The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins

Abstract

Abstract:The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code. BET proteins play a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cellular proliferation and differentiation processes. On the other hand, BET proteins have been reported to mediate latent viral infection in host cells and be involved in oncogenesis. Human BRD4 is involved in multiple processes of the DNA virus life cycle, including viral replication, genome maintenance, and gene transcription through interaction with viral proteins. Aberrant BRD4 expression contributes to carcinogenesis by mediating hyperacetylation of the chromatin containing the cell proliferation-promoting genes. BET bromodomain blockade using small-molecule inhibitors gives rise to selective repression of the transcriptional network driven by c-MYC These inhibitors are expected to be potential therapeutic drugs for a wide range of cancers. This review presents an overview of the basic roles of BET proteins and highlights the pathological functions of BET and the recent developments in cancer therapy targeting BET proteins in animal models.

Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis

“…49,50 We have shown that loss of MIR143-3p led to an increase in BRD2 protein levels, leading to transcription induction of its downstream target c-MYC. 51,52 Reconstitution of MIR143-3p reduced the protein levels of BRD2 and c-MYC, resulting in restoration of sensitivity to CDDP in vitro and in vivo. Concordant with these results, high expression levels of BRD2 were associated with poor clinical outcome and reduced overall survival in GC patients.…”

Drugging transcription in heart failure

“…The mammalian BET family of proteins comprises BRD2, BRD3, BRD4 and BRDT (Taniguchi, 2016). Encoded by paralogous genes, these proteins are characterized by two tandem BDs in their N-terminal region and a C-terminal extra-terminal (ET) domain (Jung et al 2014;Taniguchi, 2016).…”

“…The mammalian BET family of proteins comprises BRD2, BRD3, BRD4 and BRDT (Taniguchi, 2016). Encoded by paralogous genes, these proteins are characterized by two tandem BDs in their N-terminal region and a C-terminal extra-terminal (ET) domain (Jung et al 2014;Taniguchi, 2016). The BD is a conserved sequence of approximately 110 amino acids that forms four α-helices (Z, A, B, C) and two interconnected loops (ZA, BC) that form a hydrophobic pocket to encompass a recognition site for acetylated lysine (Zeng & Zhou, 2002;Berger, 2007).…”

Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies

“…Upon binding, BET proteins recruit transcription initiation and elongation complexes, including mediator, polymerase-associated factor complex, and super elongation complex; thereby promoting gene transcription (2,3). In vitro and in vivo studies have demonstrated that inhibition of BRD binding downregulates key genes [e.g., MYC, BCL-2, BCL-xl, p21(C1P1/WAF1), RUNX2, and IRF4] that promote cell-cycle progression, survival, and inflammation (4,5), leading to growth inhibition in preclinical models of solid tumors and hematologic malignancies. In these studies, tumor growth associated with dysregulation of transcription factors, such as MYC, were particularly responsive to BET inhibition (6)(7)(8).…”