Refine
Year of publication
- 2011 (2)
Document Type
- Article (2)
Language
- English (2)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Institute
The p53-family member p73 plays a role in various cellular signaling pathways during development and growth control and it can have tumor suppressor properties. Several isoforms of p73 exist with considerable differences in their function. Whereas the functions of the N-terminal isoforms (TA and delta Np73) and their opposing pro- and antiapoptotic roles have become evident, the functional differences of the distinct C-terminal splice forms of TAp73 have remained unclear. Here, we characterized the global genomic binding sites for TAp73alpha and TAp73beta by chromatin immunoprecipitation sequencing as well as the transcriptional responses by performing RNA sequencing. We identified a specific p73 consensus binding motif and found a strong enrichment of AP1 motifs in close proximity to binding sites for TAp73alpha. These AP1 motif-containing target genes are selectively upregulated by TAp73alpha, while their mRNA expression is repressed upon TAp73beta induction. We show that their expression is dependent on endogenous c-Jun and that recruitment of c-Jun to the respective AP1 sites was impaired upon TAp73beta expression, in part due to downregulation of c-Jun. Several of these AP1-site containing TAp73alpha-induced genes impinge on apoptosis induction, suggesting an underlying molecular mechanism for the observed functional differences between TAp73alpha and TAp73beta.
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 notwithstanding transcriptional differences that we observed in global transcriptome analysis. To assess the role of post-translational modifications in target gene choice and activation we investigated the genome-wide level of phosphorylation of Serine 46 of p53 bound to DNA (p53-pS46) and of Serine 15 (p53-pS15). Interestingly, the extent of S46 phosphorylation of p53 bound to DNA is considerably higher in cells directed towards apoptosis while the degree of phosphorylation at S15 remains highly similar. Moreover, our data suggest that following different chemotherapeutical treatments, the amount of chromatin-associated p53 phosphorylated at S46 but not at pS15 is higher on certain apoptosis related target genes. Our data provide evidence that cell fate decisions are not made primarily on the level of general p53 DNA-binding and that post-translationally modified p53 can have distinct DNA-binding characteristics.