PML, YAP, and p73 Are Components of a Proapoptotic Autoregulatory Feedback Loop

• DOI: 10.1016/j.molcel.2008.11.019
• Publication Date: 2008-12-25T10:32:05Z
• Authors: Eleonora Lapi; Silvia Di Agostino; Sara Donzelli; Hilah Gal; Eytan Domany; Gideon Rechavi; Pier Paolo Pandolfi; David Givol; Sabrina Strano; Xin Lu; Giovanni Blandino
• Keywords: Proteasome Endopeptidase Complex; Apoptosis; Cell Cycle Proteins; Promyelocytic Leukemia Protein; Models, Biological; Cell Line; Mice; 03 medical and health sciences; Animals; Humans; Molecular Biology; Adaptor Proteins, Signal Transducing; Oligonucleotide Array Sequence Analysis; CELLCYCLE; Adaptor Proteins; Signal Transducing; Animals; Apoptosis; Cell Line; Cisplatin; DNA-Binding Proteins; Feedback; Biochemical; Gene Expression Regulation; Neoplastic; Humans; Lactates; Mice; Models; Biological; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Phenols; Phosphoproteins; Proteasome Endopeptidase Complex; Protein Binding; Protein Processing; Post-Translational; Protein Stability; Regulatory Sequences; Nucleic Acid; Small Ubiquitin-Related Modifier Proteins; Transcription Factors; Transcription; Genetic; Transcriptional Activation; Tumor Suppressor Proteins; Ubiquitin; Feedback, Physiological; 0303 health sciences; Protein Stability; Nuclear Proteins; Cell Biology; Phosphoproteins; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Cisplatin; Protein Processing, Post-Translational; Protein Binding

p73 has been identified as a structural and functional homolog of the tumor suppressor p53. The transcriptional coactivator Yes-associated protein (YAP) has been demonstrated to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Here, we show the existence of a proapoptotic autoregulatory feedback loop between p73, YAP, and the promyelocytic leukemia (PML) tumor suppressor gene. We demonstrate that PML is a direct transcriptional target of p73/YAP, and we show that PML transcriptional activation by p73/YAP is under the negative control of the proto-oncogenic Akt/PKB kinase. Importantly, we find that PML and YAP physically interact through their PVPVY and WW domains, respectively, causing PML-mediated sumoylation and stabilization of YAP. Hence, we determine a mechanistic pathway in response to DNA damage that could have relevant implications for the treatment of human cancer.