Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA144127 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:In response to stress, the p53 tumor suppressor induces arrest or apoptosis by transcriptionally regulating genes that mediate these processes. It has been proposed that the levels of p53 can influence the choice between these different outcomes, but the mechanisms involved are not clear. To gain mechanistic understanding of this p53-dependent cell fate decision, we generated a p53 inducible system that allowed tight regulation of p53 expression in human mammary epithelial cells. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Using microarray and chromatin immunoprecipitation analysis, we showed that low and high levels of p53 bind to and activate the same set of pro arrest and pro apoptotic target genes, induced to lower and higher levels, respectively. We propose that the cell fate decision between arrest and apoptosis in these cells is determined by a higher threshold required for p53 dependent apoptosis. We suggest that high level p53 activation is crucial in order to achieve maximum efficacy of p53 targeted cancer therapies.
2011-07-19 | E-GEOD-30753 | biostudies-arrayexpress
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).
2020-05-04 | BIOMD0000000943 | BioModels
Project description:Barr2017 - Dynamics of p21 in hTert-RPE1
cells
This deteministic model reveals that a
bistable switch created by Cdt2, promotes irreversible S-phase
entry by keeping p21 levels low, prevents premature S-phase exit
upon DNA damage
This model is described in the article:
DNA damage during S-phase
mediates the proliferation-quiescence decision in the
subsequent G1 via p21 expression.
Barr AR, Cooper S, Heldt FS, Butera
F, Stoy H, Mansfeld J, Novák B, Bakal C.
Nat Commun 2017 Mar; 8: 14728
Abstract:
Following DNA damage caused by exogenous sources, such as
ionizing radiation, the tumour suppressor p53 mediates cell
cycle arrest via expression of the CDK inhibitor, p21. However,
the role of p21 in maintaining genomic stability in the absence
of exogenous DNA-damaging agents is unclear. Here, using live
single-cell measurements of p21 protein in proliferating
cultures, we show that naturally occurring DNA damage incurred
over S-phase causes p53-dependent accumulation of p21 during
mother G2- and daughter G1-phases. High p21 levels mediate G1
arrest via CDK inhibition, yet lower levels have no impact on
G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2
couple to degrade p21 prior to the G1/S transition.
Mathematical modelling reveals that a bistable switch, created
by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21
levels low, preventing premature S-phase exit upon DNA damage.
Thus, we characterize how p21 regulates the
proliferation-quiescence decision to maintain genomic
stability.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000660.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2016-06-09 | BIOMD0000000660 | BioModels
Project description:In response to stress, the p53 tumor suppressor induces arrest or apoptosis by transcriptionally regulating genes that mediate these processes. It has been proposed that the levels of p53 can influence the choice between these different outcomes, but the mechanisms involved are not clear. To gain mechanistic understanding of this p53-dependent cell fate decision, we generated a p53 inducible system that allowed tight regulation of p53 expression in human mammary epithelial cells. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process.
2011-07-20 | GSE30753 | GEO
Project description:Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53.
| PRJNA257888 | ENA
Project description:The decision of metazoan cells to live or undergo programmed cell death hinges on the balance between the levels of pro- versus anti-apoptotic gene products. The general RNA polymerase II (Pol II) transcription factor, TFIID, plays a central role in the regulation of gene expression through its core promoter recognition and co-activator functions. The core TFIID subunit TAF6 is a co-activator for the pro-apoptotic p53 tumour suppressor protein. Our previous studies identified a specialized isoform of TAF6, termed TAF6 that can specifically be induced in apoptosis. To elucidate the impact of TAF6 on gene expression and cell death, we employed modified antisense oligonucleotides to enforce expression of endogenous TAF6. The induction of endogenous TAF6 triggered apoptosis in several cancer cell lines. Importantly, TAF6 also induces apoptosis in tumor cell lines devoid of p53, placing TAF6 function downstream of p53. Microarray experiments uncovered a TAF6-induced transcriptome landscape displaying enhanced expression of genes of the Notch, oxidative stress, integrin, p53 and apoptosis pathways. Our data show that the TAF6 pathway is a pivotal signalling nexus that controls pro-apoptotic gene expression programs. Keywords: Treatment with splice site switching antisense oligonucleotides, induction of apoptosis Biological triplicates, 3 conditions: control oligonucleotide, Taf6 oligonucleotide, specificity control Bcl-x oligonucleotide
2010-11-27 | E-GEOD-8752 | biostudies-arrayexpress
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.
2020-04-27 | BIOMD0000000939 | BioModels
Project description:A better understanding of how p53 differentially activates cell cycle arrest or cell death is important to maximize benefits of therapeutic strategies dependant by wild-type p53. Here, we report that activation of pro-apoptotic p53 transcriptional targets in colorectal cancer cells imposes a critical, targetable dependence on the long splice form of the caspase-8 regulator FLIP (FLIPL) for survival. Upon Nutlin-3A induced stabilisation p53 directly upregulates FLIPL expression in a manner dependent on Class-I HDAC activity. Preventing FLIPL upregulation with the clinically relevant Class-I selective inhibitor Entinostat promotes apoptosis in response to Nutlin-3A , which predominantly induces growth arrest despite upregulating a range of pro-apoptotic target genes. Cell death in response to Nutlin-3A in FLIPL-depleted cells is mediated through two of p53's canonical transcriptional targets TRAIL-R2 and BAX and is caspase-8-dependent. This work uncovers novel, clinically relevant biology that identifies FLIPL as a key target for overcoming resistance to p53-activating agents.
2020-04-25 | GSE113682 | GEO
Project description:The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53- dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II binding protein Che-1/AATF transcriptionally activates p53. Here, we show that Che-1 binds directly p53. This interaction essentially occurs in the first hours of DNA damage, whereas it is lost when cells undergo to apoptosis in response to post-transcriptional modifications. Moreover, Che-1 sits in a ternary complex with p53 and the oncosuppressor Brca1. Accordingly, our analysis of genome-wide chromatin occupancy by p53 revealed that p53/Che1 interaction results in preferential transactivation of growth-arrest p53 target genes over its pro-apoptotic target genes. Notably, exposure of Che-1+/- mice to ionizing radiations resulted in enhanced apoptosis of thymocytes, compared to wild-type mice. These results confirm Che-1 as an important regulator of p53 activity and suggest Che-1 to be a promising yet attractive drug target for cancer therapy.
2015-06-01 | GSE60267 | GEO
Project description:The decision of metazoan cells to live or undergo programmed cell death hinges on the balance between the levels of pro- versus anti-apoptotic gene products. The general RNA polymerase II (Pol II) transcription factor, TFIID, plays a central role in the regulation of gene expression through its core promoter recognition and co-activator functions. The core TFIID subunit TAF6 is a co-activator for the pro-apoptotic p53 tumour suppressor protein. Our previous studies identified a specialized isoform of TAF6, termed TAF6 that can specifically be induced in apoptosis. To elucidate the impact of TAF6 on gene expression and cell death, we employed modified antisense oligonucleotides to enforce expression of endogenous TAF6. The induction of endogenous TAF6 triggered apoptosis in several cancer cell lines. Importantly, TAF6 also induces apoptosis in tumor cell lines devoid of p53, placing TAF6 function downstream of p53. Microarray experiments uncovered a TAF6-induced transcriptome landscape displaying enhanced expression of genes of the Notch, oxidative stress, integrin, p53 and apoptosis pathways. Our data show that the TAF6 pathway is a pivotal signalling nexus that controls pro-apoptotic gene expression programs. Keywords: Treatment with splice site switching antisense oligonucleotides, induction of apoptosis
2010-11-27 | GSE8752 | GEO