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A Theoretical Model for the Cell Cycle and Drug Induced Cell Cycle Arrest of FUCCI Systems with Cell-to-Cell Variation during Mitosis

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Abstract

Purpose

Since the molecular mechanism of the cell cycle was established, various theoretical models of this process have been developed. A recent study revealed significant variability in cell cycle duration between mother and daughter cells, but this observation has not been incorporated into the theoretical models.

Methods

We used fluorescent ubiquitination-based cell cycle indicator (FUCCI) systems and live-monitored the heterogeneity of cell cycle progression within daughter cells, which accounts for dephasing synchrony. To incorporate the variable cell cycle durations into a model, we modified a two-ordinary differential equation (ODE) model based on reciprocal activation between CDK1 and APC.

Results

Our model reproduced the experimental population profile, in which cell cycle synchrony dephased due to variability. Based on this model, we determined parameters for CDK1 and APC in the cell cycle profile after treatment with antimitotic drugs and associated the parameters with the drugs’ mode of action as cell cycle inhibitors.

Conclusion

This suggests that this model is useful for determining the mode of action of unknown small molecules on the cell cycle.

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ACKNOWLEDGMENTS AND DISCLOSURES

This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(2018R1A6A1A03024940) and Research Resettlement Fund for the new faculty of Seoul National University (370C-20180036: C.HJ). The authors would also like to acknowledge the support from KISTI supercomputing center through the strategic support program for the supercomputing application research [Grant No. KSC-2015-C2-001]. The authors declare no conflict of interest.

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Author notes

  1. Hyeonjeong Bae, Young-Hyun Go and Taejin Kwon contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul, 04107, South Korea

    Hyeonjeong Bae, Taejin Kwon & Bong June Sung

  2. Department of Life Science, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul, 04107, South Korea

    Young-Hyun Go

  3. College of Pharmacy, Seoul National University, 1 Gwanak-ro Gwanak-gu, Seoul, 08826, South Korea

    Hyuk-Jin Cha

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  1. Hyeonjeong Bae
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  2. Young-Hyun Go
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  4. Bong June Sung
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Contributions

HJ.C and BJ.S conceived the overall study design and led the experiments. H.B, YH.G and T.K mainly conducted the experiments, data analysis, and critical discussion of the results. All authors contributed to manuscript writing and revising, and endorsed the final manuscript.

Corresponding authors

Correspondence to Bong June Sung or Hyuk-Jin Cha.

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Bae, H., Go, YH., Kwon, T. et al. A Theoretical Model for the Cell Cycle and Drug Induced Cell Cycle Arrest of FUCCI Systems with Cell-to-Cell Variation during Mitosis. Pharm Res 36, 57 (2019). https://doi.org/10.1007/s11095-019-2570-2

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