Crosstalk between Plk1, p53, cell cycle, and G2/M DNA damage checkpoint regulation in cancer: computational modeling and analysis

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.

Andrographolide Induces G2/M Cell Cycle Arrest and Apoptosis in Human Glioblastoma DBTRG-05MG Cell Line via ERK1/2 /c-Myc/p53 Signaling Pathway

“…As a result, this study discovered that elevated levels of c-Myc in cancer cells result in newly activated “Myc target genes”, such as p53, for cell cycle arrest at the G2/M phase followed by apoptosis to remove undesirable or abnormal cells before continuing the cell cycle progression. More interestingly, earlier research has revealed that p53 influences the cell cycle checkpoint during G2/M, and cell arrest occurs before mitosis [ 30 ], which is supported by our findings via flow cytometry analysis.…”

Z-Guggulsterone Induces Cell Cycle Arrest and Apoptosis by Targeting the p53/CCNB1/PLK1 Pathway in Triple-Negative Breast Cancer

“…P53 is reported to regulate G2/M transition via CCNB1 and PLK1. 33,34 To further examine how Z-GS regulated CCNB1 and PLK1 via p53 to induce cell cycle arrest at the G2/M phase, we used a p53 inhibitor (PFT-α) to verify our hypothesis. PLK1 and CCNB1 expression levels were higher in Z-GS + PFT-α groups when compared with Z-GS treatment (40 μM) groups.…”

Mechanisms of carcinogenic activity triggered by lysine-specific demethylase 1A

“…LSD1 can recognise and bind to the promoter region of PLK1 to regulate its expression, which regulates the expression of cell division-related genes. However, the interaction between p53 and PLK1 is negatively regulated ( Li Y. et al, 2020 ; Jung et al, 2021 ). p53 inhibits transcription at the PLK1 promoter, whereas PLK1 inhibits the function of p53 by directly binding to it or inactivating it by promoting its degradation ( Dufies et al, 2021 ; Zhang C. et al, 2022 ; Hirschler-Laszkiewicz et al, 2022 ).…”