The Mechanisms behind the Therapeutic Activity of BET Bromodomain Inhibition

被引：722

作者：

Shi, Junwei ^{[1
,2
]}

Vakoc, Christopher R. ^{[1
]}

机构：

[1] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[2] SUNY Stony Brook, Mol & Cellular Biol Program, Stony Brook, NY 11794 USA

来源：

MOLECULAR CELL | 2014年 / 54卷 / 05期

关键词：

TRANSCRIPTIONAL PAUSE RELEASE; ACUTE MYELOID-LEUKEMIA; ELONGATION-FACTOR B; P-TEFB; PROTEIN BRD4; SELECTIVE-INHIBITION; CHROMATIN OCCUPANCY; SUPER-ENHANCERS; GENE-EXPRESSION; CELL IDENTITY;

D O I：

10.1016/j.molcel.2014.05.016

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：728 / 736

页数：9

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