BET domain co-regulators in obesity, inflammation and cancer
Open Access
- 22 June 2012
- journal article
- review article
- Published by Springer Science and Business Media LLC in Nature Reviews Cancer
- Vol. 12 (7), 465-477
- https://doi.org/10.1038/nrc3256
Abstract
Mammalian BET proteins, a class of transcriptional co-regulators that contain dual, mutually related bromodomain motifs and an extraterminal domain, are important in the control of networks of genes; these proteins bind to acetylated lysines in the histones of nucleosomal chromatin, recruit chromatin-modification enzymes to target promoters and function as co-activators or co-repressors of gene expression, depending on the context. New small-molecule inhibitors have recently been developed that disrupt the binding interface between the bromodomain and the acetylated lysine groups; the inhibitors have remarkable potency, selectivity and are well tolerated. They have recently been used as anticancer and anti-inflammatory agents. These developments are important because chromatin was not considered to be a druggable target; as a result of these new drugs, a whole field of new epigenetically targeted therapeutics has become available for investigation. As this field of therapeutics rapidly expands, several features of BET protein function will need to be considered, including possible redundancy among the closely related family members, the selectivity of next-generation agents for specific BET proteins, and possible undesirable consequences of systemic administration without cellular targeting. These side effects might include uncontrolled transcriptional derepression of genes, altered haematopoiesis, immunosuppression or reactivation of latent viruses.Keywords
This publication has 189 references indexed in Scilit:
- BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-MycCell, 2011
- Bromodomains as therapeutic targetsExpert Reviews in Molecular Medicine, 2011
- Short Hairpin RNA Screen Reveals Bromodomain Proteins as Novel Targets in Acute Myeloid LeukemiaCancer Cell, 2011
- An emerging role for bromodomain‐containing proteins in chromatin regulation and transcriptional control of adipogenesisFEBS Letters, 2010
- Catalytic activity of the proteasome fine-tunes Brg1-mediated chromatin remodeling to regulate the expression of inflammatory genesMolecular Immunology, 2009
- The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesisBiochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2009
- Double bromodomain‐containing gene Brd2 is essential for embryonic development in mouseDevelopmental Dynamics, 2009
- Brd4 associates with mitotic chromosomes throughout early zebrafish embryogenesisDevelopmental Dynamics, 2008
- The Double Bromodomain Proteins Brd2 and Brd3 Couple Histone Acetylation to TranscriptionMolecular Cell, 2008
- The Transcriptional Coactivators p300 and CBP Are Histone AcetyltransferasesCell, 1996