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Mechanisms that enhance sustainability of p53 pulses.

ABSTRACT: The tumor suppressor p53 protein shows various dynamic responses depending on the types and extent of cellular stresses. In particular, in response to DNA damage induced by γ-irradiation, cells generate a series of p53 pulses. Recent research has shown the importance of sustaining repeated p53 pulses for recovery from DNA damage. However, far too little attention has been paid to understanding how cells can sustain p53 pulses given the complexities of genetic heterogeneity and intrinsic noise. Here, we explore potential molecular mechanisms that enhance the sustainability of p53 pulses by developing a new mathematical model of the p53 regulatory system. This model can reproduce many experimental results that describe the dynamics of p53 pulses. By simulating the model both deterministically and stochastically, we found three potential mechanisms that improve the sustainability of p53 pulses: 1) the recently identified positive feedback loop between p53 and Rorα allows cells to sustain p53 pulses with high amplitude over a wide range of conditions, 2) intrinsic noise can often prevent the dampening of p53 pulses even after mutations, and 3) coupling of p53 pulses in neighboring cells via cytochrome-c significantly reduces the chance of failure in sustaining p53 pulses in the presence of heterogeneity among cells. Finally, in light of these results, we propose testable experiments that can reveal important mechanisms underlying p53 dynamics.

SUBMITTER: Kim JK

PROVIDER: S-EPMC3670918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cell fate decision mediated by p53 pulses.

Project description: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.

| S-EPMC2710988 | biostudies-literature

Pulses Twice a Week in Replacement of Meat Modestly Increases Diet Sustainability.

Project description:The French food-based dietary guidelines recommend eating pulses at least twice a week and to reduce meat consumption. This study assessed the impact on the sustainability characteristics (nutrition, cost, environment) of individual diets of meeting the pulse guideline. Dietary data of 2028 adults from the Esteban survey were completed with the nutritional content (considering bioavailability on iron, zinc and protein), price and environmental impacts of foods. When the pulse guideline (i.e., 57 g/day) was not met, two substitution scenarios raised the quantity of pulses to the recommended level, in replacement of an equivalent portion of (i) starches or (ii) meat. Only 9.6% of the participants reached the pulse guideline. Diet sustainability characteristics improved with the meat scenario (nutritional indicators improved; diet cost, greenhouse gas emissions and acidification decreased), while several indicators deteriorated with the starches scenario. Zinc available for absorption slightly decreased in both scenarios while iron available for absorption decreased in the meat scenario only. Increasing pulse consumption to two portions/week could modestly improve the sustainability of diets when pulses replace meat but not starches. Cultural acceptability of that substitution still needs to be proven, and iron and zinc status of individuals at risk of deficiency should be monitored.

| S-EPMC8466503 | biostudies-literature

Synergistic combinations of short high-voltage pulses and long low-voltage pulses enhance irreversible electroporation efficacy.

Project description:Irreversible electroporation (IRE) uses ~100 μs pulsed electric fields to disrupt cell membranes for solid tumor ablation. Although IRE has achieved exciting preliminary clinical results, implementing IRE could be challenging because of volumetric limitations at the ablation region. Combining short high-voltage (SHV: 1600V, 2 μs, 1 Hz, 20 pulses) pulses with long low-voltage (LLV: 240-480 V, 100 μs, 1 Hz, 60-80 pulses) pulses induces a synergistic effect that enhances IRE efficacy. Here, cell cytotoxicity and tissue ablation were investigated. The results show that combining SHV pulses with LLV pulses induced SKOV3 cell death more effectively, and compared to either SHV pulses or LLV pulses applied alone, the combination significantly enhanced the ablation region. Particularly, prolonging the lag time (100 s) between SHV and LLV pulses further reduced cell viability and enhanced the ablation area. However, the sequence of SHV and LLV pulses was important, and the LLV + SHV combination was not as effective as the SHV + LLV combination. We offer a hypothesis to explain the synergistic effect behind enhanced cell cytotoxicity and enlarged ablation area. This work shows that combining SHV pulses with LLV pulses could be used as a focal therapy and merits investigation in larger pre-clinical models and microscopic mechanisms.

| S-EPMC5680269 | biostudies-literature

Basal dynamics of p53 reveal transcriptionally attenuated pulses in cycling cells.

Project description:The tumor suppressor p53 is activated by stress and leads to cellular outcomes such as apoptosis and cell-cycle arrest. Its activation must be highly sensitive to ensure that cells react appropriately to damage. However, proliferating cells often encounter transient damage during normal growth, where cell-cycle arrest or apoptosis may be unfavorable. How does the p53 pathway achieve the right balance between high sensitivity and tolerance to intrinsic damage? Using quantitative time-lapse microscopy of individual human cells, we found that proliferating cells show spontaneous pulses of p53, which are triggered by an excitable mechanism during cell-cycle phases associated with intrinsic DNA damage. However, in the absence of sustained damage, posttranslational modifications keep p53 inactive, preventing it from inducing p21 expression and cell-cycle arrest. Our approach of quantifying basal dynamics in individual cells can now be used to study how other pathways in human cells achieve sensitivity in noisy environments.

| S-EPMC3003696 | biostudies-literature

Mechanisms That Generate Resource Pulses in a Fluctuating Wetland.

Project description:Animals living in patchy environments may depend on resource pulses to meet the high energetic demands of breeding. We developed two primary a priori hypotheses to examine relationships between three categories of wading bird prey biomass and covariates hypothesized to affect the concentration of aquatic fauna, a pulsed resource for breeding wading bird populations during the dry season. The fish concentration hypothesis proposed that local-scale processes concentrate wet-season fish biomass into patches in the dry season, whereas the fish production hypothesis states that the amount of dry-season fish biomass reflects fish biomass production during the preceding wet season. We sampled prey in drying pools at 405 sites throughout the Florida Everglades between December and May from 2006-2010 to test these hypotheses. The models that explained variation in dry-season fish biomass included water-level recession rate, wet-season biomass, microtopography, submerged vegetation, and the interaction between wet-season biomass and recession rate. Crayfish (Procambarus spp.) biomass was positively associated with wet-season crayfish biomass, moderate water depth, dense submerged aquatic vegetation, thin flocculent layer and a short interval of time since the last dry-down. Grass shrimp (Palaemonetes paludosus) biomass increased with increasing rates of water level recession, supporting our impression that shrimp, like fish, form seasonal concentrations. Strong support for wet-season fish and crayfish biomass in the top models confirmed the importance of wet-season standing stock to concentrations of fish and crayfish the following dry season. Additionally, the importance of recession rate and microtopography showed that local scale abiotic factors transformed fish production into the high quality foraging patches on which apex predators depended.

| S-EPMC4957811 | biostudies-literature

Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage.

Project description:DNA damage initiates a series of p53 pulses. Although much is known about the interactions surrounding p53, little is known about which interactions contribute to p53's dynamical behavior. The simplest explanation is that these pulses are oscillations intrinsic to the p53/Mdm2 negative feedback loop. Here we present evidence that this simple mechanism is insufficient to explain p53 pulses; we show that p53 pulses are externally driven by pulses in the upstream signaling kinases, ATM and Chk2, and that the negative feedback between p53 and ATM, via Wip1, is essential for maintaining the uniform shape of p53 pulses. We propose that p53 pulses result from repeated initiation by ATM, which is reactivated by persistent DNA damage. Our study emphasizes the importance of collecting quantitative dynamic information at high temporal resolution for understanding the regulation of signaling pathways and opens new ways to manipulate p53 pulses to ask questions about their function in response to DNA damage.

| S-EPMC2579769 | biostudies-literature

Modeling the role of p53 pulses in DNA damage- induced cell death decision.

Project description:BackgroundThe tumor suppressor p53 plays pivotal roles in tumorigenesis suppression. Although oscillations of p53 have been extensively studied, the mechanism of p53 pulses and their physiological roles in DNA damage response remain unclear.ResultsTo address these questions we presented an integrated model in which Ataxia-Telangiectasia Mutated (ATM) activation and p53 oscillation were incorporated with downstream apoptotic events, particularly the interplays between Bcl-2 family proteins. We first reproduced digital oscillation of p53 as the response of normal cells to DNA damage. Subsequent modeling in mutant cells showed that high basal DNA damage is a plausible cause for sustained p53 pulses observed in tumor cells. Further computational analyses indicated that p53-dependent PUMA accumulation and the PUMA-controlled Bax activation switch might play pivotal roles to count p53 pulses and thus decide the cell fate.ConclusionThe high levels of basal DNA damage are responsible for generating sustained pulses of p53 in the tumor cells. Meanwhile, the Bax activation switch can count p53 pulses through PUMA accumulation and transfer it into death signal. Our modeling provides a plausible mechanism about how cells generate and orchestrate p53 pulses to tip the balance between survival and death.

| S-EPMC2713228 | biostudies-literature

p53 pulses lead to distinct patterns of gene expression albeit similar DNA-binding dynamics.

Project description:The dynamics of transcription factors play important roles in a variety of biological systems. However, the mechanisms by which these dynamics are decoded into different transcriptional responses are not well understood. Here we focus on the dynamics of the tumor-suppressor protein p53, which exhibits a series of pulses in response to DNA damage. We performed time course RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) measurements to determine how p53 oscillations are linked with gene expression genome wide. We discovered multiple distinct patterns of gene expression in response to p53 pulses. Surprisingly, p53-binding dynamics were uniform across all genomic loci, even for genes that exhibited distinct mRNA dynamics. Using a mathematical model, supported by additional experimental measurements in response to sustained p53 input, we determined that p53 binds to and activates transcription of its target genes uniformly, whereas post-transcriptional mechanisms are responsible for the differences in gene expression dynamics.

| S-EPMC5629117 | biostudies-literature

p53 pulses lead to distinct patterns of gene expression albeit similar DNA-binding dynamics

Project description:Investigation of mechanism of gene regulation in response to pulses in p53 protein level induced by gamma irradiation. To directly connect p53 pulses with gene expression, we collected time-course ChIP-Seq and RNA-Seq data.

2017-08-21 | GSE100099 | GEO

Tumor-derived CK1? mutations enhance MDMX inhibition of p53.

Project description:Somatic missense mutations of the CSNK1A1 gene encoding casein kinase 1 alpha (CK1?) occur in a subset of myelodysplastic syndrome (MDS) with del(5q) karyotype. The chromosomal deletion causes CSNK1A1 haplo-insufficiency. CK1? mutations have also been observed in a variety of solid and hematopoietic tumors at low frequency. The functional consequence of CK1? mutation remains unknown. Here we show that tumor-associated CK1? mutations exclusively localize to the substrate-binding cleft. Functional analysis of recurrent mutants E98K and D140A revealed enhanced binding to the p53 inhibitor MDMX, increased ability to stimulate MDMX-p53 binding, and increased suppression of p21 expression. Furthermore, E98K and D140A mutants have reduced ability to promote phosphorylation of ?-catenin, resulting in enhanced Wnt signaling. The results suggest that the CK1? mutations observed in tumors cause gain-of-function in cooperating with MDMX and inhibiting p53, and partial loss-of-function in suppressing Wnt signaling. These functional changes may promote expansion of abnormal myeloid progenitors in del(5q) MDS, and in rare cases drive the progression of other tumors.

| S-EPMC7739390 | biostudies-literature

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