PDF(Pubmed)
Abstract：
Bromodomain and extra-terminal domain (BET) proteins are epigenetic modulators that regulate gene transcription through interacting with acetylated lysine residues of histone proteins. BET proteins have multiple roles in regulating key cellular functions such as cell proliferation, differentiation, inflammation, oxidative and redox balance, and immune responses. As a result, BET proteins have been found to be actively involved in a broad range of human lung diseases including acute lung inflammation, asthma, pulmonary arterial hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). Due to the identification of specific small molecular inhibitors of BET proteins, targeting BET in these lung diseases has become an area of increasing interest. Emerging evidence has demonstrated the beneficial effects of BET inhibitors in preclinical models of various human lung diseases. This is, in general, largely related to the ability of BET proteins to bind to promoters of genes that are critical for inflammation, differentiation, and beyond. By modulating these critical genes, BET proteins are integrated into the pathogenesis of disease progression. The intrinsic histone acetyltransferase activity of bromodomain-containing protein 4 (BRD4) is of particular interest, seems to act independently of its bromodomain binding activity, and has implication in some contexts. In this review, we provide a brief overview of the research on BET proteins with a focus on BRD4 in several major human lung diseases, the underlying molecular mechanisms, as well as findings of targeting BET proteins using pharmaceutical inhibitors in different lung diseases preclinically.
摘要：
溴结构域和末端外结构域（BET）蛋白是表观遗传调节剂，通过与组蛋白的乙酰化赖氨酸残基相互作用来调节基因转录。BET蛋白在调节关键细胞功能如细胞增殖中具有多种作用。分化,炎症,氧化和氧化还原平衡，和免疫反应。因此,已经发现BET蛋白积极参与广泛的人类肺部疾病，包括急性肺部炎症，哮喘,肺动脉高压,肺纤维化，和慢性阻塞性肺疾病（COPD）。由于对BET蛋白特异性小分子抑制剂的鉴定,在这些肺部疾病中靶向BET已经成为越来越感兴趣的领域。新的证据已经证明了BET抑制剂在各种人类肺部疾病的临床前模型中的有益作用。这是,总的来说,很大程度上与BET蛋白结合对炎症至关重要的基因启动子的能力有关，分化,和超越。通过调节这些关键基因，BET蛋白被整合到疾病进展的发病机理中。含溴结构域蛋白4（BRD4）的内在组蛋白乙酰转移酶活性特别令人感兴趣，似乎独立于其溴结构域结合活性，并且在某些情况下具有含义。在这次审查中,我们简要概述了BET蛋白的研究，重点是BRD4在几种主要的人类肺部疾病中，潜在的分子机制，以及在临床前不同肺部疾病中使用药物抑制剂靶向BET蛋白的发现。
