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