title: Alteration of TEAD1 expression levels confers apoptotic resistance through the transcriptional up-regulation of Livin.
abstract: BACKGROUND
  TEA domain (TEAD) proteins are highly conserved transcription factors involved in embryonic development and differentiation of various tissues. More recently, emerging evidences for a contribution of these proteins towards apoptosis and cell proliferation regulation have also been proposed. These effects appear to be mediated by the interaction between TEAD and its co-activator Yes-Associated Protein (YAP), the downstream effector of the Hippo tumour suppressor pathway.
  
  
  RESULTS
  We further investigated the mechanisms underlying TEAD-mediated apoptosis regulation and showed that overexpression or RNAi-mediated silencing of the TEAD1 protein is sufficient to protect mammalian cell lines from induced apoptosis, suggesting a proapoptotic function for TEAD1 and a non physiological cytoprotective effect for overexpressed TEAD1. Moreover we show that the apoptotic resistance conferred by altered TEAD1 expression is mediated by the transcriptional up-regulation of Livin, a member of the Inhibitor of Apoptosis Protein (IAP) family. In addition, we show that overexpression of a repressive form of TEAD1 can induce Livin up-regulation, indicating that the effect of TEAD1 on Livin expression is indirect and favoring a model in which TEAD1 activates a repressor of Livin by interacting with a limiting cofactor that gets titrated upon TEAD1 up-regulation. Interestingly, we show that overexpression of a mutated form of TEAD1 (Y421H) implicated in Sveinsson's chorioretinal atrophy that strongly reduces its interaction with YAP as well as its activation, can induce Livin expression and protect cells from induced apoptosis, suggesting that YAP is not the cofactor involved in this process.
  
  
  CONCLUSIONS
  Taken together our data reveal a new, Livin-dependent, apoptotic role for TEAD1 in mammals and provide mechanistic insight downstream of TEAD1 deregulation in cancers.
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Equipe de Génétique Moléculaire de la Différenciation, IJM, UMR 7592 CNRS, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Landin Malt
authors.forename: Julie
authors.initials: J
authors.lastname: Cagliero
authors.forename: Kevin
authors.initials: K
authors.lastname: Legent
authors.forename: Joël
authors.initials: J
authors.lastname: Silber
authors.forename: Alain
authors.initials: A
authors.lastname: Zider
authors.forename: Domenico
authors.initials: D
authors.lastname: Flagiello
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017398:Alternative Splicing; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics*; D004843:Epistasis, Genetic; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D059368:RNA Isoforms; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C419866:BIRC7 protein, human; D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D059368:RNA Isoforms; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors