Integrated computational model of cell cycle and checkpoint reveals different essential roles of Aurora-A and Plk1 in mitotic entry

• Published in: Molecular bioSystems Vol. 7; no. 1; pp. 169 - 179
• Main Authors: Zou, Jun, Luo, Shi-Dong, Wei, Yu-Quan, Yang, Sheng-Yong
• Format: Journal Article
• Language: English
• Published: England 2011
• Subjects: Algorithms; Aurora Kinases; Blotting, Western; Cell Cycle - physiology; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Survival - drug effects; Cell Survival - genetics; Computational Biology; Enzyme Inhibitors - pharmacology; HeLa Cells; Humans; Models, Biological; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism
• ISSN: 1742-206X; 1742-2051; 1742-2051
• DOI: 10.1039/C0MB00004C

Understanding the regulation of mitotic entry is one of the most important goals of modern cell biology, and computational modeling of mitotic entry has been a subject of several recent studies. However, there are still many regulation mechanisms that remain poorly characterized. Two crucial aspects are how mitotic entry is controlled by its upstream regulators Aurora-A and Plk1, and how mitotic entry is coordinated with other biological events, especially G2/M checkpoint. In this context, we reconstructed a comprehensive computational model that integrates the mitotic entry network and the G2/M checkpoint system. Computational simulation of this model and subsequent experimental verification revealed that Aurora-A and Plk1 are redundant to the activation of cyclin B/Cdk1 during normal mitotic entry, but become especially important for cyclin B/Cdk1 activation during G2/M checkpoint recovery. Further analysis indicated that, in response to DNA damage, Chk1-mediated network rewiring makes cyclin B/Cdk1 more sensitive to the down-regulation of Aurora-A and Plk1. In addition, we demonstrated that concurrently targeting Aurora-A and Plk1 during G2/M checkpoint recovery achieves a synergistic effect, which suggests the combinational use of Aurora-A and Plk1 inhibitors after chemotherapy or radiotherapy. Thus, the results presented here provide novel insights into the regulation mechanism of mitotic entry and have potential value in cancer therapy.