Biology:BRD4
Generic protein structure example |
Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene.[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 acetylated lysine residues.[4] BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members.[3]
Structure
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 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.[2]
Role in cancer
Most cases of NUT midline carcinoma involve translocation of the BRD4 gene with NUT genes.[10] 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.[11]
BRD4 is a major target of BET inhibitors,[11][12] 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 been shown to interact with GATA1,[15] JMJD6,[16] RFC2,[17] RFC3,[17] RFC1,[17] RFC4[17] and RFC5.[17]
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 apabetalone (RVX-208),[20] which is being evaluated for treatment of atherosclerosis and cardiovascular disease.
References
- ↑ "A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition". Molecular and Cellular Biology 20 (17): 6537–49. Sep 2000. doi:10.1128/MCB.20.17.6537-6549.2000. PMID 10938129.
- ↑ 2.0 2.1 "Entrez Gene: BRD4 bromodomain containing 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23476.
- ↑ 3.0 3.1 "Bromodomain: an acetyl-lysine binding domain". FEBS Letters 513 (1): 124–8. Feb 2002. doi:10.1016/s0014-5793(01)03309-9. PMID 11911891.
- ↑ "The mechanisms behind the therapeutic activity of BET bromodomain inhibition". Molecular Cell 54 (5): 728–736. Jun 2014. doi:10.1016/j.molcel.2014.05.016. PMID 24905006.
- ↑ "Two faces of brd4: mitotic bookmark and transcriptional lynchpin". Transcription 4 (1): 13–17. 1 January 2013. doi:10.4161/trns.22542. PMID 23131666.
- ↑ "The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation". The Journal of Biological Chemistry 282 (18): 13141–5. May 2007. doi:10.1074/jbc.r700001200. PMID 17329240.
- ↑ Itzen, F; Greifenberg, A. K.; Bösken, C. A.; Geyer, M (2014). "Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation". Nucleic Acids Research 42 (12): 7577–90. doi:10.1093/nar/gku449. PMID 24860166.
- ↑ Jonkers, I; Lis, J. T. (2015). "Getting up to speed with transcription elongation by RNA polymerase II". Nature Reviews Molecular Cell Biology 16 (3): 167–77. doi:10.1038/nrm3953. PMID 25693130.
- ↑ 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. PMID 16109377.
- ↑ "Demystified molecular pathology of NUT midline carcinomas". Journal of Clinical Pathology 63 (6): 492–6. Jun 2010. doi:10.1136/jcp.2007.052902. PMID 18552174.
- ↑ 11.0 11.1 Da Costa, D.; Agathanggelou, A.; Perry, T.; Weston, V.; Petermann, E.; Zlatanou, A.; Oldreive, C.; Wei, W. et al. (2013-07-19). "BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia" (in en). Blood Cancer Journal 3 (7): e126. doi:10.1038/bcj.2013.24. PMID 23872705.
- ↑ "The mechanisms behind the therapeutic activity of BET bromodomain inhibition". Molecular Cell 54 (5): 728–36. Jun 2014. doi:10.1016/j.molcel.2014.05.016. PMID 24905006.
- ↑ "Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation". Nucleic Acids Research 42 (12): 7577–7590. Jul 2014. doi:10.1093/nar/gku449. PMID 24860166.
- ↑ Quaresma, AJ; Bugai A; Barboric M. (2016). "Cracking the control of RNA polymerase II elongation by 7SK snRNP and P-TEFb.". Nucleic Acids Research 44 (8): 7527–7539. doi:10.1093/nar/gkw585. PMID 27369380.
- ↑ "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 108 (22): E159–68. May 2011. doi:10.1073/pnas.1102140108. PMID 21536911.
- ↑ "Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release". Cell 155 (7): 1581–95. Dec 2013. doi:10.1016/j.cell.2013.10.056. PMID 24360279.
- ↑ 17.0 17.1 17.2 17.3 17.4 "A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase". Molecular and Cellular Biology 22 (18): 6509–20. Sep 2002. doi:10.1128/MCB.22.18.6509-6520.2002. PMID 12192049.
- ↑ "Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer". Cancer Cell 25 (2): 210–225. Feb 2014. doi:10.1016/j.ccr.2014.01.028. PMID 24525235.
- ↑ "Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition". The Journal of Biological Chemistry 287 (34): 28840–28851. Aug 2012. doi:10.1074/jbc.M112.359505. PMID 22645123.
- ↑ "RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist". PLOS ONE 8 (12): e83190. 31 December 2013. doi:10.1371/journal.pone.0083190. PMID 24391744. Bibcode: 2013PLoSO...883190M.
External links
- Human BRD4 genome location and BRD4 gene details page in the UCSC Genome Browser.
Further reading
- "BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19)". The American Journal of Pathology 159 (6): 1987–92. Dec 2001. doi:10.1016/S0002-9440(10)63049-0. PMID 11733348.
- "A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase". Molecular and Cellular Biology 22 (18): 6509–20. Sep 2002. doi:10.1128/MCB.22.18.6509-6520.2002. PMID 12192049.
- "BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma". Cancer Research 63 (2): 304–7. Jan 2003. PMID 12543779.
- "Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes". Cell 117 (3): 349–60. Apr 2004. doi:10.1016/S0092-8674(04)00402-7. PMID 15109495.
- "Functional proteomics mapping of a human signaling pathway". Genome Research 14 (7): 1324–32. Jul 2004. doi:10.1101/gr.2334104. PMID 15231748.
- "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proceedings of the National Academy of Sciences of the United States of America 101 (33): 12130–5. Aug 2004. doi:10.1073/pnas.0404720101. PMID 15302935. Bibcode: 2004PNAS..10112130B.
- "Bromodomain protein Brd4 binds to GTPase-activating SPA-1, modulating its activity and subcellular localization". Molecular and Cellular Biology 24 (20): 9059–69. Oct 2004. doi:10.1128/MCB.24.20.9059-9069.2004. PMID 15456879.
- "The mitotic chromosome binding activity of the papillomavirus E2 protein correlates with interaction with the cellular chromosomal protein, Brd4". Journal of Virology 79 (8): 4806–18. Apr 2005. doi:10.1128/JVI.79.8.4806-4818.2005. PMID 15795266.
- "Cloned fusion product from a rare t(15;19)(q13.2;p13.1) inhibit S phase in vitro". Journal of Medical Genetics 42 (7): 558–64. Jul 2005. doi:10.1136/jmg.2004.029686. PMID 15994877.
- "Bromodomain protein 4 mediates the papillomavirus E2 transcriptional activation function". Journal of Virology 80 (9): 4276–85. May 2006. doi:10.1128/JVI.80.9.4276-4285.2006. PMID 16611886.
- "Brd4 links chromatin targeting to HPV transcriptional silencing". Genes & Development 20 (17): 2383–96. Sep 2006. doi:10.1101/gad.1448206. PMID 16921027.
- "Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes". Journal of Virology 80 (18): 8909–19. Sep 2006. doi:10.1128/JVI.00502-06. PMID 16940503.
- "Amino acid substitutions that specifically impair the transcriptional activity of papillomavirus E2 affect binding to the long isoform of Brd4". Virology 358 (1): 10–7. Feb 2007. doi:10.1016/j.virol.2006.08.035. PMID 17023018.
- "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–48. Nov 2006. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
- "Structure of the papillomavirus DNA-tethering complex E2:Brd4 and a peptide that ablates HPV chromosomal association". Molecular Cell 24 (6): 877–89. Dec 2006. doi:10.1016/j.molcel.2006.11.002. PMID 17189190.
- "Brd4-independent transcriptional repression function of the papillomavirus e2 proteins". Journal of Virology 81 (18): 9612–22. Sep 2007. doi:10.1128/JVI.00447-07. PMID 17626100.
- "Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription". Proceedings of the National Academy of Sciences of the United States of America 104 (34): 13690–5. Aug 2007. doi:10.1073/pnas.0705053104. PMID 17690245. Bibcode: 2007PNAS..10413690B.
Original source: https://en.wikipedia.org/wiki/BRD4.
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