Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4gene.[1][2]
BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT.[3] BRD4, similar to other BET family members, contains two bromodomains that recognize acetylatedlysine residues.[4] BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members.[3]
The two bromodomains in BRD4, termed BD1 and BD2, consist of 4 alpha-helices linked by 2 loops.[5] The ET domain structure is made up of 3 alpha-helices and a loop.[6] 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.[7][8][9]
Function
The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human 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.[2]
BRD4 is a major target of BET inhibitors,[12][11] 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.[13] Recent review.[14]
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.[18]
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.[19] BRD4 also interacts with RVX-208,[20] which is being evaluated for treatment of atherosclerosis and cardiovascular disease.
↑Wu SY, Chiang CM (May 2007). "The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation". The Journal of Biological Chemistry. 282 (18): 13141–5. doi:10.1074/jbc.r700001200. PMID17329240.
↑Yang, Z; Yik, J. H.; Chen, R; He, N; Jang, M. K.; Ozato, K; Zhou, Q (2005). "Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4". Molecular Cell. 19 (4): 535–45. doi:10.1016/j.molcel.2005.06.029. PMID16109377.
↑French CA (Jun 2010). "Demystified molecular pathology of NUT midline carcinomas". Journal of Clinical Pathology. 63 (6): 492–6. doi:10.1136/jcp.2007.052902. PMID18552174.
French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA (Jan 2003). "BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma". Cancer Research. 63 (2): 304–7. PMID12543779.
You J, Croyle JL, Nishimura A, Ozato K, Howley PM (Apr 2004). "Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes". Cell. 117 (3): 349–60. doi:10.1016/S0092-8674(04)00402-7. PMID15109495.
