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Wild type and tumor-derived mutant p53 share a non-canonical mode of gene occupancy [ChIP-seq]

ABSTRACT: To directly examine the interplay between mutant p53 or Mdm2 and wild type p53 in gene occupancy and expression, an integrated RNA-seq and ChIP-seq analysis was performed in vivo using isogenically matched mouse strains. Response to radiation was used as an endpoint to place findings in a biologically relevant context. Unexpectedly, mutant p53 and Mdm2 only inhibit a subset of wild type p53 gene expression. In contrast to a dominant-negative or inhibitory role, the presence of either mutant p53 or Mdm2 actually enhances the occupancy of wild type p53 on many canonical targets. The C-terminal 19 amino acids of wild type p53 suppresses the p53 response allowing for survival at sublethal doses of radiation. Further, the mutant 172H p53 is shown to occupy genes and regulate their expression via a non-canonical means that is shared with wild type p53. This results in the heterozygous 172H/+ genotype having an expanded transcriptome compared to wild type p53+/+.

ORGANISM(S): Mus musculus

PROVIDER: GSE281319 | GEO | 2025/01/04

REPOSITORIES: GEO

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Wild type and tumor-derived mutant p53 share a non-canonical mode of gene occupancy [RNA-seq]

Project description:To directly examine the interplay between mutant p53 or Mdm2 and wild type p53 in gene occupancy and expression, an integrated RNA-seq and ChIP-seq analysis was performed in vivo using isogenically matched mouse strains. Response to radiation was used as an endpoint to place findings in a biologically relevant context. Unexpectedly, mutant p53 and Mdm2 only inhibit a subset of wild type p53 gene expression. In contrast to a dominant-negative or inhibitory role, the presence of either mutant p53 or Mdm2 actually enhances the occupancy of wild type p53 on many canonical targets. The C-terminal 19 amino acids of wild type p53 suppresses the p53 response allowing for survival at sublethal doses of radiation. Further, the mutant 172H p53 is shown to occupy genes and regulate their expression via a non-canonical means that is shared with wild type p53. This results in the heterozygous 172H/+ genotype having an expanded transcriptome compared to wild type p53+/+.

2025-01-04 | GSE281318 | GEO

Wild type and tumor-derived mutant p53 share a non-canonical mode of gene occupancy [ChIP-seq]

Project description:Wild type and tumor-derived mutant p53 share a non-canonical mode of gene occupancy [ChIP-seq]

| PRJNA1183375 | ENA

Wild type and tumor-derived mutant p53 share a non-canonical mode of gene occupancy [RNA-seq]

Project description:Wild type and tumor-derived mutant p53 share a non-canonical mode of gene occupancy [RNA-seq]

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Acute and long-term effects of mutant p53 in vivo [Thymus]

Project description:The specific roles of mutant p53’s dominant-negative (DN) or gain-of-function (GOF) properties in regulating acute response and long-term tumorigenesis is unclear. Using “knock-in” mouse strains expressing varying R246S mutant levels, we show that DN effect on transactivation is universally observed after acute p53 activation whereas the effect on cellular outcome is cell-type specific. Reducing mutant p53 levels abrogated the DN effect. Mutant p53’s DN effect protected against radiation-induced death, but did not accentuate tumorigenesis. Furthermore, the R246S mutant did not promote tumorigenesis compared to p53-/- mice in various models, even in the absence of MDM2, unlike the R172H mutant. Together, these data demonstrate that mutant p53’s DN property only affects acute responses, whereas GOF is not universal, being mutation-type specific. Transcriptomes of 10 normal thymi harvested from 4-5 weeks old mice of different p53 and mdm2 genotype were profiled. Data was analysed by mixed model ANOVA using Partek.

2012-12-31 | E-GEOD-40414 | biostudies-arrayexpress

Acute and long-term effects of mutant p53 in vivo [MEF]

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Acute and long-term effects of mutant p53 in vivo [Thymus]

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Cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis

Project description:Although amplification/overexpression is the predominant mechanism for the oncogenic properties of MDM2, an increasing number of MDM2 somatic missense mutations were identified in cancer patients with the recent advances in sequencing technology. Here, we characterized an MDM2 cancer-associated mutant variant W329G identified from patient samples that contain a wild-type p53 gene. We found that the MDM2 W329G mutant was resistant to the inhibitory effect of ribosomal protein L11 (RPL11) on MDM2-mediated p53 ubiquitination and degradation, in line with its defect on RPL11 binding. Using isogenic U2OS cells with or without endogenous mdm2 W329G mutation, we demonstrated that the expression of classic p53 targets induced by ribosomal stress signals was reduced in mutant cells. RNA-seq analysis revealed that upon 5-FU treatment, the p53 response was significantly impaired. Also, the 5-FU-mediated repression of genes in cell cycle progression and DNA replication was diminished in W329G mutant-containing cells. Physiologically, U2OS W329G cells were more resistant to cell growth inhibition induced by ribosomal stress and exhibited higher glycolytic rates upon 5-FU treatment. Together, our data indicated that cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis.

2024-05-13 | GSE267150 | GEO

Genome-wide analysis of p53 transcriptional programs in B cells upon exposure to genotoxic stress in vivo [RNA-Seq]

Project description:The tumor suppressor p53 is a transcription factor that coordinates the cellular response to DNA damage. Here we provide an integrated analysis of p53 genomic occupancy and p53-dependent gene regulation in the splenic B and non-B cell compartments of mice exposed to whole-body ionizing radiation, providing insight into general principles of p53 activity in vivo. In unstressed conditions, p53 bound few genomic targets; induction of p53 by ionizing radiation increased the number of p53 bound sites, leading to highly overlapping profiles in the different cell types. Comparison of these profiles with chromatin features in unstressed B cells revealed that, upon activation, p53 localized at active promoters, distal enhancers, and a smaller set of unmarked distal regions. At promoters, recognition of the canonical p53 motif as well as binding strength were associated with p53-dependent transcriptional activation, but not repression, indicating that the latter was most likely indirect. p53-activated targets constituted the core of a cell type-independent response, superimposed onto a cell type-specific program. Core response genes included most of the known p53-regulated genes, as well as many new ones. Our data represent a unique characterization of the p53-regulated response to ionizing radiation in vivo. Total RNA profiling of gene expression in the splenic B and non-B cell compartments of wild-type and Trp53-/-mice exposed to whole-body ionizing radiation by Illumina sequencing

2015-08-24 | E-GEOD-71176 | biostudies-arrayexpress

Acute and long-term effects of mutant p53 in vivo [B cells]

Project description:The specific roles of mutant p53’s dominant-negative (DN) or gain-of-function (GOF) properties in regulating acute response and long-term tumorigenesis is unclear. Using “knock-in” mouse strains expressing varying R246S mutant levels, we show that DN effect on transactivation is universally observed after acute p53 activation whereas the effect on cellular outcome is cell-type specific. Reducing mutant p53 levels abrogated the DN effect. Mutant p53’s DN effect protected against radiation-induced death, but did not accentuate tumorigenesis. Furthermore, the R246S mutant did not promote tumorigenesis compared to p53-/- mice in various models, even in the absence of MDM2, unlike the R172H mutant. Together, these data demonstrate that mutant p53’s DN property only affects acute responses, whereas GOF is not universal, being mutation-type specific. Transcriptomes of 4 samples of normal B cells and 12 Myc-induced B lymphoma cells harvested from mice of different p53 genotypes were profiled. Data was analysed by mixed model ANOVA using Partek.

2012-12-31 | E-GEOD-40415 | biostudies-arrayexpress

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