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.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Cell Line, Tumor
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Gene Expression Regulation, Neoplastic
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Hippo Signaling Pathway
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Humans
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Intracellular Signaling Peptides and Proteins / biosynthesis
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Mechanistic Target of Rapamycin Complex 1
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Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
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Multiprotein Complexes / biosynthesis
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Neoplasms / genetics*
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Nucleosomes / genetics
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction
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TNF-Related Apoptosis-Inducing Ligand / biosynthesis
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TOR Serine-Threonine Kinases / biosynthesis
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Trans-Activators
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Transcription Factors / biosynthesis
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcriptional Activation
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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DDIT4 protein, human
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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Nucleosomes
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Phosphoproteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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WWTR1 protein, human
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YAP-Signaling Proteins
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YAP1 protein, human
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Mi-2 Nucleosome Remodeling and Deacetylase Complex