BRD4

Bromodomain containing 4

PDB rendering based on 2oss.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BRD4 ; CAP; HUNK1; HUNKI; MCAP
External IDs OMIM: 608749 MGI: 1888520 HomoloGene: 137685 IUPHAR: 1945 ChEMBL: 1163125 GeneCards: BRD4 Gene
EC number 3.1.1.31
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 23476 57261
Ensembl ENSG00000141867 ENSMUSG00000024002
UniProt O60885 Q9ESU6
RefSeq (mRNA) NM_014299 NM_020508
RefSeq (protein) NP_055114 NP_065254
Location (UCSC) Chr 19:
15.24 – 15.33 Mb		 Chr 17:
32.2 – 32.28 Mb
PubMed search

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 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 with NUT genes.[10] BRD4 is often required for expression of Myc and other "tumor driving" oncogenes in hematologic cancers including multiple myeloma and acute myelogenous leukemia. BRD4 is a major target of BET inhibitors,[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.[12]

BRD4 has been shown to interact with GATA1,[13] JMJD6,[14] RFC2,[15] RFC3,[15] RFC1,[15] RFC4[15] and RFC5.[15]

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.[16]

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.[17] BRD4 also interacts with RVX-208,[18] which is being evaluated for treatment of atherosclerosis and cardiovascular disease.

References

  1. ↑ Dey A, Ellenberg J, Farina A, Coleman AE, Maruyama T, Sciortino S, Lippincott-Schwartz J, Ozato K (Sep 2000). "A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition". Molecular and Cellular Biology 20 (17): 6537–49. doi:10.1128/MCB.20.17.6537-6549.2000. PMC 86127. PMID 10938129.
  2. 1 2 "Entrez Gene: BRD4 bromodomain containing 4".
  3. 1 2 Zeng L, Zhou MM (Feb 2002). "Bromodomain: an acetyl-lysine binding domain". FEBS Letters 513 (1): 124–8. doi:10.1016/s0014-5793(01)03309-9. PMID 11911891.
  4. ↑ Shi J, Vakoc CR (Jun 2014). "The mechanisms behind the therapeutic activity of BET bromodomain inhibition". Molecular Cell 54 (5): 728–736. doi:10.1016/j.molcel.2014.05.016. PMC 4236231. PMID 24905006.
  5. ↑ Devaiah BN, Singer DS (1 January 2013). "Two faces of brd4: mitotic bookmark and transcriptional lynchpin". Transcription 4 (1): 13–17. doi:10.4161/trns.22542. PMC 3644036. PMID 23131666.
  6. ↑ 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. PMID 17329240.
  7. ↑ 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. PMC 4081074. PMID 24860166.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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. PMID 18552174.
  11. ↑ Shi J, Vakoc CR (Jun 2014). "The mechanisms behind the therapeutic activity of BET bromodomain inhibition". Molecular Cell 54 (5): 728–36. doi:10.1016/j.molcel.2014.05.016. PMC 4236231. PMID 24905006.
  12. ↑ Itzen F, Greifenberg AK, Bösken CA, Geyer M (Jul 2014). "Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation". Nucleic Acids Research 42 (12): 7577–7590. doi:10.1093/nar/gku449. PMC 4081074. PMID 24860166.
  13. ↑ Lamonica JM, Deng W, Kadauke S, Campbell AE, Gamsjaeger R, Wang H, Cheng Y, Billin AN, Hardison RC, Mackay JP, Blobel GA (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 108 (22): E159–68. doi:10.1073/pnas.1102140108. PMC 3107332. PMID 21536911.
  14. ↑ Liu W, Ma Q, Wong K, Li W, Ohgi K, Zhang J, Aggarwal AK, Rosenfeld MG (Dec 2013). "Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release". Cell 155 (7): 1581–95. doi:10.1016/j.cell.2013.10.056. PMC 3886918. PMID 24360279.
  15. 1 2 3 4 5 Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K (Sep 2002). "A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase". Molecular and Cellular Biology 22 (18): 6509–20. doi:10.1128/MCB.22.18.6509-6520.2002. PMC 135621. PMID 12192049.
  16. ↑ 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 (Feb 2014). "Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer". Cancer Cell 25 (2): 210–225. doi:10.1016/j.ccr.2014.01.028. PMC 4004960. PMID 24525235.
  17. ↑ 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 (Aug 2012). "Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition". The Journal of Biological Chemistry 287 (34): 28840–28851. doi:10.1074/jbc.M112.359505. PMC 3436579. PMID 22645123.
  18. ↑ 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 (31 December 2013). "RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist". PLOS ONE 8 (12): e83190. doi:10.1371/journal.pone.0083190. PMC 3877016. PMID 24391744.

Further reading

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