Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1082660 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28178889.fastq.gz | Fastqsanger.gz | |||
| SRR28178890.fastq.gz | Fastqsanger.gz | |||
| SRR28178891.fastq.gz | Fastqsanger.gz | |||
| SRR28178892.fastq.gz | Fastqsanger.gz | |||
| SRR28178893.fastq.gz | Fastqsanger.gz |
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Project description:After DNA damage, cells activate p53, a tumor suppressor gene, and select a cell fate (e.g., DNA repair, cell cycle arrest, or apoptosis). Recently, a p53 oscillatory behavior was observed following DNA damage. However, the relationship between this p53 oscillation and cell-fate selection is unclear. Here, we present a novel model of the DNA damage signaling pathway that includes p53 and whole cell cycle regulation and explore the relationship between p53 oscillation and cell fate selection. The simulation run without DNA damage qualitatively realized experimentally observed data from several cell cycle regulators, indicating that our model was biologically appropriate. Moreover, the comprehensive sensitivity analysis for the proposed model was implemented by changing the values of all kinetic parameters, which revealed that the cell cycle regulation system based on the proposed model has robustness on a fluctuation of reaction rate in each process. Simulations run with four different intensities of DNA damage, i.e. Low-damage, Medium-damage, High-damage, and Excess-damage, realized cell cycle arrest in all cases. Low-damage, Medium-damage, High-damage, and Excess-damage corresponded to the DNA damage caused by 100, 200, 400, and 800 J/m(2) doses of UV-irradiation, respectively, based on expression of p21, which plays a crucial role in cell cycle arrest. In simulations run with High-damage and Excess-damage, the length of the cell cycle arrest was shortened despite the severe DNA damage, and p53 began to oscillate. Cells initiated apoptosis and were killed at 400 and 800 J/m(2) doses of UV-irradiation, corresponding to High-damage and Excess-damage, respectively. Therefore, our model indicated that the oscillatory mode of p53 profoundly affects cell fate selection.
2024-09-02 | BIOMD0000000939 | BioModels
Project description:Quiescent hematopoietic stem cells (HSCs) are prone to mutagenesis, and accumulation of mutations can result in hematological malignancies. The mechanisms through which HSCs prevent such detrimental accumulation, however, are unclear. Here, we show that Aspp1 coordinates with p53 to maintain the genomic integrity of the HSC pool. Aspp1 is preferentially expressed in HSCs and restricts HSC pool size by attenuating self-renewal under steady state conditions. After genotoxic stress, Aspp1 promotes HSC cycling and induces p53-dependent apoptosis in cells with persistent DNA damage foci. Beyond these p53-dependent functions, Aspp1 attenuates HSC self-renewal and accumulation of DNA damage in p53-null HSCs. Consequently, concomitant loss of Aspp1 and p53 leads to the development of hematological malignancies, especially T-cell leukemia and lymphoma. Together, these data highlights coordination between Aspp1 and p53 in regulating HSC self-renewal and DNA damage tolerance, and suggest that HSCs possess specific mechanisms that prevent accumulation of mutations and malignant transformation. 8-week-old WT, Aspp1-/-, Mx1-Cre(+)p53flox/flox and Mx1-Cre(+)Aspp1-/-p53flox/flox mice were intraperitoneally administered with 400 μg pIpC five times every other day to obtain WT, Aspp1-/-, p53-/- and Aspp1-/-p53-/- bone marrow. 4 weeks after pIpC treatment, bone marrow lineage(-) Sca-1(+) cKit(+) cells were isolated. RNA was extracted and pooled from 3 independent mice per genotype. RNA samples were then amplified, labeled, and hybridized to independent arrays.
2015-05-20 | E-GEOD-69032 | biostudies-arrayexpress
Project description:Quiescent hematopoietic stem cells (HSCs) are prone to mutagenesis, and accumulation of mutations can result in hematological malignancies. The mechanisms through which HSCs prevent such detrimental accumulation, however, are unclear. Here, we show that Aspp1 coordinates with p53 to maintain the genomic integrity of the HSC pool. Aspp1 is preferentially expressed in HSCs and restricts HSC pool size by attenuating self-renewal under steady state conditions. After genotoxic stress, Aspp1 promotes HSC cycling and induces p53-dependent apoptosis in cells with persistent DNA damage foci. Beyond these p53-dependent functions, Aspp1 attenuates HSC self-renewal and accumulation of DNA damage in p53-null HSCs. Consequently, concomitant loss of Aspp1 and p53 leads to the development of hematological malignancies, especially T-cell leukemia and lymphoma. Together, these data highlights coordination between Aspp1 and p53 in regulating HSC self-renewal and DNA damage tolerance, and suggest that HSCs possess specific mechanisms that prevent accumulation of mutations and malignant transformation.
2015-05-20 | GSE69032 | GEO
Project description:Ewing's sarcoma (ES) is the second most frequent bone cancer during childhood and adolescence originating from a translocation between the EWSR1 and the FLI1 gene, which inactivates BRCA-mediated DNA damage response. Both ATR and HSP90 inhibitors are promising new candidates in the field of ES treatment. We show that the HSP90 inhibitor AUY922 alone induced DNA damages, apoptosis and ER stress, while reducing the abundance of DNA repair proteins. The combinations of the ATR inhibitor VE821 and AUY922 (AUY-VE) led to strong apoptosis induction in ES cell lines, originating from a common set of molecular targets and independent of their p53 status, yet based on different molecular mechanisms. P53 wild-type ES cells activated pro-apoptotic gene transcription and underwent mitochondria-mediated apoptosis. P53 null ES cells, however, accumulated higher level of DNA damage, ER stress and autophagy, finally leading to apoptosis. Moreover, AUY-VE treatment compromised ES cell vitality due to impaired PI3K/AKT/mTOR signaling. Unexpectedly, the combinations of AUY922 with the ATM inhibitor, KU55933 failed to kill ES cells and showed protective effects compared to AUY-VE. In summary, we provide mechanistic insights into the effective ES cell killing by ATR and HSP90 inhibitor combinations, which also offers a targetable approach for BRCA-deficient tumors, irrespective of their p53 status and may give rise to new therapeutic strategies.
2021-09-09 | PXD021562 | Pride
Project description:p53, master transcriptional regulator of the genotoxic stress response, controls cell cycle arrest and apoptosis following DNA damage. Here we identify a p53-induced lncRNA SPARCLE (Suicidal PARP-1 Cleavage Enhancer) adjacent to miR-34b/c required for p53-mediated apoptosis. SPARCLE is a ~770 nucleotide, nuclear lncRNA induced one day after DNA damage. Despite low expression (<15 copies/cell), SPARCLE deletion increases DNA repair and reduces DNA damage-induced apoptosis as much as p53 deficiency, while its over-expression restores apoptosis in p53-deficient cells. SPARCLE does not alter gene expression. SPARCLE causes apoptosis by acting as a caspase-3 cofactor for PARP-1 cleavage, which separates its N-terminal (NT) DNA binding domain from PARP-1 catalytic domains. NT-PARP-1 binds to DNA breaks but, lacking its PARylation domains, does not initiate DNA repair. In fact, expressing NT-PARP-1 in SPARCLE-deficient cells increases unrepaired DNA damage and restores apoptosis after DNA damage. Thus, as a PARP-1 cleavage cofactor, SPARCLE enhances p53-induced apoptosis.
2022-02-01 | GSE144510 | GEO
Project description:Advanced colorectal cancer (CRC) is an unresolved clinical problem. Epigenetic drugs belonging to the group of histone deacetylase inhibitors (HDACi) may combat CRC in rationally designed treatment schedules. Unfortunately, there is sparse evidence on molecular mechanisms and markers that determine cellular sensitivity to HDACi. Irinotecan is widely used to treat CRC and causes replication stress (RS) and DNA damage as topoisomerase-I inhibitor. We applied irinotecan and the class I HDACi entinostat (MS-275) to isogenic p53-positive and -negative CRC cells. Combinations of irinotecan and MS-275 evoke mitochondrial damage, caspase-mediated apoptosis, and RS-associated DNA damage synergistically and p53-dependently. Targeted mass spectrometry and immunoblot show that irinotecan induces phosphorylation, acetylation, and accumulation of p53 and its target genes. Addition of MS-275 augments the irinotecan-induced acetylation of C-terminal lysine residues of p53 but decreases its phosphorylation and p53 target gene induction. Furthermore, MS-275 increases the amount of acetylated p53 at mitochondria and dysregulates the expression of pro- and anti-apoptotic BCL2 proteins in irinotecan-treated cells. Regarding DNA repair, we see that MS-275 represses the homologous recombination (HR) filament protein RAD51, which limits DNA damage and pro-apoptotic effects of irinotecan. These data suggest that key class I HDAC-dependent functions of p53 in cells with RS are linked to mitochondrial damage and a breakdown of HR. Most importantly, combinations of irinotecan plus MS-275 also kill short-term primary CRC cell cultures and organoids from CRC patients but spare organoids of adjacent matched normal tissue. Thus, irinotecan/HDACi treatment is a promising new approach for the therapy of p53-proficient tumors with clinically tractable inhibitors.
2022-02-15 | PXD019999 | Pride
Project description:Purpose: The transcription factor p53 classically regulates the cellular response to DNA damage. Inappropriate activation of p53 during embryonic development can lead to a range of developmental defects such as microcephaly. Here, we studied the cellular and molecular mechanisms underlying microcephaly induced by acute irradiation of mouse fetuses at the onset of neurogenesis. This leads to transient DNA damage followed by apoptosis and premature neuronal differentiation, both of which are p53-dependent as they are reduced in dorsal forebrain-specific Trp53 knockout mice. A functional genomics screen shows that radiation induces the p53-dependent activation of both apoptosis- and differentiation-associated genes. Irradiation furthermore induces an epithelial-to-mesenchymal transition-like process characterized by a reduction of epithelial markers and a disruption of the apical adherens junction belt. Altogether, we have identified a novel function of p53 as an activator of neuronal differentiation in response to acute embryonic DNA damage further demonstrating its importance as a regulator of cell fate. Methods: Pregnant mouse dams were (sham-)irradiated at gestational day 11 after which they were sacrificed for dissection of fetuses after 2 h, 6 h and 12 h. Cerebral cortices were removed for transcriptomic analysis via RNA-seq.
2023-03-31 | GSE140464 | GEO
Project description:Integrated-systems model of oxidative stress connecting NRF2 and p53 signaling pathways. Additional crosstalk linking oxidative stress to p53 inhibition, p53 to NRF2 through p21, and NRF2 to MDM2 was incorporated in this model. The NRF2 pathway was encoded as first- and second-order rate equations for KEAP1 oxidation and NRF2 stabilization; NRF2-mediated transcription of antioxidant enzymes was modeled as a Hill function. The p53 pathway was reconstructed from a delay differential equation model of p53 signaling in response to DNA damage. To adapt the p53 DNA-damage model to respond to oxidative stress, we used a first-order oxidation reaction of ATM/CHEK2 by intracellular H2O2.
The integrated base model of NRF2–p53 oxidative-stress signaling contains 42 reactions and 22 ordinary differential equations (ODEs).
2021-10-29 | MODEL2110270001 | BioModels
Project description:This a model from the article:
Stress-specific response of the p53-Mdm2 feedback loop
Alexander Hunziker, Mogens H Jensen and Sandeep Krishna
BMC Systems Biology 2010, Jul 12;4(1):94
20624280,
Abstract:
ABSTRACT: BACKGROUND: The p53 signalling pathway has hundreds of inputs and outputs. It can trigger cellular senescence, cell-cycle arrest and apoptosis in response to diverse stress conditions, including DNA damage, hypoxia and nutrient deprivation. Signals from all these inputs are channeled through a single node, the transcription factor p53. Yet, the pathway is flexible enough to produce different downstream gene expression patterns in response to different stresses. RESULTS: We construct a mathematical model of the negative feedback loop involving p53 and its inhibitor, Mdm2, at the core of this pathway, and use it to examine the effect of different stresses that trigger p53. In response to DNA damage, hypoxia, etc., the model exhibits a wide variety of specific output behaviour -- steady states with low or high levels of p53 and Mdm2, as well as spiky oscillations with low or high average p53 levels. CONCLUSIONS: We show that even a simple negative feedback loop is capable of exhibiting the kind of flexible stress-specific response observed in the p53 system. Further, our model provides a framework for predicting the differences in p53 response to different stresses and single nucleotide polymorphisms.
The parameters of the model corresponds to the resting state, with delta = 11hr-1, gamma = 0.2hr-1, kt = 0.03nM-1hr-1 and kf = 5000nM-1hr-1.
To simulate different stress conditions as in figure 2A (also look at the curation figure of this model) of the reference publication, the above parameter should be changed. The parameter values corresponding to different stress conditions are shown in the following table.
Stress Condition/Parameter
delta
gamma
kt
kf
Nutlin
11hr-1
0.2hr-1
0.03nM-1hr-1
500nM-1hr-1
Oncogene
2hr-1
0.2hr-1
0.03nM-1hr-1
5000nM-1hr-1
DNA damage
2hr-1
0.5hr-1
0.03nM-1hr-1
2500nM-1hr-1
Hypoxia
2hr-1
0.2hr-1
0.01nM-1hr-1
5000nM-1hr-1
This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2011 The BioModels.net Team.For more information see the terms of use.To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000252 | BioModels
Project description:The p53 transcription factor is a regulator of key cellular processes including DNA repair, cell cycle arrest, and apoptosis. In this theoretical study, we investigate how the complex circuitry of the p53 network allows for stochastic yet unambiguous cell fate decision-making. The proposed Markov chain model consists of the regulatory core and two subordinated bistable modules responsible for cell cycle arrest and apoptosis. The regulatory core is controlled by two negative feedback loops (regulated by Mdm2 and Wip1) responsible for oscillations, and two antagonistic positive feedback loops (regulated by phosphatases Wip1 and PTEN) responsible for bistability. By means of bifurcation analysis of the deterministic approximation we capture the recurrent solutions (i.e., steady states and limit cycles) that delineate temporal responses of the stochastic system. Direct switching from the limit-cycle oscillations to the "apoptotic" steady state is enabled by the existence of a subcritical Neimark-Sacker bifurcation in which the limit cycle loses its stability by merging with an unstable invariant torus. Our analysis provides an explanation why cancer cell lines known to have vastly diverse expression levels of Wip1 and PTEN exhibit a broad spectrum of responses to DNA damage: from a fast transition to a high level of p53 killer (a p53 phosphoform which promotes commitment to apoptosis) in cells characterized by high PTEN and low Wip1 levels to long-lasting p53 level oscillations in cells having PTEN promoter methylated (as in, e.g., MCF-7 cell line).
2024-09-02 | BIOMD0000000943 | BioModels