title: Hippo Component TAZ Functions as a Co-repressor and Negatively Regulates ΔNp63 Transcription through TEA Domain (TEAD) Transcription Factor.
abstract: Transcriptional co-activator with a PDZ binding domain (TAZ) is a WW domain-containing transcriptional co-activator and a core component of an emerging Hippo signaling pathway that regulates organ size, tumorigenesis, metastasis, and drug resistance. TAZ regulates these biological functions by up-regulating downstream cellular genes through transactivation of transcription factors such as TEAD and TTF1. To understand the molecular mechanisms underlying TAZ-induced tumorigenesis, we have recently performed a gene expression profile analysis by overexpressing TAZ in mammary cells. In addition to the TAZ-up-regulated genes that were confirmed in our previous studies, we identified a large number of cellular genes that were down-regulated by TAZ. In this study, we have confirmed these down-regulated genes (including cytokines, chemokines, and p53 gene family members) as bona fide downstream transcriptional targets of TAZ. By using human breast and lung epithelial cells, we have further characterized ΔNp63, a p53 gene family member, and shown that TAZ suppresses ΔNp63 mRNA, protein expression, and promoter activity through interaction with the transcription factor TEAD. We also show that TEAD can inhibit ΔNp63 promoter activity and that TAZ can directly interact with ΔNp63 promoter-containing TEAD binding sites. Finally, we provide functional evidence that down-regulation of ΔNp63 by TAZ may play a role in regulating cell migration. Altogether, this study provides novel evidence that the Hippo component TAZ can function as a co-repressor and regulate biological functions by negatively regulating downstream cellular genes.
authors.affiliation: From the Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Ivette
authors.initials: I
authors.lastname: Valencia-Sama
authors.affiliation: From the Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Dulcie
authors.initials: D
authors.lastname: Lai
authors.affiliation: From the Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Janse van Rensburg
authors.affiliation: From the Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Hao
authors.affiliation: From the Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada yang@path.queensu.ca.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Yang
mesh_terms: D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D000090683:Hippo Signaling Pathway; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D000091262:TEA Domain Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; C101205:TEAD2 protein, human; C106169:TEAD3 protein, human; C486309:TEAD4 protein, human; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D025521:Tumor Suppressor Proteins; C551991:WWTR1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; cell migration; oncogene; transcription coactivator; transcription corepressor