Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / metabolism*
-
Animals
-
Apoptosis* / drug effects
-
Cell Cycle Proteins
-
Cell Line
-
Cisplatin / pharmacology
-
DNA-Binding Proteins / metabolism*
-
Feedback, Physiological* / drug effects
-
Gene Expression Regulation, Neoplastic / drug effects
-
Humans
-
Mice
-
Models, Biological
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism*
-
Oligonucleotide Array Sequence Analysis
-
Phosphoproteins / metabolism*
-
Promyelocytic Leukemia Protein
-
Proteasome Endopeptidase Complex / metabolism
-
Protein Binding / drug effects
-
Protein Processing, Post-Translational / drug effects
-
Protein Stability / drug effects
-
Regulatory Sequences, Nucleic Acid / genetics
-
Small Ubiquitin-Related Modifier Proteins / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Transcription, Genetic / drug effects
-
Transcriptional Activation / drug effects
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism*
-
Ubiquitin / metabolism
-
YAP-Signaling Proteins
Substances
-
Adaptor Proteins, Signal Transducing
-
Cell Cycle Proteins
-
DNA-Binding Proteins
-
Nuclear Proteins
-
Phosphoproteins
-
Pml protein, mouse
-
Promyelocytic Leukemia Protein
-
Small Ubiquitin-Related Modifier Proteins
-
Transcription Factors
-
Tumor Suppressor Proteins
-
Ubiquitin
-
YAP-Signaling Proteins
-
YAP1 protein, human
-
Yap1 protein, mouse
-
PML protein, human
-
Proteasome Endopeptidase Complex
-
Cisplatin