The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage

Mol Cell. 2005 May 13;18(4):447-59. doi: 10.1016/j.molcel.2005.04.008.

Abstract

The transcriptional coactivator Yes-associated protein (YAP) has been shown to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Here, we show that YAP requires the promyelocytic leukemia gene (PML) and nuclear body localization to coactivate p73. YAP imparts selectivity to p73 by promoting the activation of a subset of p53 and/or p73 target promoters. Endogenous p73, YAP, and p300 proteins are concomitantly recruited onto the regulatory regions of the apoptotic target gene p53AIP1 only when cells are exposed to apoptotic conditions. Silencing of YAP by specific siRNA impairs p300 recruitment and reduces histone acetylation on the p53AIP1 target gene, resulting in delayed or reduced apoptosis mediated by p73. We also found that YAP contributes to the DNA damage-induced accumulation of p73 and potentiates the p300-mediated acetylation of p73. Altogether, our findings identify YAP as a key determinant of p73 gene targeting in response to DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins
  • Cisplatin / pharmacology
  • DNA Damage / physiology*
  • DNA-Binding Proteins / metabolism*
  • Doxorubicin / pharmacology
  • Genes, Reporter
  • Genes, Tumor Suppressor
  • Humans
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / metabolism*
  • Promyelocytic Leukemia Protein
  • Proteins / metabolism
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism
  • Transcription, Genetic / physiology
  • Tumor Protein p73
  • Tumor Suppressor Proteins

Substances

  • Antibiotics, Antineoplastic
  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • P53AIP1 protein, human
  • Promyelocytic Leukemia Protein
  • Proteins
  • Trans-Activators
  • Transcription Factors
  • Tumor Protein p73
  • Tumor Suppressor Proteins
  • YY1AP1 protein, human
  • p73 protein, human
  • PML protein, human
  • Doxorubicin
  • Cisplatin