A data-driven, mathematical model of mammalian cell cycle regulation

• Published in: PloS one Vol. 9; no. 5; p. e97130
• Main Authors: Weis, Michael C, Avva, Jayant, Jacobberger, James W, Sreenath, Sree N
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.05.2014; Public Library of Science (PLoS)
• Subjects: Antigens, CD; Balances (scales); Biology; Biology and Life Sciences; Cadherins - metabolism; Cell cycle; Cell Cycle - physiology; Cell growth; Computer engineering; Computer science; Computer Simulation; Cyclin A; Cyclin A - metabolism; Cyclin B; Cyclin B1; Cyclin B1 - metabolism; Cyclin-dependent kinases; Cyclins - metabolism; Cytometry; Degradation; E-cadherin; E2F protein; E2F Transcription Factors - metabolism; Electrical engineering; G2 phase; Histone H3; Humans; Hypotheses; K562 Cells; Kinases; Mathematical models; Mitosis; Mitosis - physiology; Models, Biological; Ordinary differential equations; Partial differential equations; Phosphorylation; Proteins; Research and Analysis Methods; State variable; Time Factors; Transcription; Transcriptome; Xenopus; Yeast; Cleveland Ohio; United States > US; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0097130

Few of >150 published cell cycle modeling efforts use significant levels of data for tuning and validation. This reflects the difficultly to generate correlated quantitative data, and it points out a critical uncertainty in modeling efforts. To develop a data-driven model of cell cycle regulation, we used contiguous, dynamic measurements over two time scales (minutes and hours) calculated from static multiparametric cytometry data. The approach provided expression profiles of cyclin A2, cyclin B1, and phospho-S10-histone H3. The model was built by integrating and modifying two previously published models such that the model outputs for cyclins A and B fit cyclin expression measurements and the activation of B cyclin/Cdk1 coincided with phosphorylation of histone H3. The model depends on Cdh1-regulated cyclin degradation during G1, regulation of B cyclin/Cdk1 activity by cyclin A/Cdk via Wee1, and transcriptional control of the mitotic cyclins that reflects some of the current literature. We introduced autocatalytic transcription of E2F, E2F regulated transcription of cyclin B, Cdc20/Cdh1 mediated E2F degradation, enhanced transcription of mitotic cyclins during late S/early G2 phase, and the sustained synthesis of cyclin B during mitosis. These features produced a model with good correlation between state variable output and real measurements. Since the method of data generation is extensible, this model can be continually modified based on new correlated, quantitative data.