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首页> 外文期刊>Dose-response >Computational Modeling of Signaling Pathways Mediating Cell Cycle Checkpoint Control and Apoptotic Responses to Ionizing Radiation-Induced DNA Damage
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Computational Modeling of Signaling Pathways Mediating Cell Cycle Checkpoint Control and Apoptotic Responses to Ionizing Radiation-Induced DNA Damage

机译：介导细胞周期检查点控制和对电离辐射诱导的DNA损伤的凋亡反应的信号通路的计算模型。

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摘要

The shape of dose response of ionizing radiation (IR) induced cancer at low dose region, either linear non-threshold or J-shaped, has been a debate for a long time. This dose response relationship can be influenced by built-in capabilities of cells that minimize the fixation of IR-mediated DNA damage as pro-carcinogenic mutations. Key capabilities include sensing of damage, activation of cell cycle checkpoint arrests that provide time needed for repair of the damage as well as apoptosis. Here we describe computational modeling of the signaling pathways that link sensing of DNA damage and checkpoint arrest activation/apoptosis to investigate how these molecular-level interactions influence the dose response relationship for IR induced cancer. The model provides qualitatively accurate descriptions of the IR-mediated activation of cell cycle checkpoints and the apoptotic pathway, and of time-course activities and dose response of relevant regulatory proteins (e.g. p53 and p21). Linking to a two-stage clonal growth cancer model, the model described here successfully captured a monotonically increasing to a J-shaped dose response curve and identified one potential mechanism leading to the J-shape: the cell cycle checkpoint arrest time saturates with the increase of the dose.
机译：在低剂量区域（线性非阈值或J形）的电离辐射（IR）诱发的癌症的剂量反应形状一直是争论的很长时间。这种剂量反应关系可能受到细胞内建功能的影响，该功能可将IR介导的DNA损伤固定化为致癌突变的可能性降至最低。关键功能包括感测损伤，激活细胞周期检查点，从而提供修复损伤和凋亡所需的时间。在这里，我们描述了将DNA损伤与检查点阻滞激活/凋亡联系起来的信号通路的计算模型，以研究这些分子水平的相互作用如何影响IR诱导的癌症的剂量反应关系。该模型在质量上准确地描述了IR介导的细胞周期检查点和细胞凋亡途径的激活，以及时程活性和相关调节蛋白（例如p53和p21）的剂量反应。链接到两阶段克隆生长癌模型，此处描述的模型成功捕获了单调增加的J型剂量反应曲线，并确定了导致J型的一种潜在机制：细胞周期检查点停滞时间随着增加而饱和的剂量。

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