Abstract
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.
Highlights
Disruption of cell cycle is an element of almost all diseases including cancer and viral infections
Our goal is to develop an in silico simulation of human mitosis using published experimental data by integrating subsets of mechanistic relationships into a single base computational model with enough resolution to approximate outcomes upon perturbations
We have developed a novel comprehensive computational model that simulates the human mitotic cell cycle and provides an integrated quantitative understanding of how human mitosis is altered during disease
Summary
Disruption of cell cycle is an element of almost all diseases including cancer and viral infections. Cell cycle consists of oscillating changes in protein concentrations and activities within the cell allowing for duplication of the host genome and eventual cell division. This process is highly regulated involving multiple cellular mechanisms directly participating in the process and others that sense the cellular environment. These include oscillating changes in protein expressions regulated at the transcriptional and post-transcriptional levels, changes in post-translational modifications and functional activities, and changes in protein-protein interactions and subcellular localizations (reviewed in [2,3,4]). Alteration in any one of these events can result in changes in the dynamics of each relationship, and in the cell cycle dysregulation and pseudo-cycle creation, a hallmark of cell pathobiology in cancer and viral infections
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