View source for BRD4

{{Infobox_gene}}
'''Bromodomain-containing protein 4''' is a [[protein]] that in humans is encoded by the ''BRD4'' [[gene]].<ref name="pmid10938129">{{cite journal | vauthors = Dey A, Ellenberg J, Farina A, Coleman AE, Maruyama T, Sciortino S, Lippincott-Schwartz J, Ozato K | title = A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition | journal = Molecular and Cellular Biology | volume = 20 | issue = 17 | pages = 6537–49 | date = Sep 2000 | pmid = 10938129 | pmc = 86127 | doi = 10.1128/MCB.20.17.6537-6549.2000 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: BRD4 bromodomain containing 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23476| accessdate = }}</ref>

BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes [[BRD2]], [[BRD3]], and [[BRDT]].<ref name="ReferenceA">{{cite journal | vauthors = Zeng L, Zhou MM | title = Bromodomain: an acetyl-lysine binding domain | journal = FEBS Letters | volume = 513 | issue = 1 | pages = 124–8 | date = Feb 2002 | pmid = 11911891 | doi = 10.1016/s0014-5793(01)03309-9 }}</ref> BRD4, similar to other BET family members, contains two [[bromodomain]]s that recognize [[acetylated]] [[lysine]] residues.<ref>{{cite journal | vauthors = Shi J, Vakoc CR | title = The mechanisms behind the therapeutic activity of BET bromodomain inhibition | journal = Molecular Cell | volume = 54 | issue = 5 | pages = 728–736 | date = Jun 2014 | pmid = 24905006 | doi = 10.1016/j.molcel.2014.05.016 | pmc=4236231}}</ref> BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members.<ref name="ReferenceA" />

== Structure ==

The two bromodomains in BRD4, termed BD1 and BD2, consist of 4 [[alpha-helices]] linked by 2 [[turn (biochemistry)|loops]].<ref>{{cite journal | vauthors = Devaiah BN, Singer DS | title = Two faces of brd4: mitotic bookmark and transcriptional lynchpin | journal = Transcription | volume = 4 | issue = 1 | pages = 13–17 | date = 1 January 2013 | pmid = 23131666 | pmc = 3644036 | doi = 10.4161/trns.22542 }}</ref> The ET domain structure  is made up of 3 alpha-helices and a loop.<ref>{{cite journal | vauthors = Wu SY, Chiang CM | title = The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation | journal = The Journal of Biological Chemistry | volume = 282 | issue = 18 | pages = 13141–5 | date = May 2007 | pmid = 17329240 | doi = 10.1074/jbc.r700001200 }}</ref> 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]].<ref>{{Cite journal
 | pmid = 24860166
| pmc = 4081074
| year = 2014
| author1 = Itzen
| first1 = F
| title = Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation
| journal = Nucleic Acids Research
| volume = 42
| issue = 12
| pages = 7577–90
| last2 = Greifenberg
| first2 = A. K.
| last3 = Bösken
| first3 = C. A.
| last4 = Geyer
| first4 = M
| doi = 10.1093/nar/gku449
}}</ref><ref>{{Cite journal
 | pmid = 25693130
| year = 2015
| author1 = Jonkers
| first1 = I
| title = Getting up to speed with transcription elongation by RNA polymerase II
| journal = Nature Reviews Molecular Cell Biology
| volume = 16
| issue = 3
| pages = 167–77
| last2 = Lis
| first2 = J. T.
| doi = 10.1038/nrm3953
 | pmc=4782187
}}</ref><ref>{{Cite journal
 | pmid = 16109377
| year = 2005
| author1 = Yang
| first1 = Z
| title = Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4
| journal = Molecular Cell
| volume = 19
| issue = 4
| pages = 535–45
| last2 = Yik
| first2 = J. H.
| last3 = Chen
| first3 = R
| last4 = He
| first4 = N
| last5 = Jang
| first5 = M. K.
| last6 = Ozato
| first6 = K
| last7 = Zhou
| first7 = Q
| doi = 10.1016/j.molcel.2005.06.029
}}</ref>

== 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.<ref name="entrez" />

== Role in cancer ==

Most cases of [[NUT midline carcinoma]] involve translocation of the BRD4 with NUT genes.<ref>{{cite journal | vauthors = French CA | title = Demystified molecular pathology of NUT midline carcinomas | journal = Journal of Clinical Pathology | volume = 63 | issue = 6 | pages = 492–6 | date = Jun 2010 | pmid = 18552174 | doi = 10.1136/jcp.2007.052902 }}</ref> 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 leukemia|acute lymphoblastic leukaemia.]]<ref name="Da Costa e126">{{Cite journal|last=Da Costa|first=D.|last2=Agathanggelou|first2=A.|last3=Perry|first3=T.|last4=Weston|first4=V.|last5=Petermann|first5=E.|last6=Zlatanou|first6=A.|last7=Oldreive|first7=C.|last8=Wei|first8=W.|last9=Stewart|first9=G.|date=2013-07-19|title=BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia|url=http://www.nature.com/bcj/journal/v3/n7/full/bcj201324a.html|journal=Blood Cancer Journal|language=en|volume=3|issue=7|pages=e126|doi=10.1038/bcj.2013.24|pmc=3730202|pmid=23872705}}</ref>

BRD4 is a major target of [[BET inhibitors]],<ref>{{cite journal | vauthors = Shi J, Vakoc CR | title = The mechanisms behind the therapeutic activity of BET bromodomain inhibition | journal = Molecular Cell | volume = 54 | issue = 5 | pages = 728–36 | date = Jun 2014 | pmid = 24905006 | pmc = 4236231 | doi = 10.1016/j.molcel.2014.05.016 }}</ref><ref name="Da Costa e126"/> 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]].<ref>{{cite journal | vauthors = Itzen F, Greifenberg AK, Bösken CA, Geyer M | title = Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation | journal = Nucleic Acids Research | volume = 42 | issue = 12 | date = Jul 2014 | pmid = 24860166 | doi = 10.1093/nar/gku449 | pmc=4081074 | pages=7577–7590}}</ref> Recent review.<ref>{{cite journal|last=Quaresma|first=AJ|author2=Bugai A|author3=Barboric M.|title=Cracking the control of RNA polymerase II elongation by 7SK snRNP and P-TEFb.|journal=Nucleic Acids Research|year=2016|volume=44|pages=7527–7539.|pmid=27369380|url=http://nar.oxfordjournals.org/content/44/16/7527.long|doi=10.1093/nar/gkw585|issue=8|pmc=5027500|}}</ref>

BRD4 has been shown to [[Protein-protein interaction|interact]] with [[GATA1]],<ref>{{cite journal | vauthors = Lamonica JM, Deng W, Kadauke S, Campbell AE, Gamsjaeger R, Wang H, Cheng Y, Billin AN, Hardison RC, Mackay JP, Blobel GA | title = Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 22 | pages = E159–68 | date = May 2011 | pmid = 21536911 | pmc = 3107332 | doi = 10.1073/pnas.1102140108 }}</ref> [[JMJD6]],<ref>{{cite journal | vauthors = Liu W, Ma Q, Wong K, Li W, Ohgi K, Zhang J, Aggarwal AK, Rosenfeld MG | title = Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release | journal = Cell | volume = 155 | issue = 7 | pages = 1581–95 | date = Dec 2013 | pmid = 24360279 | pmc = 3886918 | doi = 10.1016/j.cell.2013.10.056 }}</ref> [[RFC2]],<ref name=pmid12192049>{{cite journal | vauthors = Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K | title = A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase | journal = Molecular and Cellular Biology | volume = 22 | issue = 18 | pages = 6509–20 | date = Sep 2002 | pmid = 12192049 | pmc = 135621 | doi = 10.1128/MCB.22.18.6509-6520.2002 }}</ref> [[RFC3]],<ref name=pmid12192049 /> [[RFC1]],<ref name=pmid12192049 /> [[RFC4]]<ref name=pmid12192049 /> and [[RFC5]].<ref name=pmid12192049 />

BRD4 has also been implicated in binding with the diacetylated [[Twist transcription factor|Twist]] protein, and the disruption of this interaction has been shown to suppress tumorigenesis in basal-like breast cancer.<ref>{{cite journal | vauthors = Shi J, Wang Y, Zeng L, Wu Y, Deng J, Zhang Q, Lin Y, Li J, Kang T, Tao M, Rusinova E, Zhang G, Wang C, Zhu H, Yao J, Zeng YX, Evers BM, Zhou MM, Zhou BP | title = Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer | journal = Cancer Cell | volume = 25 | issue = 2 | pages = 210–225 | date = Feb 2014 | pmid = 24525235 | pmc = 4004960 | doi = 10.1016/j.ccr.2014.01.028 }}</ref>

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.<ref>{{cite journal | vauthors = Zhang G, Liu R, Zhong Y, Plotnikov AN, Zhang W, Zeng L, Rusinova E, Gerona-Nevarro G, Moshkina N, Joshua J, Chuang PY, Ohlmeyer M, He JC, Zhou MM | title = Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition | journal = The Journal of Biological Chemistry | volume = 287 | issue = 34 | pages = 28840–28851 | date = Aug 2012 | pmid = 22645123 | pmc = 3436579 | doi = 10.1074/jbc.M112.359505 }}</ref> BRD4 also interacts with [[RVX 208|RVX-208]],<ref>{{cite journal | vauthors = McLure KG, Gesner EM, Tsujikawa L, Kharenko OA, Attwell S, Campeau E, Wasiak S, Stein A, White A, Fontano E, Suto RK, Wong NC, Wagner GS, Hansen HC, Young PR | title = RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist | journal = PLOS ONE | volume = 8 | issue = 12 | pages = e83190 | date = 31 December 2013 | pmid = 24391744 | pmc = 3877016 | doi = 10.1371/journal.pone.0083190 }}</ref> which is being evaluated for treatment of [[atherosclerosis]] and [[cardiovascular disease]].
{{Clear}}

== References ==
{{reflist|33em}}

==External links==
* {{UCSC gene info|BRD4}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA | title = BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19) | journal = The American Journal of Pathology | volume = 159 | issue = 6 | pages = 1987–92 | date = Dec 2001 | pmid = 11733348 | pmc = 1850578 | doi = 10.1016/S0002-9440(10)63049-0 }}
* {{cite journal | vauthors = Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K | title = A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase | journal = Molecular and Cellular Biology | volume = 22 | issue = 18 | pages = 6509–20 | date = Sep 2002 | pmid = 12192049 | pmc = 135621 | doi = 10.1128/MCB.22.18.6509-6520.2002 }}
* {{cite journal | vauthors = French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA | title = BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma | journal = Cancer Research | volume = 63 | issue = 2 | pages = 304–7 | date = Jan 2003 | pmid = 12543779 | doi =  }}
* {{cite journal | vauthors = You J, Croyle JL, Nishimura A, Ozato K, Howley PM | title = Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes | journal = Cell | volume = 117 | issue = 3 | pages = 349–60 | date = Apr 2004 | pmid = 15109495 | doi = 10.1016/S0092-8674(04)00402-7 }}
* {{cite journal | vauthors = Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM | title = Functional proteomics mapping of a human signaling pathway | journal = Genome Research | volume = 14 | issue = 7 | pages = 1324–32 | date = Jul 2004 | pmid = 15231748 | pmc = 442148 | doi = 10.1101/gr.2334104 }}
* {{cite journal | vauthors = Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP | title = Large-scale characterization of HeLa cell nuclear phosphoproteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 33 | pages = 12130–5 | date = Aug 2004 | pmid = 15302935 | pmc = 514446 | doi = 10.1073/pnas.0404720101 }}
* {{cite journal | vauthors = Farina A, Hattori M, Qin J, Nakatani Y, Minato N, Ozato K | title = Bromodomain protein Brd4 binds to GTPase-activating SPA-1, modulating its activity and subcellular localization | journal = Molecular and Cellular Biology | volume = 24 | issue = 20 | pages = 9059–69 | date = Oct 2004 | pmid = 15456879 | pmc = 517877 | doi = 10.1128/MCB.24.20.9059-9069.2004 }}
* {{cite journal | vauthors = Baxter MK, McPhillips MG, Ozato K, McBride AA | title = The mitotic chromosome binding activity of the papillomavirus E2 protein correlates with interaction with the cellular chromosomal protein, Brd4 | journal = Journal of Virology | volume = 79 | issue = 8 | pages = 4806–18 | date = Apr 2005 | pmid = 15795266 | pmc = 1069523 | doi = 10.1128/JVI.79.8.4806-4818.2005 }}
* {{cite journal | vauthors = Haruki N, Kawaguchi KS, Eichenberger S, Massion PP, Gonzalez A, Gazdar AF, Minna JD, Carbone DP, Dang TP | title = Cloned fusion product from a rare t(15;19)(q13.2;p13.1) inhibit S phase in vitro | journal = Journal of Medical Genetics | volume = 42 | issue = 7 | pages = 558–64 | date = Jul 2005 | pmid = 15994877 | pmc = 1736105 | doi = 10.1136/jmg.2004.029686 }}
* {{cite journal | vauthors = Schweiger MR, You J, Howley PM | title = Bromodomain protein 4 mediates the papillomavirus E2 transcriptional activation function | journal = Journal of Virology | volume = 80 | issue = 9 | pages = 4276–85 | date = May 2006 | pmid = 16611886 | pmc = 1472042 | doi = 10.1128/JVI.80.9.4276-4285.2006 }}
* {{cite journal | vauthors = Wu SY, Lee AY, Hou SY, Kemper JK, Erdjument-Bromage H, Tempst P, Chiang CM | title = Brd4 links chromatin targeting to HPV transcriptional silencing | journal = Genes & Development | volume = 20 | issue = 17 | pages = 2383–96 | date = Sep 2006 | pmid = 16921027 | pmc = 1560413 | doi = 10.1101/gad.1448206 }}
* {{cite journal | vauthors = You J, Srinivasan V, Denis GV, Harrington WJ, Ballestas ME, Kaye KM, Howley PM | title = Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes | journal = Journal of Virology | volume = 80 | issue = 18 | pages = 8909–19 | date = Sep 2006 | pmid = 16940503 | pmc = 1563901 | doi = 10.1128/JVI.00502-06 }}
* {{cite journal | vauthors = Sénéchal H, Poirier GG, Coulombe B, Laimins LA, Archambault J | title = Amino acid substitutions that specifically impair the transcriptional activity of papillomavirus E2 affect binding to the long isoform of Brd4 | journal = Virology | volume = 358 | issue = 1 | pages = 10–7 | date = Feb 2007 | pmid = 17023018 | doi = 10.1016/j.virol.2006.08.035 }}
* {{cite journal | vauthors = Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M | title = Global, in vivo, and site-specific phosphorylation dynamics in signaling networks | journal = Cell | volume = 127 | issue = 3 | pages = 635–48 | date = Nov 2006 | pmid = 17081983 | doi = 10.1016/j.cell.2006.09.026 }}
* {{cite journal | vauthors = Abbate EA, Voitenleitner C, Botchan MR | title = Structure of the papillomavirus DNA-tethering complex E2:Brd4 and a peptide that ablates HPV chromosomal association | journal = Molecular Cell | volume = 24 | issue = 6 | pages = 877–89 | date = Dec 2006 | pmid = 17189190 | doi = 10.1016/j.molcel.2006.11.002 }}
* {{cite journal | vauthors = Schweiger MR, Ottinger M, You J, Howley PM | title = Brd4-independent transcriptional repression function of the papillomavirus e2 proteins | journal = Journal of Virology | volume = 81 | issue = 18 | pages = 9612–22 | date = Sep 2007 | pmid = 17626100 | pmc = 2045424 | doi = 10.1128/JVI.00447-07 }}
* {{cite journal | vauthors = Bisgrove DA, Mahmoudi T, Henklein P, Verdin E | title = Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 34 | pages = 13690–5 | date = Aug 2007 | pmid = 17690245 | pmc = 1959443 | doi = 10.1073/pnas.0705053104 }}
{{refend}}

{{PDB Gallery|geneid=23476}}

[[Category:Proteins]]