BRD4

{{Short description|Protein-coding gene in the species Homo sapiens}}

Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene.{{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 }}{{cite web | title = Entrez Gene: BRD4 bromodomain containing 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23476}}

BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT.{{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 | s2cid = 29706103 | doi-access = }} BRD4, similar to other BET family members, contains two bromodomains that recognize acetylated lysine residues.{{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}} BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members.

Structure

The two bromodomains in BRD4, termed BD1 and BD2, consist of 4 alpha-helices linked by 2 loops.{{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 }} The ET domain structure is made up of 3 alpha-helices and a loop.{{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 | doi-access = free }} 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

| pmid = 24860166

| pmc = 4081074

| year = 2014

| last1 = 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

}}{{Cite journal

| pmid = 25693130

| year = 2015

| last1 = 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

}}{{Cite journal

| pmid = 16109377

| year = 2005

| last1 = 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

| 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.{{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 | s2cid = 2200842 }} 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.{{Cite journal|last1=Da Costa|first1=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|journal=Blood Cancer Journal|language=en|volume=3|issue=7|pages=e126|doi=10.1038/bcj.2013.24|pmc=3730202|pmid=23872705}}

BRD4 is a major target of BET inhibitors,{{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 }} 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.{{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}}

Recent review

Source:{{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= |doi=10.1093/nar/gkw585|issue=8|pmc=5027500}}

BRD4 has been shown to interact with GATA1,{{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 | doi-access = free }} JMJD6,{{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 }} RFC2,{{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 }} 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.{{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 }}

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.{{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 | doi-access = free }} BRD4 also interacts with apabetalone (RVX-208),{{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 | bibcode = 2013PLoSO...883190M | doi-access = free }} which is being evaluated for treatment of atherosclerosis and cardiovascular disease.

References

External links

{{UCSC gene info|BRD4}}

Category:Proteins