Phosphorylation of p53 Serine 46 contributes to target gene selectivity of p53
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Marion Lohrum
PROVIDER: E-GEOD-22186 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Role of p53 serine 46 in p53 target gene regulation.
Smeenk Leonie L van Heeringen Simon J SJ Koeppel Max M Gilbert Bianca B Janssen-Megens Eva E Stunnenberg Hendrik G HG Lohrum Marion M
PloS one 20110304 3
The tumor suppressor p53 plays a crucial role in cellular growth control inducing a plethora of different response pathways. The molecular mechanisms that discriminate between the distinct p53-responses have remained largely elusive. Here, we have analyzed the p53-regulated pathways induced by Actinomycin D and Etoposide treatment resulting in more growth arrested versus apoptotic cells respectively. We found that the genome-wide p53 DNA-binding patterns are almost identical upon both treatments ...[more]
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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.
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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
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