HAUSP-regulated switch from auto- to p53 ubiquitination by Mdm2 (in silico discovery)
HAUSP-regulated switch from auto- to p53 ubiquitination by Mdm2 (in silico discovery)
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DOI：
10.1016/j.mbs.2007.05.005
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发表时间：
2007-11-01
影响因子：
4.3
通讯作者：
Kohn, Kurt W.
中科院分区：
文献类型：
--
作者：
Brazhnik, Paul;Kohn, Kurt W.
肿瘤抑制蛋白P53的稳定性主要是通过其泛素化来调节的。泛素特异性蛋白水解酶Hausp在这一过程中起着重要的作用。最近的实验表明，P53对Hausp的改变表现出不同的反应，其性质和意义尚不清楚。这里提出了MDM2介导的p53泛素化网络的数据驱动的数学模型，该模型为这种反应的原因提供了解释。该模型预测了存在Hausp调控的MDM2从自动泛素化到p53泛素化的转换。这种转换暗示了Hausp作为细胞内应激信号下游靶点的潜在作用。该模型解释了大量的实验数据，对一些速率常数进行了预测，并可以作为描述p53对细胞压力的复杂动态反应的更大模型的构建块。(C)2007 Elsevier Inc.保留所有权利。
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. (c) 2007 Elsevier Inc. All rights reserved.