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Zhang2007 - Mechanism of DNA damage response (Model2)

ABSTRACT: Its a mechanistic model explaining the impact of p53 on apoptosis decision. This model represents schema 2 of manuscript.

SUBMITTER: Krishna Kumar Tiwari

PROVIDER: BIOMD0000001009 | BioModels | 2022-01-20

REPOSITORIES: BioModels

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Exploring mechanisms of the DNA-damage response: p53 pulses and their possible relevance to apoptosis.

Zhang Tongli T Brazhnik Paul P Tyson John J JJ

Cell cycle (Georgetown, Tex.) 20070112 1

The transcription factor p53 plays a central role in maintaining genomic integrity. Recent experiments in MCF7 cells have shown that p53 protein level rises and falls in distinct pulses in response to DNA damage. The amplitudes of and intervals between pulses seem to be independent of the extent of damage, and some cells generate regular pulses of p53 over many days. Identifying the molecular mechanisms responsible for such interesting behavior is an important and challenging problem. This paper ...[more]

PMID: 17245126

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Zhang2007 - Mechanism of DNA damage response (Model3)

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DAZAP2 controls cancer cell chemosensitivity by orchestrating the p53 response upon DNA damage

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Iwamoto2010 - Cell cycle reponse to DNA damage

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p53 pro-apoptotic activity is regulated by the G2/M promoting factor Cdk1 in response to DNA damage.

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p53 drives premature neuronal differentiation in response to acute DNA damage during early neurogenesis

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.

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High apoptotic threshold mediates p53 dependent decision between arrest and apoptosis

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

LncRNA LIMp27 regulates the DNA damage response through p27 in p53-defective cancer cells

Project description:P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.

| MSV000090292 | MassIVE

Homo sapiens

Project description:High apoptotic threshold mediates p53 dependent decision between arrest and apoptosis

| PRJNA144127 | ENA

The effect of Δ122p53, a Δ133p53α-like isoform, on global gene expression in response to DNA damage in mouse splenocytes

Project description:The p53 protein is a pivotal tumor suppressor that is frequently mutated in many human cancers, although precisely how p53 prevents tumors is still unclear. To add to its complexity several isoforms of human p53 have now been reported. The Δ133p53α isoform is generated from an alternative transcription initiation site in intron 4 of the p53 gene (TP53) and lacks the N-terminus. Elevated expression of Δ133p53α has been observed in a variety of tumors. To explore the functions of Δ133p53α, we created a mouse expressing an N-terminal deletion mutant of p53 (Δ122p53) that corresponds to Δ133p53α. Δ122p53 mice show decreased survival and a different and more aggressive tumor spectrum compared to p53 null mice, implying that Δ122p53 is a dominant oncogene. Consistent with this, Δ122p53 also confers a marked proliferative advantage on cells and reduced apoptosis. In addition to tumor development Δ122p53 mice show a profound pro-inflammatory phenotype having increased serum concentrations of interleukin (IL)-6 and other pro-inflammatory cytokines and lymphocyte aggregates in the lung and liver as well as other pathologies. Based on these observations, we propose that human Δ133p53α also functions to promote cell proliferation and inflammation, one or both of which contribute to tumor development. Total RNA was isolated from pooled splenocytes from four 5-6 week old mice with different p53 status (wild type, p53-/-, or Δ122p53) subjected to DNA damaging or control treatments.

2011-03-02 | E-GEOD-27586 | biostudies-arrayexpress

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