Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition*
| Autor: | Pranal J. Dakle, F. Anthony Romero, Alexander B. Taylor, Charlie Hatton, Venita G. Watson, Hari Jayaram, Srimoyee Ghosh, Andres Salmeron, Peter Sandy, Steve Bellon, Deanna A. Mele, Jennifer A. Mertz, Thornik Reimer, Hon-Ren Huang, Jose M. Lora, Georgia Hatzivassiliou, Laura Zawadzke, Richard T. Cummings, Robert J. Sims, Jeremy W. Setser, Eneida Pardo, Alexandre Côté, Steven Magnuson, Barbara M. Bryant, James E. Audia, Eugene Chiang, Andrew R. Conery, Florence Poy, Andrea G. Cochran, Melissa Chin, Jean-Christophe Harmange, Vickie Tsui, Brian K. Albrecht, Terry Crawford, Denise DeAlmeida-Nagata, Jane L. Grogan |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cellular differentiation Immunology Chemical biology Biochemistry T-Lymphocytes Regulatory Cell Line Histones Small Molecule Libraries 03 medical and health sciences Humans Epigenetics CREB-binding protein Molecular Biology Cells Cultured biology Acetylation Cell Differentiation Forkhead Transcription Factors Cell Biology CREB-Binding Protein Bromodomain Chromatin Cell biology Protein Structure Tertiary Molecular Docking Simulation 030104 developmental biology Histone biology.protein Cancer research Transcriptome E1A-Associated p300 Protein |
| Popis: | Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/EP300 bromodomain inhibition as a novel, small molecule-based approach for cancer immunotherapy. |
| Databáze: | OpenAIRE |
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