Zhu Yan, Poyurovsky Masha V, Li Yingchun, Biderman Lynn, Stahl Joachim, Jacq Xavier, Prives Carol
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Mol Cell. 2009 Aug 14;35(3):316-26. doi: 10.1016/j.molcel.2009.07.014.
MDM2 associates with ribosomal protein S7, and this interaction is required to inhibit MDM2's E3 ligase activity, leading to stabilization of MDM2 and p53. Notably, the MDM2 homolog MDMX facilitates the inhibition of MDM2 E3 ligase activity by S7. Further, ablation of S7 inhibits MDM2 and p53 accumulation induced by different stress signals in some cell types. Thus, ribosomal/nucleolar stress is likely a key integrating event in DNA damage signaling to p53. Interestingly, S7 is itself a substrate for MDM2 E3 ligase activity both in vitro and in vivo. An S7-ubiquitin fusion protein (S7-Ub) selectively inhibits MDM2 degradation of p53 and is unaffected by MDMX. S7-Ub promotes apoptosis to a greater extent than S7 alone. This indicates that MDM2 ubiquitination of S7 is involved in sustaining the p53 response. Thus, S7 functions as both effector and affector of MDM2 to ensure a proper cellular response to different stress signals.
MDM2与核糖体蛋白S7结合，这种相互作用对于抑制MDM2的E3连接酶活性是必需的，从而导致MDM2和p53的稳定。值得注意的是，MDM2同源物MDMX促进了S7对MDM2 E3连接酶活性的抑制。此外，在某些细胞类型中，S7的缺失会抑制由不同应激信号诱导的MDM2和p53的积累。因此核糖体/核仁应激可能是DNA损伤信号传导至p53的关键整合事件。有趣的是，S7在体外和体内都是MDM2 E3连接酶活性的底物。一种S7-泛素融合蛋白（S7-Ub）选择性地抑制MDM2对p53的降解，并且不受MDMX的影响。S7-Ub比单独的S7更能促进细胞凋亡。这表明S7的MDM2泛素化参与维持p53反应。因此，S7作为MDM2的效应器和影响因子发挥作用，以确保细胞对不同应激信号做出适当反应。
