The tumor suppressor p53 mainly induces cell cycle arrest/DNA repair or apoptosis in the DNA damage response. How to choose between these two outcomes is not fully understood. We proposed a four-module model of the p53 signaling network and associated the network dynamics with cellular outcomes after ionizing radiation. We found that the cellular response is mediated by both the level and posttranslational modifications of p53 and that p53 is activated in a progressive manner. First, p53 is partially activated by primary modifications such as phosphorylation at Ser-15/20 to induce cell cycle arrest, with its level varying in a series of pulses. If the damage cannot be fixed after a critical number of p53 pulses, then p53 is fully activated by further modifications such as phosphorylation at Ser-46 to trigger apoptosis, with its concentration switching to rather high levels. Thus, p53 undergoes a two-phase response in irreparably damaged cells. Such combinations of pulsatile and switch-like behaviors of p53 may represent a flexible and efficient control mode, avoiding the premature apoptosis and promoting the execution of apoptosis. In our model, p53 pulses are recurrently driven by ataxia telangiectasia mutated (ATM) pulses triggered by DNA damage. The p53-Mdm2 and ATM-p53-Wip1 negative feedback loops are responsible for p53 pulses, whereas the switching behavior occurs when the p53-PTEN-Akt-Mdm2 positive feedback loop becomes dominant. Our results suggest that a sequential predominance of distinct feedback loops may elicit multiple-phase dynamical behaviors. This work provides a new mechanism for p53 dynamics and cell fate decision.

The tumor suppressor p53 plays a crucial role in cellular response to various stresses. Recent experiments have shown that p53 level exhibits a series of pulses after DNA damage caused by ionizing radiation (IR). However, how the p53 pulses govern cell survival and death remains unclear. Here, we develop an integrated model with four modules for the p53 network and explore the mechanism for cell fate decision based on the dynamics of the network. By numerical simulations, the following processes are characterized. First, DNA repair proteins bind to IR-induced double-strand breaks, forming complexes, which are then detected by ataxia telangiectasia mutated (ATM). Activated ATM initiates the p53 oscillator to produce pulses. Consequently, the target genes of p53 are selectively induced to control cell fate. We propose that p53 promotes the repair of minor DNA damage but suppresses the repair of severe damage. We demonstrate that cell fate is determined by the number of p53 pulses relying on the extent of DNA damage. At low damage levels, few p53 pulses evoke cell cycle arrest by inducing p21 and promote cell survival, whereas at high damage levels, sustained p53 pulses trigger apoptosis by inducing p53AIP1. We find that p53 can effectively maintain genomic integrity by regulating the efficiency and fidelity of DNA repair. We also show that stochasticity in the generation and repair of DNA damage leads to variability in cell fate. These findings are consistent with experimental observations and advance our understanding of the dynamics and functions of the p53 network.

Positive and negative feedback loops are often coupled to perform various functions in gene regulatory networks, acting as bistable switches, oscillators, and excitable devices. It is implied that such a system with interlinked positive and negative feedback loops is a flexible motif that can modulate itself among various functions. Here, we developed a minimal model for the system and systematically explored its dynamics and performance advantage in response to stimuli in a unifying framework. The system indeed displays diverse behaviors when the strength of feedback loops is changed. First, the system can be tunable from monostability to bistability by increasing the strength of positive feedback, and the bistability regime is modulated by the strength of negative feedback. Second, the system undergoes transitions from bistability to excitability and to oscillation with increasing the strength of negative feedback, and the reverse conversion occurs by enhancing the strength of positive feedback. Third, the system is more flexible than a single feedback loop; it can produce robust larger-amplitude oscillations over a wider stimulus regime compared with a single time-delayed negative feedback loop. Furthermore, the tunability of the system depends mainly on the topology of coupled feedback loops but less on the exact parameter values or the mode of interactions between model components. Thus, our results interpret why such a system represents a tunable motif and can accomplish various functions. These also suggest that coupled feedback loops can act as toolboxes for engineering diverse functional circuits in synthetic biology.

After DNA damage, cells must decide between different fates including growth arrest, DNA repair, and apoptosis. Both p53 and E2F1 are transcription factors involved in the decision process. However, the mechanism for cross-talk between the p53 and E2F1 pathways still remains unclear. Here, we proposed a four-module kinetic model of the decision process and explored the interplay between these two pathways in response to ionizing radiation via computer simulation. In our model the levels of p53 and E2F1 separately exhibit pulsatile and switching behaviors. Upon DNA damage, p53 is first activated, whereas E2F1 is inactivated, leading to cell cycle arrest in the G(1) phase. We found that the ultimate decision between cell life and death is determined by the number of p53 pulses depending on the extent of DNA damage. For repairable DNA damage, the cell can survive and reenter the S phase because of the activation of E2F1 and inactivation of p53. For irreparable DNA damage, growth arrest is overcome by growth factors, and activated p53 and E2F1 cooperate to initiate apoptosis. We showed that E2F1 promotes apoptosis by up-regulating the proapoptotic cofactors of p53 and procaspases. It was also revealed that deregulated E2F1 by oncogene activation can make cells sensitive to DNA damage even in low serum medium. Our model consistently recapitulates the experimental observations of the intricate relationship between p53 and E2F1 in the DNA damage response. This work underscores the significance of E2F1 in p53-mediated cell fate decision and may provide clues to cancer therapy.

Propagation of the firing rate and synchronous firings in a 10-layer feed-forward neuronal network are studied. When neurons in layer 1 are subject to white noise, synchrony can be built up in deep layers and the firing rate can be propagated. A network with 6 layers is found to be enough for such behavior. A periodic signal with frequencies of 30–80 Hz can be selectively transmitted through the network. These abilities in information processing due to synchrony can be modulated by noise and the operating mode of neurons, and our results are relevant to experimental findings.

Both the hypoxia-inducible factor-1 (HIF-1) and tumor suppressor p53 are involved in the cellular response to hypoxia. How the two transcription factors interact to determine cell fates is less well understood. Here, we developed a network model to characterize crosstalk between the HIF-1 and p53 pathways, taking into account that HIF-1α and p53 are targeted for proteasomal degradation by Mdm2 and compete for binding to limiting co-activator p300. We reported the network dynamics under various hypoxic conditions and revealed how the stabilization and transcriptional activities of p53 and HIF-1α are modulated to determine the cell fate. We showed that both the transrepression and transactivation activities of p53 promote apoptosis induction. This work provides new insight into the mechanism for the cellular response to hypoxia.