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Crosstalk between c-Jun and TAp73α/β contributes to the apoptosis-survival balance

Koeppel, Max, van Heeringen, Simon J., Kramer, Daniela, Smeenk, Leonie, Janssen-Megens, Eva, Hartmann, Marianne, Stunnenberg, Hendrik G., Lohrum, Marion
Nucleic acids research 2011 v.39 no.14 pp. 6069-6085
apoptosis, binding sites, chromatin, gene expression, gene expression regulation, genes, messenger RNA, precipitin tests, signal transduction, transcription (genetics)
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 ΔNp73) 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 TAp73α and TAp73β 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 TAp73α. These AP1 motif-containing target genes are selectively upregulated by TAp73α, while their mRNA expression is repressed upon TAp73β 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 TAp73β expression, in part due to downregulation of c-Jun. Several of these AP1-site containing TAp73α-induced genes impinge on apoptosis induction, suggesting an underlying molecular mechanism for the observed functional differences between TAp73α and TAp73β.