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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


  • Lapi E
  • Di Agostino S
  • Donzelli S
  • Gal H
  • Domany E
  • Rechavi G
  • Pandolfi PP
  • Givol D
  • Strano S
  • Lu X
  • Blandino G


Molecular cell

Publication Data

December 26, 2008

Associated Grants


Mesh Terms

  • 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
  • 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