Disease relevance of BRD4

• Four published carcinomas with BRD4 and NUT rearrangements were also evaluated [1].
• Our data are in keeping with the notion that the direct interaction of KSHV LANA-1 with BRD4 and other BRD proteins could play a role in the G(1)/S phase-promoting functions of KSHV LANA-1 [2].
• Here, we present the X-ray crystal structure of the carboxy-terminal domain of Brd4 in complex with HPV-16 E2, and with this information have developed a Brd4-Tat fusion protein that is efficiently taken up by different transformed cells harboring HPV plasmids [3].
• Although generally required for transcription, the P-TEFb-recruitment function of Brd4 can be substituted by that of HIV-1 Tat, which recruits P-TEFb directly for activated HIV-1 transcription [4].
• However, the HPV-11 E2 protein did not associate with Brd4 during mitosis [5].

High impact information on BRD4

• Our finding that Brd4 is a component of the virus-assembled transcriptional silencing complex uncovers a novel function of Brd4 as a cellular cofactor modulating viral gene expression [6].
• Notably, E2 W130R binds Brd4, which reportedly acts as a mitotic tether, indicating this interaction is insufficient for E2 association with mitotic chromosomes [7].
• The association with Brd4 is necessary to form the transcriptionally active P-TEFb, recruits P-TEFb to a promoter, and enables P-TEFb to contact the Mediator complex, a potential target for the Brd4-mediated recruitment [4].
• Furthermore ectopic expression of SPA-1 and Brd4 redirected subcellular localization of the partner and disrupted normal cell cycle progression [8].
• These effects were, however, reversed by coexpression of the two proteins, indicating that a proper balance between Brd4 and SPA-1 in G2 is required for cell division [8].

Biological context of BRD4

• Herein we demonstrate that BRD4 is fused with nearly the entire transcript of the novel 15q13 gene, NUT (nuclear protein in testis), forming a 6.4-kb fusion oncogene, BRD4-NUT [9].
• The chromosome 19 translocation breakpoint targets the BRD4 double bromodomain-containing gene, which functions in regulation of cell cycle progression [9].
• Our findings reveal a novel oncogenic mechanism in which the chromosome 19 translocation breakpoint interrupts the coding sequence of a bromodomain gene, BRD4 [10].
• BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19) [10].
• The most notable feature of MCAP was its association with chromosomes during mitosis, observed at a time when the majority of nuclear regulatory factors were released into the cytoplasm, coinciding with global cessation of transcription [11].

Anatomical context of BRD4

• We measured the MCAP (middle cerebral artery pressure)/MSBP (mean systemic blood pressure) ratio in 76 patients who underwent an EIAB (extracranial-intracranial arterial bypass) [12].
• This study tested the general hypothesis that high- and low-hostile respondents would show different patterns of change in monocyte cytokine and adhesion protein (MCAP) expression in response to pharmacologically induced alterations in sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) balance [13].

Associations of BRD4 with chemical compounds

• By analyzing the binding of Brd4 to a series of alanine-scanning substitution mutants of the human papillomavirus type 16 E2 N-terminal transactivation domain, we found that amino acids required for Brd4 binding were also required for transcriptional activation but not for viral DNA replication [14].

Physical interactions of BRD4

• In vitro binding studies suggest that Tax and Brd4 compete for binding to P-TEFb through direct interaction with cyclin T1 [15].

Other interactions of BRD4

• A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase [16].
• Kaposi's Sarcoma-Associated Herpesvirus LANA-1 Interacts with the Short Variant of BRD4 and Releases Cells from a BRD4- and BRD2/RING3-Induced G1 Cell Cycle Arrest [2].
• In this work, we identify the double-bromodomain proteins BRD4 and BRD3/ORFX as additional LANA-1 interaction partners [2].

Analytical, diagnostic and therapeutic context of BRD4

• PATIENTS AND METHODS: Carcinomas (N = 98) in young individuals (median age, 32.5 years) were screened for NUT and BRD4 rearrangements using dual-color fluorescence in situ hybridization [1].
• The major TAD-binding protein was identified by mass spectrometry and western blotting as the long isoform of Brd4 [17].
• The breakpoints on chromosomes 15 and 19 were cloned using long distance inverse PCR and we determined by RT-PCR that the translocation results in a novel fusion transcript in which the 3' end Brd4 on chromosome 19p is fused to the 5' end of NUT on chromosome 15q [18].

References