin ligase MDM2, is critical for the viability of unstressed, cycling cells. We demonstrate that MDM2 induces the degradation of p53 in both the nucleus and the cytoplasm. As p53 and MDM2 accumulate in the nuclei of stressed cells, we investigated mechanisms enabling p53 activation despite the high MDM2 levels generated during a DNA-damage response. We show that DNA damage destabilized MDM2 by a mechanism involving damage-activated kinases and MDM2 auto-ubiquitination. p53 was stable and transcriptionally active when MDM2 was unstable, but became unstable and inactive as the damage response waned and MDM2 stabilized. Importantly, blocking MDM2 destabilization in DNA-damaged cells prevented p53 target gene activation. Our data reveal that controlled MDM2 degradation is an important new step in p53 regulation.
p53激活可防止基因不稳定细胞的增殖。相反，其转录靶标E3泛素连接酶MDM2对p53的拮抗作用对于未受应激的循环细胞的生存能力至关重要。我们证明MDM2可诱导p53在细胞核和细胞质中降解。由于p53和MDM2在应激细胞的细胞核中积累，我们研究了尽管在DNA损伤反应过程中产生了高水平的MDM2，但仍能使p53激活的机制。我们发现DNA损伤通过一种涉及损伤激活激酶和MDM2自身泛素化的机制使MDM2不稳定。当MDM2不稳定时，p53稳定且具有转录活性，但随着损伤反应减弱和MDM2稳定，p53变得不稳定且无活性。重要的是，在DNA损伤细胞中阻断MDM2的不稳定会阻止p53靶基因的激活。我们的数据表明，受控的MDM2降解是p53调节中的一个重要新步骤。
