Transcriptional co-repressor function of the hippo pathway transducers YAP and TAZ

Cell Rep. 2015 Apr 14;11(2):270-82. doi: 10.1016/j.celrep.2015.03.015. Epub 2015 Apr 2.

Abstract

YAP (yes-associated protein) and TAZ are oncogenic transcriptional co-activators downstream of the Hippo tumor-suppressor pathway. However, whether YAP and/or TAZ (YAP/TAZ) engage in transcriptional co-repression remains relatively unexplored. Here, we directly demonstrated that YAP/TAZ represses numerous target genes, including tumor-suppressor genes such as DDIT4 (DNA-damage-inducible transcript 4) and Trail (TNF-related apoptosis-inducing ligand). Mechanistically, the repressor function of YAP/TAZ requires TEAD (TEA domain) transcription factors. A YAP/TAZ-TEAD complex recruits the NuRD complex to deacetylate histones and alters nucleosome occupancy at target genes. Functionally, repression of DDIT4 and Trail by YAP/TAZ is required for mTORC1 (mechanistic target of rapamycin complex 1) activation and cell survival, respectively. Our demonstration of the transcriptional co-repressor activity of YAP/TAZ opens a new avenue for understanding the Hippo signaling pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / biosynthesis
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
  • Multiprotein Complexes / biosynthesis
  • Neoplasms / genetics*
  • Nucleosomes / genetics
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand / biosynthesis
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TOR Serine-Threonine Kinases / biosynthesis
  • Trans-Activators
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation

Substances

  • Adaptor Proteins, Signal Transducing
  • DDIT4 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Nucleosomes
  • Phosphoproteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Trans-Activators
  • Transcription Factors
  • WWTR1 protein, human
  • YAP1 protein, human
  • TOR Serine-Threonine Kinases
  • Hippo protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex

Associated data

  • GEO/GSE60579