Miliani de Marval Paula L, Zhang Yanping
Department of Radiation Oncology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Oncotarget. 2011 Mar;2(3):234-8. doi: 10.18632/oncotarget.228.
The dynamic processes of cell growth and division are under constant surveillance. As one of the primary "gatekeepers" of the cell, the p53 tumor suppressor plays a major role in sensing and responding to a variety of stressors to maintain cellular homeostasis. Recent studies have shown that inhibition of ribosomal biogenesis can activate p53 through ribosomal protein (RP)-mediated suppression of Mdm2 E3 ligase activity. Mutations in Mdm2 that disrupt RP binding have been detected in human cancers; however, the physiological significance of the RP-Mdm2 interaction is not completely understood. We generated mice carrying a single cysteine-to-phenylalanine substitution in the central zinc finger of Mdm2 (Mdm2C305F) that disrupts Mdm2's binding to RPL11 and RPL5. Despite being developmentally normal and maintaining an intact p53 response to DNA damage, the Mdm2C305F mice demonstrate a diminished p53 response to perturbations in ribosomal biogenesis, providing the first in vivo evidence for an RP-Mdm2-p53 signaling pathway. Here we review some recent studies about RP-Mdm2-p53 signaling and speculate on the relevance of this pathway to human cancer.
细胞生长和分裂的动态过程受到持续监测。作为细胞的主要“守门人”之一，p53肿瘤抑制因子在感知和应对各种应激源以维持细胞内稳态方面发挥着重要作用。最近的研究表明，抑制核糖体生物合成可通过核糖体蛋白（RP）介导的Mdm2 E3连接酶活性抑制来激活p53。在人类癌症中已检测到破坏RP结合的Mdm2突变；然而，RP-Mdm2相互作用的生理意义尚未完全了解。我们生成了在Mdm2的中央锌指中携带单个半胱氨酸到苯丙氨酸取代（Mdm2C305F）的小鼠，该取代破坏了Mdm2与RPL11和RPL5的结合。尽管Mdm2C305F小鼠发育正常且对DNA损伤保持完整的p53反应，但它们对核糖体生物合成扰动的p53反应减弱，为RP-Mdm2-p53信号通路提供了首个体内证据。在此，我们回顾了一些关于RP-Mdm2-p53信号传导的最新研究，并推测该通路与人类癌症的相关性。
