From structure to dynamics: Frequency tuning in the p53-Mdm2 network I. Logical approach
From structure to dynamics: Frequency tuning in the p53-Mdm2 network I. Logical approach
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DOI：
10.1016/j.jtbi.2009.02.005
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发表时间：
2009-06-21
影响因子：
2
通讯作者：
Kaufman, Marcelle
中科院分区：
文献类型：
--
作者：
Abou-Jaoude, Wassim;Ouattara, Djomangan A.;Kaufman, Marcelle
我们研究了一个简单的四变量模型的动力学性质，该模型描述了肿瘤抑制蛋白p53，其主要负调节因子Mdm 2和DNA损伤之间的相互作用，该模型受到Ciliberto等人[2005]的工作的启发。p53/Mdm 2网络的稳态和振荡。Cell Cycle 4（3），488-493]。其核心是p53和核Mdm 2之间的拮抗剂回路，该回路嵌入在涉及p53、细胞质和核Mdm 2的三元件负回路中。一个主要的关切是制定一种综合办法，使各种类型的说明相互补充。在这里，我们提出了我们的网络的逻辑分析，并简要讨论了相应的差分模型。引入“逻辑分叉图”的新概念，我们证明了Our网络的基本定性动力学性质可以用少量的分叉场景来概括，这些分叉场景可以理解为核心网络的正负回路之间的平衡。该模型显示了各种各样的行为，这取决于损伤的水平，损伤修复的效率，重要的是，DNA结合亲和力和转录活性的p53，这是压力和细胞类型特异性。我们的研究结果定性地解释了几个实验观察，如照射后的p53脉冲，对照射的反应失败，振荡频率的变化，或细胞群中振荡的快速衰减。它们还表明，基于p53的不同翻译后修饰和反式激活特性，细胞与细胞之间以及不同细胞类型之间的行为具有很大的可变性。最后，我们的差分分析提供了Geva-Zatorsky等人[2006]观察到的高频和低频振荡的解释。p53系统的振荡和变异性。摩尔Syst.Biol.2，2006.0033]，这取决于辐照剂量。更详细的分析我们的微分模型，以及它的随机分析将在下一篇论文。(c)2009爱思唯尔有限公司保留所有权利。
We investigate the dynamical properties of a simple four-variable model describing the interactions between the tumour suppressor protein p53, its main negative regulator Mdm2 and DNA damage, a model inspired by the work of Ciliberto et al. [2005. Steady states and oscillations in the p53/Mdm2 network. Cell Cycle 4(3), 488-493]. Its core consists of an antagonist circuit between p53 and nuclear Mdm2 embedded in a three-element negative circuit involving p53, cytoplasmic and nuclear Mdm2. A major concern has been to develop an integrated approach in which various types of descriptions complement each other. Here we present the logical analysis of our network and briefly discuss the corresponding differential model. Introducing the new notion of "logical bifurcation diagrams", we show that the essential qualitative dynamical properties Of Our network can be summarized by a small number of bifurcation scenarios, which can be understood in terms of the balance between the positive and negative circuits of the core network. The model displays a wide variety of behaviours depending on the level of damage, the efficiency of damage repair and, importantly, the DNA-binding affinity and transcriptional activity of p53, which are both stress- and cell-type specific. Our results qualitatively account for several experimental observations such as p53 pulses after irradiation, failure to respond to irradiation, shifts in the frequency of the oscillations, or rapid dampening of the oscillations in a cell population. They also suggest a great variability of behaviour from cell to cell and between different cell-types on the basis of different post-translational modifications and transactivation properties of p53. Finally, our differential analysis provides an interpretation of the high and low frequency oscillations observed by Geva-Zatorsky et al. [2006. Oscillations and variability in the p53 system. Mol. Syst. Biol. 2, 2006.0033] depending on the irradiation dose. A more detailed analysis of our differential model as well as its stochastic analysis will be developed in a next paper. (c) 2009 Elsevier Ltd. All rights reserved.