The DNA binding selectivity by wild-type p53 and PANDAs
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ABSTRACT:
PROVIDER: PRJNA801502 | ENA |
REPOSITORIES: ENA
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Project description:We performed ChIP-seq analysis of p53-null HCT116 cells stably expressed wild-type p53 or mutant p53 followed by ATO treatment (PANDAs) to identify p53 binding characteristics by wild-type p53 and PANDAs.
2024-01-31 | GSE195622 | GEO
Project description:Our RNA-seq data suggested the different transcriptional profiles of wild-type p53 and PANDAs treated with or without ATO.
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Project description:Transcriptome-wide expression analysis of wild-type p53 and PANDAs in p53-null HCT116 cells
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Project description:The tumor suppressor p53 integrates stress response pathways, triggering the appropriate cell fate by selectively engaging one of a diverse set of transcriptomes (e.g., cell cycle arrest, apoptosis). Foundational to this process is the binding of tetrameric p53 to response elements (REs) in the genome, of the consensus sequence (RRRCWWGYYYN0-13RRRCWWGYYY). This unusually long and degenerate RE provides a potential mechanism for contextually activating distinct sets of downstream targets. However, the RE code underlying this selectivity remains undeciphered. p53 REs exhibit the highest sequence variability at the triplets RRR/YYY, which flank the core (CWWG) sequence, and p53 tetramers interact with REs at those bases via Arg248 from the DNA minor groove and Lys120 from the DNA major groove. This set of observations triggered our hypothesis that the interplay of Lys120 and Arg248 residues with variable sequences of REs might be a potential source of p53 selectivity. To gain insight into the role of Lys120 integrity in the recognition of specific RE sequences, we performed a ChIP-seq experiment and analyzed genome-wide occupancy of conditionally-expressed wild-type (WT) and K120R forms of p53 in isogenic human cell lines that are null for endogenous p53. Using an optimized data analysis workflow, we mapped about 35 million unique sequence reads per sample to the human genome, and the number of significantly enriched peaks in each replicate was detected by setting an enrichment cutoff of 0.3 counts per million reads. This study presents a foundation for analysis of differences in sequences between K120R-sensitive and K120R-insensitive p53 binding sites.
2020-12-02 | GSE159945 | GEO
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. 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 effects of diverse stresses on promoter selectivity and transcription regulation by the tumor suppressor p53 are poorly understood. We have taken a comprehensive approach to characterizing the human p53 network that includes p53 levels, binding, expression and chromatin changes under diverse stresses. Human osteosarcoma U2OS cells treated with anti-cancer drugs Doxorubicin or Nutlin-3 led to strikingly different p53 gene binding patterns based on ChIP-seq experiments. While two contiguous RRRCWWGYYY decamers is the consensus binding motif, p53 can bind a single decamer and function in vivo. Although the number of sites bound by p53 was 6-times greater for Nutlin-3 than Doxorubicin, expression changes induced by Nutlin-3 were much less dramatic compared to Doxorubicin. Unexpectedly, the solvent DMSO alone induced p53 binding to many sites common to Doxorubicin; however, this binding had no effect on target gene expression. Together, these data imply a two-stage mechanism for p53 transactivation where p53 binding only constitutes the first stage. Furthermore, both p53 binding and transactivation were associated with increased active histone modification H3K4me3. We discovered 149 putative new p53 target genes including several that are relevant to tumor suppression, revealing potential new targets for cancer therapy and expanding our understanding of the p53 regulatory network. Gene expression analysis (using Affymetrix Human Genome U133 Plus 2.0 GeneChip® arrays) of the p53 response in U2OS cells treated with either Doxorubicin or Nutlin-3, relative to their controls No Treatment and DMSO, respectively.
2013-07-01 | E-GEOD-46493 | biostudies-arrayexpress
Project description:In an attempt to find new effective p53-activating agents with antitumor activity, the anti-proliferative activity of a small chemical library of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles was investigated in a panel of human cancer cells with different p53 status. The (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO) was selected due to its noticeable selectivity to cancer cells expressing p53. The IC50 values of MANIO ranged from 0.20 – 0.97 µM or 0.088 – 2.90 µM in wtp53- or mutp53-expressing cells, respectively, to 26.20 – 48.25 µM in p53-null cells.
2022-08-30 | GSE145482 | GEO
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 | GSE22184 | GEO
Project description:p53 binding was studied using ChIP on chip technique in breast epithelial HME1 cell lines overexpressing wt or mutant p53
2008-10-25 | E-MEXP-1491 | biostudies-arrayexpress