Paper Info
Title
Network mechanisms and dysfunction within an integrated computational model of progression through mitosis in the human cell cycle.
Abstract
Author summary The knowledge of cellular protein-protein interaction networks and their regulatory mechanisms governing cell cycle is ever expanding at an extraordinary rate. This includes many publications defining small and disconnected subsets of functional interactions occurring at limited time points. For cellular mitosis, mechanisms underlying the process have been experimentally investigated for several decades. However, we do not have an integrated quantitative understanding of mitosis and relative contributions of different regulatory mechanisms under normal conditions and their dysregulations in diseases. 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. In achieving this goal, 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. We have suitably defined model parameter values and tested the model to reproduce the cardinal features of human mitosis determined experimentally by numerous laboratories. The developed model will be highly valuable in helping us to understand complex network relationships, build new hypotheses, design new experiments, and identify points of therapeutic interventions. 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.
Year
DOI
Venue
2020
10.1371/journal.pcbi.1007733; 10.1371/journal.pcbi.1007733.r001; 10.1371/journal.pcbi.1007733.r002; 10.1371/journal.pcbi.1007733.r003; 10.1371/journal.pcbi.1007733.r004; 10.1371/journal.pcbi.1007733.r005; 10.1371/journal.pcbi.1007733.r006
PLOS COMPUTATIONAL BIOLOGY
DocType
Volume
Issue
Journal
16
4
ISSN
Citations 
PageRank 
1553-734X
0
0.34
References 
Authors
0
4
Name
Order
Citations
PageRank
Scott S Terhune100.34
Yongwoon Jung200.34
Katie M Cataldo300.34
Ranjan K Dash400.68