Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Characterization of the p53 cistrome - DNA binding cooperativity dissects p53's tumor suppressor functions - Expression profiling

ABSTRACT: P53 wildtype or complementing DNA binding cooperativity versions (p53EE, p53RR, p53EE/RR) were overexpressed in SAOS cells. After 18h cells were harvested and subjected to expression profiling.

ORGANISM(S): Homo sapiens

SUBMITTER: Thorsten Stiewe

PROVIDER: E-MTAB-1403 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions.

Schlereth Katharina K Heyl Charlotte C Krampitz Anna-Maria AM Mernberger Marco M Finkernagel Florian F Scharfe Maren M Jarek Michael M Leich Ellen E Rosenwald Andreas A Stiewe Thorsten T

PLoS genetics 20130815 8

p53 protects us from cancer by transcriptionally regulating tumor suppressive programs designed to either prevent the development or clonal expansion of malignant cells. How p53 selects target genes in the genome in a context- and tissue-specific manner remains largely obscure. There is growing evidence that the ability of p53 to bind DNA in a cooperative manner prominently influences target gene selection with activation of the apoptosis program being completely dependent on DNA binding coopera ...[more]

PMID: 23966881

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Project description:p53 protects us from cancer by transcriptionally regulating tumor suppressive programs designed to either prevent the development or clonal expansion of malignant cells. How p53 selects target genes in the genome in a context- and tissue-specific manner remains largely obscure. There is growing evidence that the ability of p53 to bind DNA in a cooperative manner prominently influences target gene selection with activation of the apoptosis program being completely dependent on DNA binding cooperativity. Here, we used ChIP-seq to comprehensively profile the cistrome of p53 mutants with reduced or increased cooperativity. The analysis highlighted a particular relevance of cooperativity for extending the p53 cistrome to non-canonical binding sequences characterized by deletions, spacer insertions and base mismatches. Furthermore, it revealed a striking functional separation of the cistrome on the basis of cooperativity; with low cooperativity genes being significantly enriched for cell cycle and high cooperativity genes for apoptotic functions. Importantly, expression of high but not low cooperativity genes was correlated with superior survival in breast cancer patients. Interestingly, in contrast to most p53-activated genes, p53-repressed genes did not commonly contain p53 binding elements. Nevertheless, both the degree of gene activation and repression were cooperativity-dependent, suggesting that p53-mediated gene repression is largely indirect and mediated by cooperativity-dependently transactivated gene products such as CDKN1A, E2F7 and non-coding RNAs. Since both activation of apoptosis genes with non-canonical response elements and repression of pro-survival genes are crucial for p53's apoptotic activity, the cistrome analysis comprehensively explains why p53-induced apoptosis, but not cell cycle arrest, strongly depends on the intermolecular cooperation of p53 molecules as a possible safeguard mechanism protecting from accidental cell killing.

Dataset Information

Characterization of the p53 cistrome - DNA binding cooperativity dissects p53's tumor suppressor functions - Expression profiling

Publications

Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions.

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