Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY 11794, USA.
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Mol Cell. 2014 Jun 5;54(5):728-36. doi: 10.1016/j.molcel.2014.05.016.
The bromodomain and extraterminal (BET) protein Brd4 recruits transcriptional regulatory complexes to acetylated chromatin. While Brd4 is considered to be a general transcriptional regulator, pharmacological inhibition of BET proteins shows therapeutic activity in a variety of different pathologies, particularly in models of cancer and inflammation. Such effects have been attributed to a specific set of downstream target genes whose expression is disproportionately sensitive to pharmacological targeting of BET proteins. Emerging evidence links the transcriptional consequences of BET inhibition to the association of Brd4 with enhancer elements, which tend to be involved in lineage-specific gene regulation. Furthermore, Brd4 engages in direct regulatory interactions with several DNA-binding transcription factors to influence their disease-relevant functions. Here we review the current understanding of molecular mechanisms that underlie the promising therapeutic effects of BET bromodomain inhibition.
溴结构域和末端（BET）蛋白 Brd4 将转录调控复合物募集到乙酰化染色质上。虽然 Brd4 被认为是一种通用转录调节剂，但 BET 蛋白的药理学抑制在多种不同的病理中显示出治疗活性，特别是在癌症和炎症模型中。这些影响归因于一组特定的下游靶基因，其表达对 BET 蛋白的药理学靶向具有不成比例的敏感性。新出现的证据将 BET 抑制的转录后果与 Brd4 与增强子元件的关联联系起来，这些元件往往参与谱系特异性基因调控。此外，Brd4 与几个 DNA 结合转录因子直接进行调节相互作用，以影响它们与疾病相关的功能。在这里，我们回顾了目前对 BET 溴结构域抑制有希望的治疗效果的基础分子机制的理解。
