BRD4

Structure

The two bromodomains in BRD4, termed BD1 and BD2, consist of 4 alpha-helices linked by 2 loops. The ET domain structure is made up of 3 alpha-helices and a loop. The C-terminal domain of BRD4 has been implicated in promoting gene transcription through interaction with the transcription elongation factor P-TEFb and RNA polymerase II.{{Cite journal | doi-access = free

Function

The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human BRD2 (RING3) protein, a serine/threonine kinase. Each of these proteins contains two bromodomains, a conserved sequence motif which may be involved in chromatin targeting. This gene has been implicated as the chromosome 19 target of translocation t(15;19)(q13;p13.1), which defines the NUT midline carcinoma. Two alternatively spliced transcript variants have been described.

Role in cancer

Most cases of NUT midline carcinoma involve translocation of the BRD4 gene with NUT genes. BRD4 is often required for expression of Myc and other "tumor driving" oncogenes in hematologic cancers including multiple myeloma, acute myelogenous leukemia and acute lymphoblastic leukaemia.

BRD4 is a major target of BET inhibitors, a class of pharmaceutical drugs currently being evaluated in clinical trials.

Interactions

Notably, BRD4 interacts with P-TEFb via its P-TEFb interaction domain (PID), thereby stimulating its kinase activity and stimulating its phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II.

BRD4 has been shown to interact with GATA1, JMJD6, RFC2, RFC3, RFC1, RFC4 and RFC5.

BRD4 has also been implicated in binding with the diacetylated Twist protein, and the disruption of this interaction has been shown to suppress tumorigenesis in basal-like breast cancer.

BRD4 has also been shown to interact with a variety of inhibitors, such as MS417; inhibition of BRD4 with MS417 has been shown to down-regulate NF-κB activity seen in HIV-associated kidney disease. BRD4 also interacts with apabetalone (RVX-208), which is being evaluated for treatment of atherosclerosis and cardiovascular disease.

References

References

1. (Sep 2000). "A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition". Molecular and Cellular Biology.
2. "Entrez Gene: BRD4 bromodomain containing 4".
3. (Feb 2002). "Bromodomain: an acetyl-lysine binding domain". FEBS Letters.
4. (Jun 2014). "The mechanisms behind the therapeutic activity of BET bromodomain inhibition". Molecular Cell.
5. (1 January 2013). "Two faces of brd4: mitotic bookmark and transcriptional lynchpin". Transcription.
6. (May 2007). "The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation". The Journal of Biological Chemistry.
7. (Jun 2010). "Demystified molecular pathology of NUT midline carcinomas". Journal of Clinical Pathology.
8. (2013-07-19). "BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia". Blood Cancer Journal.
9. (Jun 2014). "The mechanisms behind the therapeutic activity of BET bromodomain inhibition". Molecular Cell.
10. (Jul 2014). "Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation". Nucleic Acids Research.
11. (May 2011). "Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes". Proceedings of the National Academy of Sciences of the United States of America.
12. (Dec 2013). "Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release". Cell.
13. (Sep 2002). "A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase". Molecular and Cellular Biology.
14. (Feb 2014). "Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer". Cancer Cell.
15. (Aug 2012). "Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition". The Journal of Biological Chemistry.
16. (31 December 2013). "RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist". PLOS ONE.