PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop

Mol Cell. 2008 Dec 26;32(6):803-14. doi: 10.1016/j.molcel.2008.11.019.

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

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
  • YAP1 protein, human
  • Yap1 protein, mouse
  • PML protein, human
  • Proteasome Endopeptidase Complex
  • Cisplatin