Crosstalk between Plk1, p53, cell cycle, and G2/M DNA damage checkpoint regulation in cancer: computational modeling and analysis
dc.contributor.author | Jung, Yongwoon | en |
dc.contributor.author | Kraikivski, Pavel | en |
dc.contributor.author | Shafiekhani, Sajad | en |
dc.contributor.author | Terhune, Scott S. | en |
dc.contributor.author | Dash, Ranjan K. | en |
dc.date.accessioned | 2022-09-06T12:51:16Z | en |
dc.date.available | 2022-09-06T12:51:16Z | en |
dc.date.issued | 2021-12-09 | en |
dc.description.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. | en |
dc.description.notes | This work was supported by the Advancing Healthier Wisconsin, Research and Education Program grant 5520429 to S.S.T. and R.K.D., and by the National Institutes of Allergy and Infectious Disease division of the National Institutes of Health under award number R21-AI149039 to S.S.T. and R.K.D. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Advancing Healthier Wisconsin or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | en |
dc.description.sponsorship | Advancing Healthier Wisconsin, Research and Education Program [5520429]; National Institutes of Allergy and Infectious Disease division of the National Institutes of Health [R21-AI149039] | en |
dc.description.version | Published version | en |
dc.format.mimetype | application/pdf | en |
dc.identifier.doi | https://doi.org/10.1038/s41540-021-00203-8 | en |
dc.identifier.eissn | 2056-7189 | en |
dc.identifier.issue | 1 | en |
dc.identifier.other | 46 | en |
dc.identifier.pmid | 34887439 | en |
dc.identifier.uri | http://hdl.handle.net/10919/111710 | en |
dc.identifier.volume | 7 | en |
dc.language.iso | en | en |
dc.publisher | Nature Portfolio | en |
dc.rights | Creative Commons Attribution 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en |
dc.subject | polo-like kinase-1 | en |
dc.subject | anaphase-promoting complex/cyclosome | en |
dc.subject | activation | en |
dc.subject | depletion | en |
dc.subject | target | en |
dc.subject | cdc20 | en |
dc.subject | identification | en |
dc.subject | oscillations | en |
dc.subject | uncertainty | en |
dc.subject | initiation | en |
dc.title | Crosstalk between Plk1, p53, cell cycle, and G2/M DNA damage checkpoint regulation in cancer: computational modeling and analysis | en |
dc.title.serial | Npj Systems Biology and Applications | en |
dc.type | Article - Refereed | en |
dc.type.dcmitype | Text | en |
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