A predictive mathematical model of the DNA damage G2 checkpoint.
A predictive mathematical model of the DNA damage G2 checkpoint.
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DOI：
10.1016/j.jtbi.2012.12.011
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发表时间：
2013-03-07
影响因子：
2
通讯作者：
Simpson, Dennis A.
中科院分区：
文献类型：
--
作者：
Kesseler, Kevin J.;Blinov, Michael L.;Elston, Timothy C.;Kaufmann, William K.;Simpson, Dennis A.
关键词：
根据已知的蛋白质相互作用构建了细胞周期从 G2 期到有丝分裂 (M) 期转变的预测数学模型，这些蛋白质被认为在 G2 到 M 期的转变以及 DNA 损伤诱导的 G2 检查点中发挥着重要作用。该模型模拟活性细胞周期蛋白 B1/Cdk1 (MPF) 复合物在细胞核中的积累，以激活有丝分裂、DNA 损伤对该过程的抑制，以及成分蛋白在细胞质和细胞核之间的运输。模型中的相互作用基于单个磷酸表位的活性和参与 G2/M 的蛋白质的结合位点。由于跟踪磷酸形式会导致组合爆炸，因此我们使用 BioNetGen 软件采用基于规则的方法。该模型用于确定在存在和不存在 DNA 损伤的情况下参与 G2 到 M 转变调节的选定蛋白质的消耗或过度表达的影响。 Plk1 的缺失延迟了有丝分裂的进入和从 DNA 损伤诱导的 G2 停滞中恢复，而 MPF 的过度表达减弱了 DNA 损伤诱导的 G2 延迟。该模型概括了在不同水平的 DNA 损伤信号的生物反应中观察到的 G2 延迟。该模型产生了新的预测，即 pkMyt1 的耗尽会导致异常的生物状态，其中 DNA 损伤的 G2 细胞会积累无活性的核 MPF。这样一个详细的模型可能有助于预测癌症中 DNA 损伤 G2 检查点的功能，从而预测癌症治疗的敏感性。
A predictive mathematical model of the transition from the G2 phase in the cell cycle to mitosis (M) was constructed from the known interactions of the proteins that are thought to play significant roles in the G2 to M transition as well as the DNA damage- induced G2 checkpoint. The model simulates the accumulation of active cyclin B1/Cdk1 (MPF) complexes in the nucleus to activate mitosis, the inhibition of this process by DNA damage, and transport of component proteins between cytoplasm and nucleus. Interactions in the model are based on activities of individual phospho-epitopes and binding sites of proteins involved in G2/M. Because tracking phosphoforms leads to combinatorial explosion, we employ a rule-based approach using the BioNetGen software. The model was used to determine the effects of depletion or over-expression of selected proteins involved in the regulation of the G2 to M transition in the presence and absence of DNA damage. Depletion of Plk1 delayed mitotic entry and recovery from the DNA damage-induced G2 arrest and over-expression of MPF attenuated the DNA damage-induced G2 delay. The model recapitulates the G2 delay observed in the biological response to varying levels of a DNA damage signal. The model produced the novel prediction that depletion of pkMyt1 results in an abnormal biological state in which G2 cells with DNA damage accumulate inactive nuclear MPF. Such a detailed model may prove useful for predicting DNA damage G2 checkpoint function in cancer and, therefore, sensitivity to cancer therapy.
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DOI：
10.1126/stke.3442006re6
发表时间：
2006-07-18
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Hlavacek, William S;Faeder, James R;Fontana, Walter
通讯作者：
Fontana, Walter
影响因子：
21.3
作者：
Pomerening, JR;Sontag, ED;Ferrell, JE
通讯作者：
Ferrell, JE
影响因子：
3.8
作者：
Novak, B;Csikasz-Nagy, A;Tyson, JJ
通讯作者：
Tyson, JJ
影响因子：
21.3
作者：
Novak, Bela;Tyson, John J.;Csikasz-Nagy, Attila
通讯作者：
Csikasz-Nagy, Attila
影响因子：
7.7
作者：
Toyoshima-Morimoto, F;Taniguchi, E;Nishida, E
通讯作者：
Nishida, E