Ontology highlight
ABSTRACT:
PROVIDER: PRJNA945397 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23875800.fastq.gz | Fastqsanger.gz | |||
| SRR23875801.fastq.gz | Fastqsanger.gz | |||
| SRR23875802.fastq.gz | Fastqsanger.gz | |||
| SRR23875803.fastq.gz | Fastqsanger.gz | |||
| SRR23875804.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Excessive amounts of Reactive Oxygen Species (ROS) lead to macromolecular damage and high levels of cell death and pathological sequelae. Switching cell death to a tissue regenerativestate can potentially improve short – and long-term consequences of ROS-associated acute tissueinjury. However, the mechanisms regulating oxidative stress-induced cell fate decision and their manipulation for improving repair remain poorly understood. Here, we show that cells exposed tohigh oxidative stress enter a PARP1-mediated regulated cell death, and that blocking PARP1activation promotes conversion of cell death into senescence (CODIS). We demonstrate that CODIS depends on reducing mitochondrial Ca2+ overload as a consequence of retaining thehexokinase HKII onto mitochondria. In a mouse model of kidney ischemia/reperfusion damage,PARP1 inhibition lowers necrosis and increases acute and transient senescence at the injury site,leading to improved recovery from damage. For the first time, we provide evidence that strategiesconverting cell death into acute senescence can therapeutically reduce the detriment of accidental tissue damage. _x000B_
2024-03-07 | GSE260758 | GEO
Project description:ABSTRACT Rationale Premature senescence is conducive to aging and cardiovascular diseases. Nrf2 transcription factor, the master orchestrator of adoptive response to cellular stress, has been implicated in regulation of premature senescence in fibroblasts, neural and mesenchymal stem cells by transactivation of antioxidant gene expression. However, as we show here, human primary endothelial cells (ECs) devoid of Nrf2 and murine Nrf2 transcriptional knockout (tKO) aortas are senescent but do not encounter oxidative stress and damage, what contradicts this mechanism. Moreover, a molecular switch between normal, senescent and apoptotic fate remains unknown. Objective To elucidate the mechanism of Nrf2-related premature senescence of vascular system, to understand why Nrf2 deregulation does not cause oxidative stress exclusionary in ECs and to indicate a molecular switch determining ECs fate. Methods and Results Herein we evidence that ECs deficient in Nrf2 protein, or with limited Nrf2 activity in shear stress conditions, exhibit excessive S-nitrosylation of proteins. It is also a characteristic of Nrf2 tKO murine aortas, as determined by biotin switch assay in situ. Mass spectrometry analysis reveals that NOX4 is S-nitrosylated exclusively in ECs devoid of Nrf2. A functional role of S-nitrosylation is protection of ECs from death by inhibition of NOX4-mediated oxidative damage. As a result Nrf2-deficient ECs preserve oxidative balance but are redirected to premature senescence. The same phenotype is seen in Nrf2 tKO aortas. These effects are mediated by Keap1, a direct binding partner of Nrf2 and repressor of its transcriptional activity, remaining in cytoplasm unrestrained by Nrf2. S-nitrosylation, followed by senescence, can also be triggered in smooth muscle cells (SMCs) by EC-derived paracrine induction of iNOS. Conclusions Collectively, Keap1-dependent S-nitrosylation of NOX4 hampers oxidative detriment in ECs with disturbed Nrf2 signaling and may provide defence in the adjacent aortic cells. Overabundance of unrestrained Keap1 in the cytoplasm determines fate of ECs.
2020-08-12 | PXD013640 | Pride
Project description:Cell death is a fundamental process for health and disease. Emerging research unveiled numerous distinct cell death modalities with similar and intertwined signaling pathways, but different outcomes, rising the need to understand the decision points during cell death signaling. Paracetamol (Acetaminophen, APAP)-induced hepatocyte death includes several apoptotic processes, but eventually ends as oncotic necrosis without any caspase activation. Here, we studied this paradoxical form of cell death and revealed that APAP not only fails to activate caspases, but also strongly impedes their activation upon classical apoptosis induction. We explored different hypotheses and deciphered that high oxidative stress consistently blocks caspase activity. Importantly, caspase inhibition and the associated switch from apoptotic to necrotic cell death is reversible through the administration of antioxidants. Thus, exemplified by APAP-induced cell death, our study stresses that the cellular redox status is a critical decision maker between different forms of cell death as it directly affects caspase activity.
2024-09-24 | PXD050155 | Pride
Project description:Exacerbating the DNA replication problem of cancer cells serves as a viable therapeutic approach. Nevertheless, the cytotoxicity of cancer drugs is often hampered by therapy-induced senescence, leading to unfavorable patient outcomes. Here, we employ acute replisome dysfunction in combination with ATR inhibition as a strategy to divert senescent cells toward death by triggering DNA replication catastrophe, a form of irreversible replication fork collapse caused by excessive single-stranded DNA (ssDNA) accumulation. RNA-sequencing revealed a distinct set of p53-responsive genes responsible for death. We identify c-Jun N-terminal kinase (JNK) to be essential for augmenting p53-dependent apoptotic programs and inducing pan-nuclear distribution of H2AX, together constituting a feed-forward loop to drive cell death. Activation of DNA-PKcs initiates the signaling cascade of replication catastrophe, including CHK1-dependent JNK activation, which relies on MRE11 and PARP1 to expand and recognize ssDNA gaps, defining replication-associated gaps as an underlying basis for replication catastrophe. Our study elucidates the dynamic regulation of proximal and distal effectors along the DNA-PKcs/JNK/p53 axis that govern the cell fate decision between senescence and death. We propose that key determinants of replication catastrophe signaling are targetable vulnerabilities that can be exploited to limit senescent cell populations and increase the efficacy of anti-cancer therapies.
2025-07-02 | GSE285638 | GEO
Project description:Cellular senescence is an irreversible growth arrest with a highly dynamic secretome, termed the senescence-associated secretory phenotype (SASP). Senescence has been implicated in somatic reprogramming to pluripotency. The cell-intrinsic proliferation arrest is a barrier for reprogramming, whereas the SASP facilitates the cell fate conversion in nonsenescent cells. However, the mechanisms by which reprogramming-induced senescence regulates cell plasticity are not well understood. Here, we have further investigated how the heterogeneity of paracrine senescence impacts reprogramming. We show that senescence promotes in vitro reprogramming in a stress-dependent manner. We identified a catalog of SASP factors and pathways potentially involved in the cell fate conversion using an unbiased proteomic analysis. Amphiregulin (AREG), a growth factor frequently secreted by the senescent cells, promotes in vitro reprogramming by accelerating proliferation and MET via the EGFR signaling pathway. Of note, AREG treatment diminished the negative effect of donor age on reprogramming. Finally, AREG enhances in vivo reprogramming in the skeletal muscle. Hence, senescence could facilitate cellular plasticity via various SASP factors to promote reprogramming and tissue repair.
2022-07-28 | PXD028590 | Pride
Project description:Cell competition regulates the fate decision of neural stem cells
| PRJNA925106 | ENA
Project description:A decision point between transdifferentiation and programmed cell death priming controls
| PRJNA1190954 | ENA
Project description:Kollarovic2016 - Cell fate decision at G1-S
transition
This model is described in the article:
To senesce or not to
senesce: how primary human fibroblasts decide their cell fate
after DNA damage.
Kollarovic G, Studencka M, Ivanova
L, Lauenstein C, Heinze K, Lapytsko A, Talemi SR, Figueiredo AS,
Schaber J.
Aging (Albany NY) 2016 Jan;
Abstract:
Excessive DNA damage can induce an irreversible cell cycle
arrest, called senescence, which is generally perceived as an
important tumour-suppressor mechanism. However, it is unclear
how cells decide whether to senesce or not after DNA damage. By
combining experimental data with a parameterized mathematical
model we elucidate this cell fate decision at the G1-S
transition. Our model provides a quantitative and conceptually
new understanding of how human fibroblasts decide whether DNA
damage is beyond repair and senesce. Model and data imply that
the G1-S transition is regulated by a bistable hysteresis
switch with respect to Cdk2 activity, which in turn is
controlled by the Cdk2/p21 ratio rather than cyclin abundance.
We experimentally confirm the resulting predictions that to
induce senescence i) in healthy cells both high initial and
elevated background DNA damage are necessary and sufficient,
and ii) in already damaged cells much lower additional DNA
damage is sufficient. Our study provides a mechanistic
explanation of a) how noise in protein abundances allows cells
to overcome the G1-S arrest even with substantial DNA damage,
potentially leading to neoplasia, and b) how accumulating DNA
damage with age increasingly sensitizes cells for
senescence.
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BIOMD0000000632.
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2024-09-02 | BIOMD0000000632 | BioModels
Project description:Bcl6 regulates CD8+ T cell fate decision in cancer [ChIP-Seq]
| PRJNA754302 | ENA
Project description:Bcl6 regulates CD8+ T cell fate decision in cancer [RNA-Seq]
| PRJNA754303 | ENA