Network mechanisms and dysfunction within an integrated computational model of progression through mitosis in the human cell cycle

The cellular protein-protein interaction network that governs cellular proliferation (cell cycle) is highly complex. Here, we have developed a novel computational model of human mitotic cell cycle, integrating diverse cellular mechanisms, for the purpose of generating new hypotheses and predicting new experiments designed to help understand complex diseases. The pathogenic state investigated is infection by a human herpesvirus. The model starts at mitotic entry initiated by the activities of Cyclin-dependent kinase 1 (CDK1) and Polo-like kinase 1 (PLK1), transitions through Anaphase-promoting complex (APC/C) bound to Cell division cycle protein 20 (CDC20), and ends upon mitotic exit mediated by APC/C bound to CDC20 homolog 1 (CDH1). It includes syntheses and multiple mechanisms of degradations of the mitotic proteins. Prior to this work, no such comprehensive model of the human mitotic cell cycle existed. The new model is based on a hybrid framework combining Michaelis-Menten and mass action kinetics for the mitotic interacting reactions. It simulates temporal changes in 12 different mitotic proteins and associated protein complexes in multiple states using 15 interacting reactions and 26 ordinary differential equations. We have defined model parameter values using both quantitative and qualitative data and using parameter values from relevant published models, and we have tested the model to reproduce the cardinal features of human mitosis determined experimentally by numerous laboratories. Like cancer, viruses create dysfunction to support infection. By simulating infection of the human herpesvirus, cytomegalovirus, we hypothesize that virus-mediated disruption of APC/C is necessary to establish a unique mitotic collapse with sustained CDK1 activity, consistent with known mechanisms of virus egress. With the rapid discovery of cellular protein-protein interaction networks and regulatory mechanisms, we anticipate that this model will be highly valuable in helping us to understand the network dynamics and identify potential points of therapeutic interventions.

调控细胞增殖（细胞周期）的细胞内蛋白质-蛋白质相互作用网络极为复杂。本研究构建了一款整合多种细胞机制的新型人类有丝分裂细胞周期计算模型，旨在生成全新假说并预测可助力解析复杂疾病的实验方案。本研究关注的致病状态为人类疱疹病毒感染。该模型以细胞周期蛋白依赖性激酶1（Cyclin-dependent kinase 1, CDK1）与polo样激酶1（Polo-like kinase 1, PLK1）活性引发的有丝分裂进入为起点，经由结合细胞分裂周期蛋白20（Cell division cycle protein 20, CDC20）的后期促进复合物（Anaphase-promoting complex, APC/C）完成过程转换，最终以结合CDC20同源物1（CDC20 homolog 1, CDH1）的APC/C介导的有丝分裂退出为终点。模型涵盖有丝分裂蛋白的合成与多种降解机制。在本研究开展前，尚无此类完整的人类有丝分裂细胞周期模型问世。这款新模型基于混合框架构建，将米氏动力学（Michaelis-Menten kinetics）与质量作用动力学（mass action kinetics）相结合，用于描述有丝分裂相互作用反应。该模型通过15个相互作用反应与26个常微分方程，模拟12种不同有丝分裂蛋白及其多状态相关复合物的时序变化。研究团队结合定量与定性数据，以及已发表相关模型的参数值，确定了本模型的参数取值，并通过复现多个实验室实验测得的人类有丝分裂核心特征对模型进行了验证。与癌症类似，病毒会通过引发功能障碍以支持自身感染过程。通过模拟人类疱疹病毒之一的巨细胞病毒（cytomegalovirus）感染过程，本研究提出假说：病毒介导的后期促进复合物（APC/C）破坏，是建立伴随持续CDK1活性的特异性有丝分裂崩溃的必要条件，这一结论与已知的病毒出芽机制相符。随着细胞内蛋白质-蛋白质相互作用网络与调控机制研究的快速推进，我们预期该模型将在助力解析网络动态特征、识别潜在治疗干预靶点方面发挥重要价值。