Mechanism of cell cycle disruption by multiple p53 pulses

When the DNA damage is generated, the tumor suppressor gene p53 is activated and selects the cell fate such as the cell cycle arrest, the DNA repair and the induction of apoptosis. Recently, the p53 oscillation was observed in MCF7 cell line. However, the biological meaning of p53 oscillation was still unclear. Here, we constructed a novel mathematical model of cell cycle regulatory system with p53 signaling network to investigate the relationship between the p53 oscillation and the cell cycle progression. First, the simulated result without DNA damage agreed with the biological findings. Next, the simulations with DNA damage realized both the p53 oscillation and the cell cycle arrest, and indicated that the generation of multiple p53 pulses disrupted the cell cycle progression. Moreover, the simulated results showed that the cell cycle disruption was caused by the catastrophe of M phase in the cell cycle, which resulted from the decline in cyclin A/cyclin-dependent kinase 2. The results in this study suggested that the generation of multiple p53 pulses against DNA damage may be used as a marker of cell cycle disruption.