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Crosstalk between Plk1, p53, cell cycle, and G2/M DNA damage checkpoint regulation in cancer: computational modeling and analysis. NPJ Syst Biol Appl 2021 12 09;7(1):46

Date

12/11/2021

Pubmed ID

34887439

Pubmed Central ID

PMC8660825

DOI

10.1038/s41540-021-00203-8

Scopus ID

2-s2.0-85121043614   2 Citations

Abstract

Different cancer cell lines can have varying responses to the same perturbations or stressful conditions. Cancer cells that have DNA damage checkpoint-related mutations are often more sensitive to gene perturbations including altered Plk1 and p53 activities than cancer cells without these mutations. The perturbations often induce a cell cycle arrest in the former cancer, whereas they only delay the cell cycle progression in the latter cancer. To study crosstalk between Plk1, p53, and G2/M DNA damage checkpoint leading to differential cell cycle regulations, we developed a computational model by extending our recently developed model of mitotic cell cycle and including these key interactions. We have used the model to analyze the cancer cell cycle progression under various gene perturbations including Plk1-depletion conditions. We also analyzed mutations and perturbations in approximately 1800 different cell lines available in the Cancer Dependency Map and grouped lines by genes that are represented in our model. Our model successfully explained phenotypes of various cancer cell lines under different gene perturbations. Several sensitivity analysis approaches were used to identify the range of key parameter values that lead to the cell cycle arrest in cancer cells. Our resulting model can be used to predict the effect of potential treatments targeting key mitotic and DNA damage checkpoint regulators on cell cycle progression of different types of cancer cells.

Author List

Jung Y, Kraikivski P, Shafiekhani S, Terhune SS, Dash RK

Authors

Ranjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Cycle
Cell Division
Computer Simulation
DNA Damage
Neoplasms
Tumor Suppressor Protein p53