PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop.
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.
Pubmed ID: 19111660 RIS Download
Adaptor Proteins, Signal Transducing | Animals | Apoptosis | Cell Line | Cisplatin | DNA-Binding Proteins | Feedback, Physiological | Gene Expression Regulation, Neoplastic | Humans | Mice | Models, Biological | Nuclear Proteins | Oligonucleotide Array Sequence Analysis | Phosphoproteins | Promyelocytic Leukemia Protein | 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