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Both hypoxia-inducible factor-1 (HIF-1) and tumor suppressor p53 are involved in the cellular response to hypoxia. It has been reported that HIF-1α induces cockayne syndrome B (CSB) to compete with p53 for limited p300. We developed a network model to clarify how the interplay between HIF-1 and p53 modulates cellular output in the presence of CSB. Our results revealed that HIF-1α is progressively activated depending on the severity of hypoxia. Activated HIF-1α promotes its own activation by inducing CSB to dissociate p300 from p53 under moderate hypoxia; in severe hypoxia, p53 accumulates remarkably due to ATR-dependent phosphorylation and wins the competition for p300. As a result, HIF-1α induces PFKL and VEGF to facilitate cellular adaptation to mild and moderate hypoxia respectively, while p53 is activated to induce apoptosis under severe hypoxia. This work may advance the understanding of the modulation of the interplay between HIF-1 and p53 in the hypoxic response.

MicroRNAs are key regulators of gene expression at the posttranscriptional level. In this study, we focus on miR-605 and miR-34a, which are direct transcriptional targets of p53 and in turn enhance its tumor suppressor function by acting upstream and downstream of it, respectively. miR-605 promotes p53 activation by repressing the expression of mdm2, whereas miR-34a promotes p53-dependent apoptosis by suppressing the expression of antiapoptotic genes such as bcl-2. What roles they play in the p53-mediated DNA damage response is less well understood. Here, we develop a four-module model of the p53 network to investigate the effect of miR-605 and miR-34a on the cell-fate decision after ionizing radiation. Results of numerical simulation indicate that the cell fate is closely associated with network dynamics. The concentration of p53 undergoes few pulses in response to repairable DNA damage, or it first oscillates and then switches to high plateau levels after irreparable damage. The amplitude of p53 pulses rises to various extents depending on miR-605 expression, and miR-605 accelerates the switching behavior of p53 levels to induce apoptosis. In parallel, miR-34a promotes apoptosis by enhancing the accumulation of free p53AIP1, a key proapoptotic protein. Thus, both miR-605 and miR-34a can mediate cellular outcomes and the timing of apoptosis. Moreover, miR-605 and PTEN complement each other in elevating p53 levels to trigger apoptosis. Taken together, miR-605 and miR-34a cooperate to endow the network with a fail-safe mechanism for apoptosis induction. This computational study also enriches our understanding of the action modes of p53-targeted microRNAs., (Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

The tumor suppressor p53 has a crucial role in the DNA damage response. Here, we proposed an integrated model of the p53 network and explored how the nuclear and mitochondrial p53 pathways are coordinated to determine cell fates after [Formula: see text]-irradiation in radiosensitive tissues. Using numerical simulations, we found that depending on the extent of DNA damage, cells may survive, commit apoptosis after cell cycle arrest, or undergo apoptosis soon after irradiation. There exists a large cell-to-cell variability in outcome because of stochasticity in the generation and repair of DNA damage as well as cellular heterogeneity. At the cell population level, there occur two waves of apoptosis: a fast wave mediated by mitochondrial p53 within three hours postirradiation, and a slow wave mediated by nuclear p53 after eight hours postirradiation. Thus, we propose a two-step mechanism for cell fate decision. The first step is to decide whether DNA damage is severe enough to trigger apoptosis directly through the mitochondrial p53 pathway, while the second step is to determine whether the damage is fixed after cell cycle arrest. Such a mechanism may represent an efficient and reliable control mode, avoiding unnecessary death or greatly promoting the execution of apoptosis. It was also demonstrated that nuclear p53 can inhibit the pro-apoptotic activity of mitochondrial p53 by transactivating p21, and Mdm2 can facilitate apoptosis by promoting the mono-ubiquitination of p53. These results are either in good agreement with experimental observations or experimentally testable. Our work suggests that both the transcription-independent and -dependent p53 activities are indispensable for a reliable choice of cell fate and also provides clues to therapeutic manipulation of the p53 pathway in cancer treatment.

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.

Recurrence and progression are the major problems in the treatment of bladder cancer. Increased expression of Id-1, a basic helix-loop-helix transcription factor, has recently been shown in several types of advanced cancer. Some studies have provided evidence to suggest that Id-1 can be considered a potential therapeutic target. The objective of this study was to investigate the role of Id-1 in the chemosensitivity of bladder cancer cells, and the effect of Id-1 on chemotherapeutic drug-induced apoptosis in bladder cancer cells. We compared the different sensitivity to epirubicin in RT112 and MGH-U1 cell lines with different Id-1 expression. Then, we transfected different vectors into RT112 and MGH-U1 respectively, and generated the stable Id-1 up-regulation and down-regulation transfectants. The results of cell viability assay showed up-regulation of Id-1 in RT112 leading to increased sensitivity in response to epirubicin, and down-regulation of Id-1 increased cellular sensitivity to epirubicin. Furthermore, the analysis of apoptosis related protein revealed that up-regulation of Id-1 suppressed epirubicin-induced apoptosis and down-regulation of Id-1 leading to increased epirubicin-induced apoptosis. Wound closure assay showed up-regulation of Id-1 leading to improved migration abilities of bladder cancer cells under chemotherapy. Our results suggest that up-regulation of Id-1 in bladder cancer cells lead to increased cell viability in response to epirubicin by its improved anti-apoptotic role, and down-regulation of Id-1 increases cellular sensitivity to epirubicin by increased anticancer drug-induced apoptosis.

The acetylation of p53 plays an essential role in regulating its transcriptional activity. Nevertheless, how p53 acetylation is modulated in cell fate decision is less understood. We developed a network model to reveal how Tip60‐dependent p53 acetylation is regulated to modulate cellular outcome. We proposed that p53 is progressively activated and exhibits distinct dynamics depending on the severity of DNA damage. For mild damage, p53 is primarily activated to trigger cell cycle arrest by transactivating p21, with its concentration showing pulses. For severe damage, p53 is acetylated at Lysine 120 (K120) by Tip60 to trigger apoptosis by inducing PUMA, and its concentration increases to high levels. Several p53‐centered feedback loops coordinate to regulate its acetylation status, ensuring a robust decision on cell fate. [ABSTRACT FROM AUTHOR]

p53-targeted microRNAs (miRNAs) markedly affect cellular response to DNA damage. These miRNAs may contribute to either cell cycle arrest or apoptosis induction. However, how these miRNAs coordinate to modulate the decision between cell survival and death remains less understood. Here, we developed an integrated model of p53 signaling network to investigate how p53-targeted miR-192 and miR-22 modulate cellular outcome in response to DNA damage. By numerical simulations, we found that p53 is activated progressively depending on the extent of DNA damage. Upon moderate damage, p53 rises to medium levels and induces miR-192 to promote its own activation, facilitating p21 induction and cell cycle arrest. Upon severe damage, p53 reaches high levels and is fully activated due to phosphatase and tensin homolog (PTEN) induction. As a result, it transactivates miR-22 to repress p21 expression and activate E2F1, resulting in apoptosis. Therefore, miR-192 promotes primary activation of p53, while miR-22 promotes apoptosis by downregulating p21. This work may advance the understanding of the mechanism for cell fate decision between life and death by p53-inducible miRNAs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]