A mathematical model of the effects of hypoxia on the cell-cycle of normal and cancer cells
A mathematical model of the effects of hypoxia on the cell-cycle of normal and cancer cells
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DOI：
10.1016/j.jtbi.2004.04.016
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发表时间：
2004-08-07
影响因子：
2
通讯作者：
Maini, PK
中科院分区：
文献类型：
--
作者：
Alarcón, T;Byrne, HM;Maini, PK
已知细胞周期的演变受到环境条件的影响，包括细胞外氧的缺乏（缺氧）。值得注意的是，缺氧似乎对正常细胞和癌细胞有不同的影响。而两者都经历缺氧诱导的细胞周期G期停滞（即通过限制点的转变延迟），实验证据表明，只有癌细胞才会经历缺氧诱导的静止（即细胞向潜伏状态的转变，其中大多数细胞功能（包括增殖）被暂停）。我们扩展了Tyson和Novak的细胞周期模型（J. Theor. 210（2001）249）来解释蛋白质p27的作用。这种蛋白质在缺氧条件下表达上调，抑制细胞周期蛋白依赖性激酶（CDK）的活化，从而阻止DNA合成并延迟细胞周期的正常进程。我们使用数值和分析技术相结合来研究我们的模型。我们表明，它再现了许多功能的正常和癌细胞缺氧的反应，以及产生实验可测试的预测。例如，我们的模型预测癌细胞可以通过增加其p27水平而经历静止，而对于正常细胞，当细胞生长速率增加时，p27表达降低。(C)2004爱思唯尔有限公司保留所有权利。
The evolution of the cell-cycle is known to be influenced by environmental conditions, including lack of extracellular oxygen (hypoxia). Notably, hypoxia appears to have different effects on normal and cancer cells. Whereas both experience hypoxia-induced arrest of the G, phase of the cell-cycle (i.e. delay in the transition through the restriction point), experimental evidence suggests that only cancer cells undergo hypoxia-induced quiescence (i.e. the transition of the cell to a latent state in which most of the cell functions, including proliferation, are suspended).Here, we extend a model for the cell-cycle due to Tyson and Novak (J. Theor. Biol. 210 (2001) 249) to account for the action of the protein p27. This protein, whose expression is upregulated under hypoxia, inhibits the activation of the cyclin dependent kinases (CDKs), thus preventing DNA synthesis and delaying the normal progression through the cell-cycle. We use a combination of numerical and analytic techniques to study our model. We show that it reproduces many features of the response to hypoxia of normal and cancer cells, as well as generating experimentally testable predictions. For example our model predicts that cancer cells can undergo quiescence by increasing their levels of p27, whereas for normal cells p27 expression decreases when the cellular growth rate increases. (C) 2004 Elsevier Ltd. All rights reserved.