Mathematical Model Of P53 Signaling Network Regulating Cell Fate

DNA is often damaged because cells are affected by endogenous or exogenous factors.When DNA is damaged,cells must make appropriate decisions including cell growth arrest,DNA repair,and apoptosis.The tumor suppressor p53 plays a central role in determining cell fate after DNA damage.Studies have shown that p53 regulates cell fate by regulating the expression of downstream genes.E2F1 and Programmed Cell Death 5(PDCD5)have been shown to play an important role in the decision-making of p53 regulation of cell fate,but the specific regulatory mechanisms are still unclear.In order to better understand the effect of p53-regulated signaling network on cell fate,a comprehensive model containing E2F1 and PDCD5 to regulate p53 signaling pathway was constructed.The cell fate regulated by p53 during DNA damage due to ionizing radiation(IR)was simulated.First,we considered the effect of p53 downstream gene wip1 on p53 dynamics and found that wip1 has an important regulatory effect on p53 pulse production.Secondly,it was found that the level of E2F1 shows the switching behavior in the model.It can promote cell cycle progression and induce apoptosis.When DNA is damaged,growth factors overcome growth arrest and activate E2F1.For repairable DNA damage,E2F1 promotes cell cycle progression after DNA has been repaired,allowing cells to survive and enter S phase.For irreparable DNA damage,E2F1 synergizes with the gene of p53 downstream to promote apoptosis.The model herein also demonstrates that the interaction of PDCD5 with the p53 pathway promotes apoptosis,which is dose-dependent and regulates p53-dependent cell fate.The comprehensive model validates the experimental results of the complex relationship between p53,PDCD5 and E2F1 in DNA damage response.This work highlights the importance of E2F1 and PDCD5 in p53-mediated cell fate decision making and provides some clues for further study of p53 dynamics.