Dynamic analysis of the combinatorial regulation involving transcription factors and microRNAs in cell fate decisions.
Dynamic analysis of the combinatorial regulation involving transcription factors and microRNAs in cell fate decisions.
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DOI：
10.1016/j.bbapap.2013.06.022
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
Fang Yan;Haihong Liu;Zengrong Liu
中科院分区：
文献类型：
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作者：
Fang Yan;Haihong Liu;Zengrong Liu
P53和E2 F1是参与不同细胞命运（包括细胞分化、细胞周期停滞或凋亡）之间的选择的关键转录因子。最近的实验表明，两个家族的microRNA（miRNA），p53-响应性miR 34（miRNA-34 a、B和c）和E2 F1-诱导性miR 449（miRNA-449 a、B和c）是这些不同命运的有效诱导剂，并且可能在使癌细胞对药物治疗和肿瘤抑制敏感方面具有重要作用。确定这两种转录因子和两种miRNA的组合调控作用的机制是一个重要而具有挑战性的问题。在此，部分基于Tongli Zhang et al.（2007）提出的模型，我们开发了决策过程的数学模型，并探索了这两种转录因子和两种miRNA之间响应DNA损伤的组合调控。通过分析模型的非线性动力学行为，我们发现p53具有脉动行为。此外，给出了一个比较，以揭示细胞命运的决定过程中的微小差异的调控和去调控的miR 34对E2 F1。它预测miR 34在促进细胞周期停滞中起关键作用。此外，计算机模拟结果还预测，miR 449是响应持续DNA损伤的凋亡所必需的。与实验观察一致，我们的模型可以解释这两个转录因子和两个miRNA在DNA损伤后细胞命运决定过程中的复杂调控关系。这些理论结果表明，miR 34和miR 449是有效的肿瘤抑制因子，并在细胞命运决定中发挥关键作用。这项工作提供了一种动态机制，显示了细胞命运决定如何由两个转录因子和两个miRNA协调。这篇文章是题为：计算蛋白质组学，系统生物学和临床意义的特刊的一部分。特约编辑：蔡玉东。
P53 and E2F1 are critical transcription factors involved in the choices between different cell fates including cell differentiation, cell cycle arrest or apoptosis. Recent experiments have shown that two families of microRNAs (miRNAs), p53-responsive miR34 (miRNA-34 a, b and c) and E2F1-inducible miR449 (miRNA-449 a, b and c) are potent inducers of these different fates and might have an important role in sensitizing cancer cells to drug treatment and tumor suppression. Identifying the mechanisms responsible for the combinatorial regulatory roles of these two transcription factors and two miRNAs is an important and challenging problem. Here, based in part on the model proposed in Tongli Zhang et al. (2007), we developed a mathematical model of the decision process and explored the combinatorial regulation between these two transcription factors and two miRNAs in response to DNA damage. By analyzing nonlinear dynamic behaviors of the model, we found that p53 exhibits pulsatile behavior. Moreover, a comparison is given to reveal the subtle differences of the cell fate decision process between regulation and deregulation of miR34 on E2F1. It predicts that miR34 plays a critical role in promoting cell cycle arrest. In addition, a computer simulation result also predicts that the miR449 is necessary for apoptosis in response to sustained DNA damage. In agreement with experimental observations, our model can account for the intricate regulatory relationship between these two transcription factors and two miRNAs in the cell fate decision process after DNA damage. These theoretical results indicate that miR34 and miR449 are effective tumor suppressors and play critical roles in cell fate decisions. The work provides a dynamic mechanism that shows how cell fate decisions are coordinated by two transcription factors and two miRNAs. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology and Clinical Implications. Guest Editor: Yudong Cai.