Phosphorylation of p53 Serine 46 contributes to target gene selectivity of p53 (Exon)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE22184 | GEO | 2011/03/24
SECONDARY ACCESSION(S): PRJNA129187
REPOSITORIES: GEO
Similar Datasets
Project description:The tumor suppressor p53 plays a crucial role in cellular growth control inducing a plethora of cellular response pathways. The molecular mechanisms that discriminate between the distinct p53-responses towards different stress treatments have remained largely elusive. Here, we have analyzed the p53-regulated pathways induced by two chemotherapeutical treatments, Actinomycin D inducing growth arrest and Etoposide resulting in apoptosis. We found that the genome-wide p53-binding patterns are almost identical upon both treatments notwithstanding transcriptional differences that we observed in genome-wide transcriptome analysis. To assess the role of post-translational modifications in target gene choice and activation we investigated the extent of phosphorylation of Serine 46 of p53 bound to DNA (p53-pS46), a modification that has been linked to apoptosis-pathways, and the extent of phosphorylation of Serine 15 (p53-pS15), a general p53-activation mark. Interestingly, the overall extent of S46 phosphorylation of p53 bound to DNA is considerably higher in cells directed towards apoptosis while the degree of phosphorylation at S15 of DNA bound p53 remains highly similar upon both treatments. Moreover, our data suggest that, following different chemotherapeutical treatments, the extent of chromatin-associated p53 phosphorylated at S46 but not at pS15 is higher on certain apoptosis related target genes, including the BAX and PUMA genes. These data provide evidence that cell fate decisions are not made primarily on the level of general p53 DNA-binding, but possibly through post-translational modifications of chromatin bound p53. ChIP-seq profiles of p53, p53phosphorylated at Serine 15 (p53-pS15) and p53 phosphorylated at Serine 46 (p53-pS46) in U2OS cells treated with either Actinomycin D or Etoposide.
2011-03-24 | E-GEOD-21939 | biostudies-arrayexpress
Project description:The tumor suppressor p53 plays a crucial role in cellular growth control inducing a plethora of cellular response pathways. The molecular mechanisms that discriminate between the distinct p53-responses towards different stress treatments have remained largely elusive. Here, we have analyzed the p53-regulated pathways induced by two chemotherapeutical treatments, Actinomycin D inducing growth arrest and Etoposide resulting in apoptosis. We found that the genome-wide p53-binding patterns are almost identical upon both treatments notwithstanding transcriptional differences that we observed in genome-wide transcriptome analysis. To assess the role of post-translational modifications in target gene choice and activation we investigated the extent of phosphorylation of Serine 46 of p53 bound to DNA (p53-pS46), a modification that has been linked to apoptosis-pathways, and the extent of phosphorylation of Serine 15 (p53-pS15), a general p53-activation mark. Interestingly, the overall extent of S46 phosphorylation of p53 bound to DNA is considerably higher in cells directed towards apoptosis while the degree of phosphorylation at S15 of DNA bound p53 remains highly similar upon both treatments. Moreover, our data suggest that, following different chemotherapeutical treatments, the extent of chromatin-associated p53 phosphorylated at S46 but not at pS15 is higher on certain apoptosis related target genes, including the BAX and PUMA genes. These data provide evidence that cell fate decisions are not made primarily on the level of general p53 DNA-binding, but possibly through post-translational modifications of chromatin bound p53. Microarray analysis (Affymetrix Human Exon array) of the p53 response in U2OS cells treated with either Etoposide or Actinomycin D
2011-03-23 | E-GEOD-22184 | biostudies-arrayexpress
Project description:The tumor suppressor p53 plays a crucial role in cellular growth control inducing a plethora of cellular response pathways. The molecular mechanisms that discriminate between the distinct p53-responses towards different stress treatments have remained largely elusive. Here, we have analyzed the p53-regulated pathways induced by two chemotherapeutical treatments, Actinomycin D inducing growth arrest and Etoposide resulting in apoptosis. We found that the genome-wide p53-binding patterns are almost identical upon both treatments notwithstanding transcriptional differences that we observed in genome-wide transcriptome analysis. To assess the role of post-translational modifications in target gene choice and activation we investigated the extent of phosphorylation of Serine 46 of p53 bound to DNA (p53-pS46), a modification that has been linked to apoptosis-pathways, and the extent of phosphorylation of Serine 15 (p53-pS15), a general p53-activation mark. Interestingly, the overall extent of S46 phosphorylation of p53 bound to DNA is considerably higher in cells directed towards apoptosis while the degree of phosphorylation at S15 of DNA bound p53 remains highly similar upon both treatments. Moreover, our data suggest that, following different chemotherapeutical treatments, the extent of chromatin-associated p53 phosphorylated at S46 but not at pS15 is higher on certain apoptosis related target genes, including the BAX and PUMA genes. These data provide evidence that cell fate decisions are not made primarily on the level of general p53 DNA-binding, but possibly through post-translational modifications of chromatin bound p53.
2011-03-24 | GSE21939 | GEO
Project description:p53 is a critical tumor suppressor and works as a stress-induced transcription factor to induce target genes mediating apoptosis, cell cycle arrest and senescence or other responses. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. ChIP-sequencing reveals 4785 p53-bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA-sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Furthermore, we define a list of 1269 basal-p53 regulated genes, of which 253 are p53-bound and basal-p53 regulated. ChIP-seq was performed to determine the genome-wide p53 binding sites in doxorubicin-treated primary MEFs. RNA-seq was used to define differentially expressed genes in response to DNA damage in wild-type and p53-/- MEFs, and basal p53 regulated genes by deriving differentially expressed genes between untreated wild-type and p53-/- MEFs.
2013-04-21 | E-GEOD-46240 | biostudies-arrayexpress
Project description:p53 is a critical tumor suppressor and works as a stress-induced transcription factor to induce target genes mediating apoptosis, cell cycle arrest and senescence or other responses. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. ChIP-sequencing reveals 4785 p53-bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA-sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Furthermore, we define a list of 1269 basal-p53 regulated genes, of which 253 are p53-bound and basal-p53 regulated.
2013-04-21 | GSE46240 | 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:Proctor2008 - p53/Mdm2 circuit - p53 stabilisation by p14ARF
This model is described in the article:
Explaining oscillations and
variability in the p53-Mdm2 system.
Proctor CJ, Gray DA.
BMC Syst Biol 2008; 2: 75
Abstract:
BACKGROUND: In individual living cells p53 has been found to
be expressed in a series of discrete pulses after DNA damage.
Its negative regulator Mdm2 also demonstrates oscillatory
behaviour. Attempts have been made recently to explain this
behaviour by mathematical models but these have not addressed
explicit molecular mechanisms. We describe two stochastic
mechanistic models of the p53/Mdm2 circuit and show that
sustained oscillations result directly from the key biological
features, without assuming complicated mathematical functions
or requiring more than one feedback loop. Each model examines a
different mechanism for providing a negative feedback loop
which results in p53 activation after DNA damage. The first
model (ARF model) looks at the mechanism of p14ARF which
sequesters Mdm2 and leads to stabilisation of p53. The second
model (ATM model) examines the mechanism of ATM activation
which leads to phosphorylation of both p53 and Mdm2 and
increased degradation of Mdm2, which again results in p53
stabilisation. The models can readily be modified as further
information becomes available, and linked to other models of
cellular ageing. RESULTS: The ARF model is robust to changes in
its parameters and predicts undamped oscillations after DNA
damage so long as the signal persists. It also predicts that if
there is a gradual accumulation of DNA damage, such as may
occur in ageing, oscillations break out once a threshold level
of damage is acquired. The ATM model requires an additional
step for p53 synthesis for sustained oscillations to develop.
The ATM model shows much more variability in the oscillatory
behaviour and this variability is observed over a wide range of
parameter values. This may account for the large variability
seen in the experimental data which so far has examined ARF
negative cells. CONCLUSION: The models predict more regular
oscillations if ARF is present and suggest the need for further
experiments in ARF positive cells to test these predictions.
Our work illustrates the importance of systems biology
approaches to understanding the complex role of p53 in both
ageing and cancer.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000188.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
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.
2024-09-02 | BIOMD0000000189 | BioModels
Project description:Proctor2008 - p53/Mdm2 circuit - p53 stabilisation by ATM
This model is described in the article:
Explaining oscillations and
variability in the p53-Mdm2 system.
Proctor CJ, Gray DA.
BMC Syst Biol 2008; 2: 75
Abstract:
BACKGROUND: In individual living cells p53 has been found to
be expressed in a series of discrete pulses after DNA damage.
Its negative regulator Mdm2 also demonstrates oscillatory
behaviour. Attempts have been made recently to explain this
behaviour by mathematical models but these have not addressed
explicit molecular mechanisms. We describe two stochastic
mechanistic models of the p53/Mdm2 circuit and show that
sustained oscillations result directly from the key biological
features, without assuming complicated mathematical functions
or requiring more than one feedback loop. Each model examines a
different mechanism for providing a negative feedback loop
which results in p53 activation after DNA damage. The first
model (ARF model) looks at the mechanism of p14ARF which
sequesters Mdm2 and leads to stabilisation of p53. The second
model (ATM model) examines the mechanism of ATM activation
which leads to phosphorylation of both p53 and Mdm2 and
increased degradation of Mdm2, which again results in p53
stabilisation. The models can readily be modified as further
information becomes available, and linked to other models of
cellular ageing. RESULTS: The ARF model is robust to changes in
its parameters and predicts undamped oscillations after DNA
damage so long as the signal persists. It also predicts that if
there is a gradual accumulation of DNA damage, such as may
occur in ageing, oscillations break out once a threshold level
of damage is acquired. The ATM model requires an additional
step for p53 synthesis for sustained oscillations to develop.
The ATM model shows much more variability in the oscillatory
behaviour and this variability is observed over a wide range of
parameter values. This may account for the large variability
seen in the experimental data which so far has examined ARF
negative cells. CONCLUSION: The models predict more regular
oscillations if ARF is present and suggest the need for further
experiments in ARF positive cells to test these predictions.
Our work illustrates the importance of systems biology
approaches to understanding the complex role of p53 in both
ageing and cancer.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000188.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
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.
2024-09-02 | BIOMD0000000188 | BioModels
Project description:53BP1 is a well-established DNA damage repair factor that has recently been shown to regulate gene expression and critically influence tumor suppression and neural development. For gene regulation, how 53BP1 is regulated remains unclear. Here, we showed that 53BP1-serine 25 phosphorylation by ATM is required for neural progenitor cell proliferation and neuronal differentiation in cortical organoids. 53BP1-serine 25 phosphorylation dynamics controls 53BP1 target genes for neuronal differentiation and function, cellular response to stress, and apoptosis. Beyond 53BP1, ATM is required for phosphorylation of factors in neuronal differentiation, cytoskeleton, p53 regulation, and ATM, BNDF, and WNT signaling pathways for cortical organoid differentiation. Overall, our data suggest that 53BP1 and ATM control key genetic programs required for human cortical development.
2024-08-11 | GSE231321 | GEO
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