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Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.
Lambert, Jean-Philippe; Picaud, Sarah; Fujisawa, Takao; Hou, Huayun; Savitsky, Pavel; Uusküla-Reimand, Liis; Gupta, Gagan D; Abdouni, Hala; Lin, Zhen-Yuan; Tucholska, Monika; Knight, James D R; Gonzalez-Badillo, Beatriz; St-Denis, Nicole; Newman, Joseph A; Stucki, Manuel; Pelletier, Laurence; Bandeira, Nuno; Wilson, Michael D; Filippakopoulos, Panagis; Gingras, Anne-Claude.
  • Lambert JP; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Picaud S; Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
  • Fujisawa T; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
  • Hou H; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Genetics and Genome Biology Program, SickKids Research Institute, Toronto, ON, Canada.
  • Savitsky P; Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
  • Uusküla-Reimand L; Genetics and Genome Biology Program, SickKids Research Institute, Toronto, ON, Canada; Department of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
  • Gupta GD; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Abdouni H; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Lin ZY; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Tucholska M; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Knight JDR; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Gonzalez-Badillo B; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • St-Denis N; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Newman JA; Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
  • Stucki M; Department of Gynecology, University of Zurich, Wagistrasse 14, 8952 Schlieren, Switzerland.
  • Pelletier L; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • Bandeira N; Center for Computational Mass Spectrometry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San
  • Wilson MD; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Genetics and Genome Biology Program, SickKids Research Institute, Toronto, ON, Canada; Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada.
  • Filippakopoulos P; Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: panagis.filippakopoulos@sgc.ox.ac.uk.
  • Gingras AC; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address: gingras@lunenfeld.ca.
Mol Cell ; 73(3): 621-638.e17, 2019 02 07.
Article en En | MEDLINE | ID: mdl-30554943
ABSTRACT
Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, BRD3, BRD4, and BRDT following treatment with the pan-BET BRD inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behavior for the 603 unique interactors identified. A group of proteins associate in a JQ1-sensitive manner with BET BRDs through canonical and new binding modes, while two classes of extra-terminal (ET)-domain binding motifs mediate acetylation-independent interactions. Last, we identify an unexpected increase in several interactions following JQ1 treatment that define negative functions for BRD3 in the regulation of rRNA synthesis and potentially RNAPII-dependent gene expression that result in decreased cell proliferation. Together, our data highlight the contributions of BET protein modules to their interactomes allowing for a better understanding of pharmacological rewiring in response to JQ1.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Azepinas / Factores de Transcripción / Triazoles / Proteínas Nucleares / Proteínas de Unión al ARN / Proteínas Serina-Treonina Quinasas / Terapia Molecular Dirigida / Mapas de Interacción de Proteínas / Neoplasias / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Año: 2019 Tipo del documento: Article
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Azepinas / Factores de Transcripción / Triazoles / Proteínas Nucleares / Proteínas de Unión al ARN / Proteínas Serina-Treonina Quinasas / Terapia Molecular Dirigida / Mapas de Interacción de Proteínas / Neoplasias / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Año: 2019 Tipo del documento: Article