Laboratory of Protein Dynamics and Signaling, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-0189, USA.
Cold Spring Harb Perspect Biol. 2010 Jan;2(1):a000968. doi: 10.1101/cshperspect.a000968.
Exquisite control of the activity of p53 is necessary for mammalian survival. Too much p53 is lethal, whereas too little permits tumorigenesis. MDM2 and MDM4 are structurally related proteins critical for the control of p53 activity during development, homeostasis, and the response to stress. These two essential proteins regulate both the activation of p53 in response to stress and the recovery of cells following resolution of the damage, yet both are oncogenic when overexpressed. Thus, multiple regulatory circuits ensure that their activities are fine-tuned to promote tumor-free survival. Numerous diverse stressors activate p53, and much research has gone into trying to find commonalities between them that would explain the mechanism by which p53 becomes active. It is now clear that although these diverse stressors activate p53 by different biochemical pathways, one common feature is the effort they direct, through a variety of means, toward disrupting the functions of both MDM2 and MDM4. This article provides an overview of the relationship between MDM2 and MDM4, features the various biochemical mechanisms by which p53 is activated through inhibition of their functions, and proposes some emerging areas for investigation of the p53-mediated stress response.
对 p53 活性的精细控制对于哺乳动物的生存是必要的。过多的 p53 是致命的，而过少的 p53 则允许肿瘤发生。MDM2 和 MDM4 是结构上相关的蛋白质，对于 p53 活性在发育、内稳态和应激反应中的控制至关重要。这两种必需的蛋白质调节 p53 在应激反应中的激活以及细胞在损伤解决后的恢复，但当过度表达时两者都是致癌的。因此，多个调节回路确保它们的活性被精细调节以促进无肿瘤生存。许多不同的应激源激活 p53，并且已经进行了大量研究试图找出它们之间的共同点，以解释 p53 变得活跃的机制。现在很清楚，尽管这些不同的应激源通过不同的生化途径激活 p53，但一个共同的特征是它们通过各种手段努力破坏 MDM2 和 MDM4 的功能。本文概述了 MDM2 和 MDM4 之间的关系，介绍了通过抑制其功能激活 p53 的各种生化机制，并提出了一些研究 p53 介导的应激反应的新领域。
