title: The Mediator complex subunit MED25 is targeted by the N-terminal transactivation domain of the PEA3 group members.
abstract: PEA3, ERM and ER81 belong to the PEA3 subfamily of Ets transcription factors and play important roles in a number of tissue-specific processes. Transcriptional activation by PEA3 subfamily factors requires their characteristic amino-terminal acidic transactivation domain (TAD). However, the cellular targets of this domain remain largely unknown. Using ERM as a prototype, we show that the minimal N-terminal TAD activates transcription by contacting the activator interacting domain (ACID)/Prostate tumor overexpressed protein 1 (PTOV) domain of the Mediator complex subunit MED25. We further show that depletion of MED25 disrupts the association of ERM with the Mediator in vitro. Small interfering RNA-mediated knockdown of MED25 as well as the overexpression of MED25-ACID and MED25-VWA domains efficiently inhibit the transcriptional activity of ERM. Moreover, mutations of amino acid residues that prevent binding of MED25 to ERM strongly reduce transactivation by ERM. Finally we show that siRNA depletion of MED25 diminishes PEA3-driven expression of MMP-1 and Mediator recruitment. In conclusion, this study identifies the PEA3 group members as the first human transcriptional factors that interact with the MED25 ACID/PTOV domain and establishes MED25 as a crucial transducer of their transactivation potential.
authors.affiliation: IRI USR 3078 CNRS, Parc CNRS de la Haute Borne, 50 avenue de Halley, B.P. 70478, 59658 Villeneuve d'Ascq Cedex, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Verger
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Baert
authors.forename: Kathye
authors.initials: K
authors.lastname: Verreman
authors.forename: Frédérique
authors.initials: F
authors.lastname: Dewitte
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ferreira
authors.forename: Zoé
authors.initials: Z
authors.lastname: Lens
authors.forename: Yvan
authors.initials: Y
authors.lastname: de Launoit
authors.forename: Vincent
authors.initials: V
authors.lastname: Villeret
authors.forename: Didier
authors.initials: D
authors.lastname: Monté
mesh_terms: D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056892:Mediator Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; C483045:MED25 protein, human; D056892:Mediator Complex; D014157:Transcription Factors; C065788:transcription factor PEA3