title: Crosstalk between c-Jun and TAp73alpha/beta contributes to the apoptosis-survival balance.
abstract: 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.
authors: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors: Max
authors: M
authors: Koeppel
authors: Simon J
authors: SJ
authors: van Heeringen
authors: Daniela
authors: D
authors: Kramer
authors: Leonie
authors: L
authors: Smeenk
authors: Eva
authors: E
authors: Janssen-Megens
authors: Marianne
authors: M
authors: Hartmann
authors: Hendrik G
authors: HG
authors: Stunnenberg
authors: Marion
authors: M
authors: Lohrum
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics; D006801:Humans; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C507765:IL1RAP protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D009687:Nuclear Proteins; D020033:Protein Isoforms; D016755:Proto-Oncogene Proteins c-jun; C000606460:TP73 protein, human; D018808:Transcription Factor AP-1; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D000075702:Nedd4 Ubiquitin Protein Ligases; D044767:Ubiquitin-Protein Ligases