title: The human T cell leukemia/lymphotropic virus type 1 Tax protein represses MyoD-dependent transcription by inhibiting MyoD-binding to the KIX domain of p300. A potential mechanism for Tax-mediated repression of the transcriptional activity of basic helix-loop-helix factors.
abstract: The human T cell leukemia/lymphotropic virus type 1 (HTLV-1) Tax protein strongly activates viral and cellular gene transcription. It mainly functions by interacting with cellular transcription factors and the KIX domain of the p300/CBP coactivators. Tax can also repress the transcription of cellular genes through the basic helix-loop-helix (bHLH) protein family. To investigate the molecular mechanisms of this Tax-mediated inhibition, we analyzed its effect on the transcriptional activity of the myogenic MyoD protein, which was used as a paradigm of bHLH factors. In this study, we show that overexpression of the p300 coactivator in transient transfection assays was sufficient to rescue MyoD repression by Tax. Furthermore, an N-terminal domain of p300 (amino acids 379-654) containing the region of KIX serving as the Tax binding site was found, when overexpressed, to potentiate Tax-mediated transactivation of HTLV-1 proviral as well as MyoD-dependent transcription, and to antagonize the inhibition by Tax of the transcriptional activity of MyoD. These results revealing the presence of an N-terminal MyoD binding site were confirmed by in vitro protein-protein interaction assays that demonstrate that MyoD binds to the KIX domain of p300 and that Tax competes with MyoD binding in a nonreciprocal manner. These observations provide evidence that Tax binding to the KIX domain of p300 prevents bHLH proteins from contacting this N-terminal domain of the coactivator, thus resulting in their transcriptional repression. As bHLH proteins are implicated in many developmental fate decisions, especially during thymopoiesis, Tax-mediated inhibition of their transcriptional activity may contribute to the induction of HTLV-1-linked leukemogenesis.
authors.affiliation: Immuno-Virologie Moléculaire et Cellulaire, Unité Mixte de Recherche 5537, CNRS-Université Claude Bernard Lyon I, Faculté de Médecine Lyon Laennec, 69372 Lyon Cedex 8, France.
authors.forename: P
authors.initials: P
authors.lastname: Riou
authors.forename: F
authors.initials: F
authors.lastname: Bex
authors.forename: L
authors.initials: L
authors.lastname: Gazzolo
mesh_terms: D000818:Animals; D001665:Binding Sites; D050882:CREB-Binding Protein; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D016356:Gene Products, tax / Q000378:metabolism*; D018257:Helix-Loop-Helix Motifs; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D017570:MyoD Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D016356:Gene Products, tax; D017570:MyoD Protein; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D015500:Chloramphenicol O-Acetyltransferase; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse