The Regulation of the p53-mediated Stress Response by MDM2 and MDM4
The Regulation of the p53-mediated Stress Response by MDM2 and MDM4
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DOI：
10.1101/cshperspect.a000968
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发表时间：
2010-01-01
影响因子：
7.2
通讯作者：
Perry, Mary Ellen
中科院分区：
文献类型：
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作者：
Perry, Mary Ellen
精确控制p53的活性对于哺乳动物的生存是必要的。过多的p53是致命的，而过少则允许肿瘤发生。MDM2和MDM4是结构相关的蛋白质，在发育、稳态和应激反应期间对p53活性的控制至关重要。这两种必需的蛋白质调节p53在应激反应中的激活和损伤消退后细胞的恢复，但两者在过度表达时都是致癌的。因此，多个调节回路确保它们的活动被微调以促进无肿瘤生存。许多不同的压力源激活p53，许多研究试图找到它们之间的共性，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直接破坏MDM2和MDM4的功能。本文概述了MDM2和MDM4之间的关系，功能的各种生化机制，其中p53被激活，通过抑制其功能，并提出了一些新兴领域的p53介导的应激反应的调查。
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.