Brazhnik Paul, Kohn Kurt W
Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, United States.
Math Biosci. 2007 Nov;210(1):60-77. doi: 10.1016/j.mbs.2007.05.005. Epub 2007 May 23.
Stability of the 'guardian of the genome' tumor suppressor protein p53 is regulated predominantly through its ubiquitination. The ubiquitin-specific protease HAUSP plays an important role in this process. Recent experiments showed that p53 demonstrates a differential response to changes in HAUSP which nature and significance are not understood yet. Here a data-driven mathematical model of the Mdm2-mediated p53 ubiquitination network is presented which offers an explanation for the cause of such a response. The model predicts existence of the HAUSP-regulated switch from auto- to p53 ubiquitination by Mdm2. This switch suggests a potential role of HAUSP as a downstream target of stress signals in cells. The model accounts for a significant amount of experimental data, makes predictions for some rate constants, and can serve as a building block for the larger model describing a complex dynamic response of p53 to cellular stresses.
“基因组守护者”肿瘤抑制蛋白p53的稳定性主要通过其泛素化作用来调节。泛素特异性蛋白酶HAUSP在此过程中发挥重要作用。最近的实验表明，p53对HAUSP变化表现出不同的反应，但其本质和意义尚不清楚。本文提出了一个由Mdm2介导的p53泛素化网络的数据驱动数学模型，该模型为这种反应的原因提供了解释。该模型预测存在由HAUSP调节的从Mdm2自身泛素化到p53泛素化的转换。这种转换表明HAUSP在细胞中作为应激信号下游靶点的潜在作用。该模型解释了大量实验数据，对一些速率常数进行了预测，并可作为描述p53对细胞应激复杂动态反应的更大模型的构建模块。
