Institut Curie, Paris, France.
PLoS Comput Biol. 2010 Mar 5;6(3):e1000702. doi: 10.1371/journal.pcbi.1000702.
Cytokines such as TNF and FASL can trigger death or survival depending on cell lines and cellular conditions. The mechanistic details of how a cell chooses among these cell fates are still unclear. The understanding of these processes is important since they are altered in many diseases, including cancer and AIDS. Using a discrete modelling formalism, we present a mathematical model of cell fate decision recapitulating and integrating the most consistent facts extracted from the literature. This model provides a generic high-level view of the interplays between NFkappaB pro-survival pathway, RIP1-dependent necrosis, and the apoptosis pathway in response to death receptor-mediated signals. Wild type simulations demonstrate robust segregation of cellular responses to receptor engagement. Model simulations recapitulate documented phenotypes of protein knockdowns and enable the prediction of the effects of novel knockdowns. In silico experiments simulate the outcomes following ligand removal at different stages, and suggest experimental approaches to further validate and specialise the model for particular cell types. We also propose a reduced conceptual model implementing the logic of the decision process. This analysis gives specific predictions regarding cross-talks between the three pathways, as well as the transient role of RIP1 protein in necrosis, and confirms the phenotypes of novel perturbations. Our wild type and mutant simulations provide novel insights to restore apoptosis in defective cells. The model analysis expands our understanding of how cell fate decision is made. Moreover, our current model can be used to assess contradictory or controversial data from the literature. Ultimately, it constitutes a valuable reasoning tool to delineate novel experiments.
细胞因子，如 TNF 和 FASL，可以根据细胞系和细胞状态触发细胞的死亡或存活。细胞在这些细胞命运之间做出选择的机制细节尚不清楚。这些过程的理解很重要，因为它们在许多疾病中发生改变，包括癌症和艾滋病。我们使用离散建模形式主义，提出了一个细胞命运决策的数学模型，该模型概括和整合了从文献中提取的最一致的事实。该模型提供了 NFkappaB 促生存途径、RIP1 依赖性坏死和凋亡途径对死亡受体介导的信号反应之间相互作用的通用高级视图。野生型模拟表明细胞对受体结合的反应具有强大的分离性。模型模拟再现了蛋白质敲低的已有表型，并能够预测新敲低的影响。在计算机模拟实验中，模拟了在不同阶段去除配体后的结果，并提出了实验方法来进一步验证和专门化该模型用于特定细胞类型。我们还提出了一个简化的概念模型，实现了决策过程的逻辑。该分析对三条途径之间的串扰以及 RIP1 蛋白在坏死中的瞬时作用提出了具体预测，并证实了新型扰动的表型。我们的野生型和突变型模拟为恢复有缺陷细胞中的凋亡提供了新的见解。模型分析扩展了我们对细胞命运决策如何做出的理解。此外，我们当前的模型可用于评估来自文献中的矛盾或有争议的数据。最终，它构成了一个有价值的推理工具，用于描绘新的实验。
