Dynamical Modeling Of P53Signaling Pathways

The tumor suppressor p53is a central node in cellular signaling pathways. Cells are constantly confronted with intrinsic and extrinsic DNA damage. While minor DNA damage can usually be repaired, severe damage especially genomic damage will always increase the risk of carcinogenesis. Delicate stress responses are strongly required to eradicate the damaged cells in response to detrimental damage signals. As the guardian of the genome, p53plays crucial roles in stress responses. Therefore, in-depth understanding of the dynamical properties of p53is critically important for evaluating cellular stress responses. In current study, we aim to investigate the dynamical properties of p53using systems biology techniques in different respect.Under ionizing radiation, cells can initiate digital p53pulses and the mechanisms leading to digital pulses have been the focus of current research in dynamical p53modeling. Generally, the duration in the limit cycle region determines the number of digital pulses. However, numerous mathematical models mainly investigate how digital pulses are produced, while ignore the physiological significance of digital pulses. To explore this point, we developed a mathematical model using deterministic ordinary differential equations. The results suggested that ionizing irradiation can induce DNA double strand breaks and trigger digital pulses. The number of p53pulses increases with damage. Many proapoptotic factors such as PUMA, Noxa are induced via digital p53pulses and affect downstream Bax activation switch. We have identified that intricate interactions among BCL-2family members form a bistable biological switch and exert controls over intrinsic apoptotic pathway. A supra-threshold DNA damage will probably turn on the Bax activation switch and trigger apoptosis. Therefore, the digital pulses may serve as a sentinel to the severity of genomic integrity and lead to lethal outcomes when the genomic integrity is severely compromised.More and more models on p53mediated cell fate decision have been proposed recently. However, whether the digital or sustained pulse is the only choice in response to DNA damaging agents is still on debate. To investigate the possibility of non-oscillating or non-pulsing behavior of p53, we constructed a two-component mathematical model. Using bifurcation analysis and stochastic simulation, we found that as the strength of negative feedback increases, p53can display various dynamics such as bistability and oscillation. While in real biological system, the strength of negative feedback may differ under different stressed conditions. For example, under ultraviolet light (UV) radiation, p53-mediated MDM2transcription will be attenuated leading to decreased negative feedback. Meanwhile, UV can bypass ATM responses and therefore another ATM-p53-Wipl negative feedback is nearly compromised. Taken together, the overall reduction in negative feedback will lower the possibility of pulsing behavior and on the contrary increase the occurrence of other dynamical patterns. We for the first time proposed that digital or sustained pulses are not the only dynamics in radiation induced p53responses and this hypothesis has been recently verified experimentally.Recently, basal p53pulses under nonstressed conditions are identified. These basal p53pulses are spontaneous, irregular and asynchronous. Experiments suggested that intrinsic DSB production during normal cell cycle progression is probably the trigger for basal pulses. To mechanistically investigate basal p53pulses, we constructed a simplified mathematical model combining delayed stochastic simulation and found that basal pulses might be produced via an excitable mechanism. Owing to the stochasticity in intrinsic DSB production and excitability, there exists strong asynchrony in basal pulses. Therefore, by dynamical simulation, we successfully identified the mechanisms for basal p53pulses.In all, we investigated the dynamical properties of p53using dynamical modeling approaches from systems biology. These findings may deepen our knowledge about dynamical behavior of p53. Along with ever increasing efforts in p53modeling, we can better elucidate the role of p53in stress responses and provide novel insights into cancer therapy.