BCL3

For BCl₃, see Boron trichloride.

B-cell lymphoma 3-encoded protein is a protein that in humans is encoded by the BCL3 gene.^[5][6]

BCL3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1K1A, 1K1B
Identifiers
Aliases	BCL3, BCL4, D19S37, B-cell CLL/lymphoma 3, B cell CLL/lymphoma 3, transcription coactivator, BCL3 transcription coactivator
External IDs	OMIM: 109560; MGI: 88140; HomoloGene: 81738; GeneCards: BCL3; OMA:BCL3 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.32 Start 44,747,705 bp[1] End 44,760,044 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7 A3|7 9.95 cM Start 19,542,387 bp[2] End 19,556,695 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left uterine tube right lobe of liver upper lobe of left lung gastric mucosa mucosa of transverse colon spleen apex of heart olfactory zone of nasal mucosa left adrenal cortex right lung Top expressed in lumbar spinal ganglion granulocyte mesenteric lymph nodes intestinal villus jejunum left lobe of liver duodenum colon ileum ankle joint More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding protein-macromolecule adaptor activity DNA-binding transcription factor activity transcription factor binding protein binding Cellular component cytoplasm Bcl3-Bcl10 complex nucleoplasm perinuclear region of cytoplasm Bcl3/NF-kappaB2 complex nucleus cytosol plasma membrane midbody intracellular membrane-bounded organelle protein-containing complex Biological process regulation of apoptotic process intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator regulation of DNA binding regulation of transcription, DNA-templated T-helper 2 cell differentiation antimicrobial humoral response germinal center formation response to virus DNA damage response, signal transduction by p53 class mediator extracellular matrix organization positive regulation of interferon-gamma production negative regulation of apoptotic process spleen development marginal zone B cell differentiation positive regulation of translation transcription, DNA-templated cellular response to DNA damage stimulus positive regulation of transcription, DNA-templated humoral immune response mediated by circulating immunoglobulin follicular dendritic cell differentiation defense response to bacterium T-helper 1 type immune response negative regulation of transcription, DNA-templated I-kappaB kinase/NF-kappaB signaling response to UV-C maintenance of protein location in nucleus positive regulation of transcription by RNA polymerase II defense response to protozoan negative regulation of receptor signaling pathway via JAK-STAT regulation of NIK/NF-kappaB signaling Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 602 12051 Ensembl ENSG00000069399 ENSMUSG00000053175 UniProt P20749 Q9Z2F6 RefSeq (mRNA) NM_005178 NM_033601 RefSeq (protein) NP_005169 NP_291079 Location (UCSC) Chr 19: 44.75 – 44.76 Mb Chr 7: 19.54 – 19.56 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

This gene is a proto-oncogene candidate. It is identified by its translocation into the immunoglobulin alpha-locus in some cases of B-cell leukemia. The protein encoded by this gene contains seven ankyrin repeats, which are most closely related to those found in I kappa B proteins. This protein functions as a transcriptional coactivator that activates through its association with NF-kappa B homodimers. The expression of this gene can be induced by NF-kappa B, which forms a part of the autoregulatory loop that controls the nuclear residence of p50 NF-kappa B.^[7]

Like BCL2, BCL5, BCL6, BCL7A, BCL9, and BCL10, it has clinical significance in lymphoma.

Interactions

BCL3 has been shown to interact with:

• BARD1,^[8]
• C-Fos,^[9]
• C-jun,^[9]
• C22orf25,^[10]
• COPS5,^[8]
• EP300,^[9]
• HTATIP,^[8]
• NFKB1,^[11][12][13]
• NFKB2,^[11][14]
• PIR,^[8] and
• NR2B1.^[15]

Clinical significance

Genetic variations in BCL3 gene have been associated with late-onset Alzheimer's disease (LOAD) and chronic lymphocytic leukemia. β-amyloid accumulation in neurons of Alzheimer's patients results in activation of NF-κB, which induces BCL3 expression.^[16] Increased expression of BCL3 has been observed in the brains of patients with LOAD.^[17]

The role of Bcl3 in solid tumors was established through the ability of Bcl3 to promote metastasis without affecting primary tumor growth or normal mammary function, within models of ErbB2-positive breast cancer.^[18] Further research has uncovered the role of Bcl3 in promoting progression of other solid tumors. The role of Bcl3 in promoting tumor hallmarks has been most widely reported for advanced colorectal cancer; where Bcl3 expression is up-regulated in >30% of colorectal cancer cases and is associated with a poor prognosis. For example, in colorectal cancer models, elevated Bcl3 expression was found to activate AKT signalling,^[19] drive a cancer stem cell phenotype through enhancing β-catenin signalling,^[20] drive the COX-2 mediated response to inflammatory cytokines,^[21] and protect colorectal tumor cells against DNA damage.^[22] The role of Bcl3 in enabling multiple cancer hallmarks in colorectal carcinogenesis has been reviewed.^[23]

More recently other cancer cell signalling pathways have been shown to be modulated by Bcl3. These include Wnt/beta-catenin through direct protein interaction;^[20] Smad3, through an unknown mechanism of protein stabilisation^[24] and transcriptional regulation of Stat3.^[25][26] Other pathways influenced by Bcl3 activity include phosphorylation of AKT through an unknown mechanism.^[19]

Role in cancer therapy

Bcl3 also influences responses of cancer cells to treatment. Bcl3 promotes resistance to alkylating chemotherapy in gliomas,^[27] DNA damaging agents in colorectal cancer,^[22] and regulates the cancer immune checkpoint control gene PD-L1 in ovarian cancer cells.^[28]

The first discovery of a small molecule anti-metastatic Bcl3 inhibitor was reported utilising a virtual drug design and screening approach, targeting the protein-protein interaction between Bcl3 and partner protein p50.^[29] The virtual screening hit compound showed potent intracellular Bcl3-inhibitory activity, and led to reductions in NF-κB signalling, tumor colony formation and cancer cell migration within in vitro cellular models of breast cancer. In vivo inhibition of tumor growth and anti-metastatic activity was observed in invasive breast cancer models, without overt systemic toxicity.

Development

TNA Therapeutics, is the only company engaged in developing a BCL3 inhibitor. TNAT-101, is an orally bioavailable, small molecule inhibitor of the novel target BCL3. BCL3 is a transcriptional regulator of multiple pathways critical for cancer initiation, maintenance and progression. It plays an important role in tumor growth, cell death, migration, metastasis and cancer stem cell viability.

https://www.tnatherapeutics.com/

References

1. GRCh38: Ensembl release 89: ENSG00000069399 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000053175 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Wulczyn FG, Naumann M, Scheidereit C (August 1992). "Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-kappa B". Nature. 358 (6387): 597–599. Bibcode:1992Natur.358..597W. doi:10.1038/358597a0. PMID 1501714. S2CID 4363340.
6. Ohno H, Takimoto G, McKeithan TW (March 1990). "The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control". Cell. 60 (6): 991–997. doi:10.1016/0092-8674(90)90347-H. PMID 2180580. S2CID 1919787.
7. "Entrez Gene: BCL3 B-cell CLL/lymphoma 3".
8. Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, et al. (June 1999). "The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators". Oncogene. 18 (22): 3316–3323. doi:10.1038/sj.onc.1202717. PMID 10362352. S2CID 2356435.
9. Na SY, Choi JE, Kim HJ, Jhun BH, Lee YC, Lee JW (October 1999). "Bcl3, an IkappaB protein, stimulates activating protein-1 transactivation and cellular proliferation". The Journal of Biological Chemistry. 274 (40): 28491–28496. doi:10.1074/jbc.274.40.28491. PMID 10497212.
10. "Molecular Interaction Database". Archived from the original on 2006-05-06. Retrieved 2012-05-08.
11. Thornburg NJ, Pathmanathan R, Raab-Traub N (December 2003). "Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma". Cancer Research. 63 (23): 8293–8301. PMID 14678988.
12. Naumann M, Wulczyn FG, Scheidereit C (January 1993). "The NF-kappa B precursor p105 and the proto-oncogene product Bcl-3 are I kappa B molecules and control nuclear translocation of NF-kappa B". The EMBO Journal. 12 (1): 213–222. doi:10.1002/j.1460-2075.1993.tb05647.x. PMC 413194. PMID 8428580.
13. Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C (September 1999). "NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of Bcl-3-p50 complexes". The EMBO Journal. 18 (17): 4766–4778. doi:10.1093/emboj/18.17.4766. PMC 1171549. PMID 10469655.
14. Bours V, Franzoso G, Azarenko V, Park S, Kanno T, Brown K, Siebenlist U (March 1993). "The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers". Cell. 72 (5): 729–739. doi:10.1016/0092-8674(93)90401-b. PMID 8453667.
15. Na SY, Choi HS, Kim JW, Na DS, Lee JW (November 1998). "Bcl3, an IkappaB protein, as a novel transcription coactivator of the retinoid X receptor". The Journal of Biological Chemistry. 273 (47): 30933–30938. doi:10.1074/jbc.273.47.30933. PMID 9812988.
16. Nho K, Kim S, Horgusluoglu E, Risacher SL, Shen L, Kim D, et al. (May 2017). "Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer's disease". BMC Medical Genomics. 10 (Suppl 1): 29. doi:10.1186/s12920-017-0267-0. PMC 5461522. PMID 28589856.
17. Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. (September 2021). "A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease". Nature Genetics. 53 (9): 1276–1282. doi:10.1038/s41588-021-00921-z. hdl:1871.1/61f01aa9-6dc7-4213-be2a-d3fe622db488. PMC 10243600. PMID 34493870. S2CID 237442349.
18. Wakefield A, Soukupova J, Montagne A, Ranger J, French R, Muller WJ, Clarkson RW (January 2013). "Bcl3 selectively promotes metastasis of ERBB2-driven mammary tumors". Cancer Research. 73 (2): 745–755. doi:10.1158/0008-5472.CAN-12-1321. PMID 23149915. S2CID 342425.
19. Urban BC, Collard TJ, Eagle CJ, Southern SL, Greenhough A, Hamdollah-Zadeh M, et al. (July 2016). "BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling". Gut. 65 (7): 1151–1164. doi:10.1136/gutjnl-2014-308270. PMC 4941180. PMID 26033966.
20. Legge DN, Shephard AP, Collard TJ, Greenhough A, Chambers AC, Clarkson RW, et al. (March 2019). "BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells". Disease Models & Mechanisms. 12 (3): dmm037697. doi:10.1242/dmm.037697. PMC 6451435. PMID 30792270.
21. Collard TJ, Fallatah HM, Greenhough A, Paraskeva C, Williams AC (May 2020). "BCL‑3 promotes cyclooxygenase‑2/prostaglandin E2 signalling in colorectal cancer". International Journal of Oncology. 56 (5): 1304–1313. doi:10.3892/ijo.2020.5013. hdl:1983/bef31cac-06ce-4c40-99ed-d8e0ac1d04e1. PMID 32319612. S2CID 216073785.
22. Parker C, Chambers AC, Flanagan DJ, Ho JW, Collard TJ, Ngo G, et al. (July 2022). "BCL-3 loss sensitises colorectal cancer cells to DNA damage by targeting homologous recombination" (PDF). DNA Repair. 115: 103331. doi:10.1016/j.dnarep.2022.103331. hdl:1983/a562c74f-57b8-47be-b70e-d9e1984cfa3d. PMC 10618080. PMID 35468497. S2CID 248220856.
23. Legge DN, Chambers AC, Parker CT, Timms P, Collard TJ, Williams AC (May 2020). "The role of B-Cell Lymphoma-3 (BCL-3) in enabling the hallmarks of cancer: implications for the treatment of colorectal carcinogenesis". Carcinogenesis. 41 (3): 249–256. doi:10.1093/carcin/bgaa003. PMC 7221501. PMID 31930327.
24. Chen X, Cao X, Sun X, Lei R, Chen P, Zhao Y, et al. (December 2016). "Bcl-3 regulates TGFβ signaling by stabilizing Smad3 during breast cancer pulmonary metastasis". Cell Death & Disease. 7 (12): e2508. doi:10.1038/cddis.2016.405. PMC 5261001. PMID 27906182.
25. Wu J, Li L, Jiang G, Zhan H, Wang N (December 2016). "B-cell CLL/lymphoma 3 promotes glioma cell proliferation and inhibits apoptosis through the oncogenic STAT3 pathway". International Journal of Oncology. 49 (6): 2471–2479. doi:10.3892/ijo.2016.3729. PMID 27748795.
26. Zhao H, Wang W, Zhao Q, Hu G, Deng K, Liu Y (Oct 2016). "BCL3 exerts an oncogenic function by regulating STAT3 in human cervical cancer". OncoTargets and Therapy. 9: 6619–6629. doi:10.2147/OTT.S118184. PMC 5087794. PMID 27822067.
27. Wu L, Bernal GM, Cahill KE, Pytel P, Fitzpatrick CA, Mashek H, et al. (July 2018). "BCL3 expression promotes resistance to alkylating chemotherapy in gliomas". Science Translational Medicine. 10 (448): eaar2238. doi:10.1126/scitranslmed.aar2238. PMC 6613219. PMID 29973405.
28. Zou Y, Uddin MM, Padmanabhan S, Zhu Y, Bu P, Vancura A, Vancurova I (October 2018). "The proto-oncogene Bcl3 induces immune checkpoint PD-L1 expression, mediating proliferation of ovarian cancer cells". The Journal of Biological Chemistry. 293 (40): 15483–15496. doi:10.1074/jbc.RA118.004084. PMC 6177577. PMID 30135206.
29. Soukupová J, Bordoni C, Turnham DJ, Yang WW, Seaton G, Gruca A, et al. (May 2021). "The Discovery of a Novel Antimetastatic Bcl3 Inhibitor". Molecular Cancer Therapeutics. 20 (5): 775–786. doi:10.1158/1535-7163.MCT-20-0283. PMID 33649105. S2CID 232088625.

Further reading

• Franzoso G, Bours V, Park S, Tomita-Yamaguchi M, Kelly K, Siebenlist U (September 1992). "The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition". Nature. 359 (6393): 339–342. Bibcode:1992Natur.359..339F. doi:10.1038/359339a0. PMID 1406939. S2CID 4322739.
• Bhatia K, Huppi K, McKeithan T, Siwarski D, Mushinski JF, Magrath I (September 1991). "Mouse bcl-3: cDNA structure, mapping and stage-dependent expression in B lymphocytes". Oncogene. 6 (9): 1569–1573. PMID 1923524.
• Mills FC, Brooker JS, Camerini-Otero RD (December 1990). "Sequences of human immunoglobulin switch regions: implications for recombination and transcription". Nucleic Acids Research. 18 (24): 7305–7316. doi:10.1093/nar/18.24.7305. PMC 332867. PMID 2124350.
• Crossen PE, Kennedy MA, Heaton DC, Morrison MJ (September 1993). "Cloning and sequencing of a t(14;19) breakpoint that involves the C mu switch region". Genes, Chromosomes & Cancer. 8 (1): 60–62. doi:10.1002/gcc.2870080110. PMID 7691160. S2CID 85217954.
• McKeithan TW, Ohno H, Dickstein J, Hume E (November 1994). "Genomic structure of the candidate proto-oncogene BCL3". Genomics. 24 (1): 120–126. doi:10.1006/geno.1994.1588. PMID 7896265.
• Zhang Q, Didonato JA, Karin M, McKeithan TW (June 1994). "BCL3 encodes a nuclear protein which can alter the subcellular location of NF-kappa B proteins". Molecular and Cellular Biology. 14 (6): 3915–3926. doi:10.1128/MCB.14.6.3915. PMC 358758. PMID 8196632.
• Fujita T, Nolan GP, Liou HC, Scott ML, Baltimore D (July 1993). "The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-kappa B p50 homodimers". Genes & Development. 7 (7B): 1354–1363. doi:10.1101/gad.7.7b.1354. PMID 8330739.
• Naumann M, Wulczyn FG, Scheidereit C (January 1993). "The NF-kappa B precursor p105 and the proto-oncogene product Bcl-3 are I kappa B molecules and control nuclear translocation of NF-kappa B". The EMBO Journal. 12 (1): 213–222. doi:10.1002/j.1460-2075.1993.tb05647.x. PMC 413194. PMID 8428580.
• Bours V, Franzoso G, Azarenko V, Park S, Kanno T, Brown K, Siebenlist U (March 1993). "The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers". Cell. 72 (5): 729–739. doi:10.1016/0092-8674(93)90401-B. PMID 8453667.
• Nolan GP, Fujita T, Bhatia K, Huppi C, Liou HC, Scott ML, Baltimore D (June 1993). "The bcl-3 proto-oncogene encodes a nuclear I kappa B-like molecule that preferentially interacts with NF-kappa B p50 and p52 in a phosphorylation-dependent manner". Molecular and Cellular Biology. 13 (6): 3557–3566. doi:10.1128/MCB.13.6.3557. PMC 359825. PMID 8497270.
• Watanabe N, Iwamura T, Shinoda T, Fujita T (June 1997). "Regulation of NFKB1 proteins by the candidate oncoprotein BCL-3: generation of NF-kappaB homodimers from the cytoplasmic pool of p50-p105 and nuclear translocation". The EMBO Journal. 16 (12): 3609–3620. doi:10.1093/emboj/16.12.3609. PMC 1169985. PMID 9218802.
• Bundy DL, McKeithan TW (December 1997). "Diverse effects of BCL3 phosphorylation on its modulation of NF-kappaB p52 homodimer binding to DNA". The Journal of Biological Chemistry. 272 (52): 33132–33139. doi:10.1074/jbc.272.52.33132. PMID 9407099.
• Weyrich AS, Dixon DA, Pabla R, Elstad MR, McIntyre TM, Prescott SM, Zimmerman GA (May 1998). "Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets". Proceedings of the National Academy of Sciences of the United States of America. 95 (10): 5556–5561. Bibcode:1998PNAS...95.5556W. doi:10.1073/pnas.95.10.5556. PMC 20416. PMID 9576921.
• Na SY, Choi HS, Kim JW, Na DS, Lee JW (November 1998). "Bcl3, an IkappaB protein, as a novel transcription coactivator of the retinoid X receptor". The Journal of Biological Chemistry. 273 (47): 30933–30938. doi:10.1074/jbc.273.47.30933. PMID 9812988.
• Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, et al. (June 1999). "The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators". Oncogene. 18 (22): 3316–3323. doi:10.1038/sj.onc.1202717. PMID 10362352. S2CID 2356435.
• Na SY, Choi JE, Kim HJ, Jhun BH, Lee YC, Lee JW (October 1999). "Bcl3, an IkappaB protein, stimulates activating protein-1 transactivation and cellular proliferation". The Journal of Biological Chemistry. 274 (40): 28491–28496. doi:10.1074/jbc.274.40.28491. PMID 10497212.
• Neumann M, Fries H, Scheicher C, Keikavoussi P, Kolb-Mäurer A, Bröcker E, et al. (January 2000). "Differential expression of Rel/NF-kappaB and octamer factors is a hallmark of the generation and maturation of dendritic cells". Blood. 95 (1): 277–285. doi:10.1182/blood.V95.1.277. PMID 10607713.
• Brasier AR, Lu M, Hai T, Lu Y, Boldogh I (August 2001). "NF-kappa B-inducible BCL-3 expression is an autoregulatory loop controlling nuclear p50/NF-kappa B1 residence". The Journal of Biological Chemistry. 276 (34): 32080–32093. doi:10.1074/jbc.M102949200. PMID 11387332.

External links

• FactorBook BCL3
• Human BCL3 genome location and BCL3 gene details page in the UCSC Genome Browser.