BCL3 explained

B-cell lymphoma 3-encoded protein is a protein that in humans is encoded by the BCL3 gene.[1] [2]

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.[3]

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

Interactions

BCL3 has been shown to interact with:

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.[12] Increased expression of BCL3 has been observed in the brains of patients with LOAD.[13]

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.[14] 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,[15] drive a cancer stem cell phenotype through enhancing β-catenin signalling,[16] drive the COX-2 mediated response to inflammatory cytokines,[17] and protect colorectal tumor cells against DNA damage.[18] The role of Bcl3 in enabling multiple cancer hallmarks in colorectal carcinogenesis has been reviewed.[19]

More recently other cancer cell signalling pathways have been shown to be modulated by Bcl3. These include Wnt/beta-catenin through direct protein interaction; Smad3, through an unknown mechanism of protein stabilisation[20] and transcriptional regulation of Stat3.[21] [22]  Other pathways influenced by Bcl3 activity include phosphorylation of AKT through an unknown mechanism.

Role in cancer therapy

Bcl3 also influences responses of cancer cells to treatment. Bcl3 promotes resistance to alkylating chemotherapy in gliomas,[23] DNA damaging agents in colorectal cancer, and regulates the cancer immune checkpoint control gene PD-L1 in ovarian cancer cells.[24]

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.[25] 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/

Further reading

Notes and References

  1. Wulczyn FG, Naumann M, Scheidereit C . Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-kappa B . Nature . 358 . 6387 . 597–599 . August 1992 . 1501714 . 10.1038/358597a0 . 4363340 . 1992Natur.358..597W .
  2. Ohno H, Takimoto G, McKeithan TW . The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control . Cell . 60 . 6 . 991–997 . March 1990 . 2180580 . 10.1016/0092-8674(90)90347-H . 1919787 .
  3. Web site: Entrez Gene: BCL3 B-cell CLL/lymphoma 3.
  4. Web site: Molecular Interaction Database. 2012-05-08. https://web.archive.org/web/20060506110418/http://mint.bio.uniroma2.it/mint/Welcome.do. 2006-05-06. dead.
  5. Na SY, Choi JE, Kim HJ, Jhun BH, Lee YC, Lee JW . Bcl3, an IkappaB protein, stimulates activating protein-1 transactivation and cellular proliferation . The Journal of Biological Chemistry . 274 . 40 . 28491–28496 . October 1999 . 10497212 . 10.1074/jbc.274.40.28491 . free.
  6. Naumann M, Wulczyn FG, Scheidereit C . 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 . January 1993 . 8428580 . 413194 . 10.1002/j.1460-2075.1993.tb05647.x .
  7. Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C . 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 . September 1999 . 10469655 . 1171549 . 10.1093/emboj/18.17.4766 .
  8. Thornburg NJ, Pathmanathan R, Raab-Traub N . Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma . Cancer Research . 63 . 23 . 8293–8301 . December 2003 . 14678988 .
  9. Bours V, Franzoso G, Azarenko V, Park S, Kanno T, Brown K, Siebenlist U . The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers . Cell . 72 . 5 . 729–739 . March 1993 . 8453667 . 10.1016/0092-8674(93)90401-b . free .
  10. Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, Scheidereit C, Leutz A . 6 . The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators . Oncogene . 18 . 22 . 3316–3323 . June 1999 . 10362352 . 10.1038/sj.onc.1202717 . 2356435 .
  11. Na SY, Choi HS, Kim JW, Na DS, Lee JW . Bcl3, an IkappaB protein, as a novel transcription coactivator of the retinoid X receptor . The Journal of Biological Chemistry . 273 . 47 . 30933–30938 . November 1998 . 9812988 . 10.1074/jbc.273.47.30933 . free .
  12. Nho K, Kim S, Horgusluoglu E, Risacher SL, Shen L, Kim D, Lee S, Foroud T, Shaw LM, Trojanowski JQ, Aisen PS, Petersen RC, Jack CR, Weiner MW, Green RC, Toga AW, Saykin AJ . 6 . 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 . May 2017 . 28589856 . 5461522 . 10.1186/s12920-017-0267-0 . free .
  13. Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, Rongve A, Børte S, Winsvold BS, Drange OK, Martinsen AE, Skogholt AH, Willer C, Bråthen G, Bosnes I, Nielsen JB, Fritsche LG, Thomas LF, Pedersen LM, Gabrielsen ME, Johnsen MB, Meisingset TW, Zhou W, Proitsi P, Hodges A, Dobson R, Velayudhan L, Heilbron K, Auton A, Sealock JM, Davis LK, Pedersen NL, Reynolds CA, Karlsson IK, Magnusson S, Stefansson H, Thordardottir S, Jonsson PV, Snaedal J, Zettergren A, Skoog I, Kern S, Waern M, Zetterberg H, Blennow K, Stordal E, Hveem K, Zwart JA, Athanasiu L, Selnes P, Saltvedt I, Sando SB, Ulstein I, Djurovic S, Fladby T, Aarsland D, Selbæk G, Ripke S, Stefansson K, Andreassen OA, Posthuma D . 6 . A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease . Nature Genetics . 53 . 9 . 1276–1282 . September 2021 . 34493870 . 10.1038/s41588-021-00921-z . 10243600 . 237442349 . 1871.1/61f01aa9-6dc7-4213-be2a-d3fe622db488 . free .
  14. Wakefield A, Soukupova J, Montagne A, Ranger J, French R, Muller WJ, Clarkson RW . Bcl3 selectively promotes metastasis of ERBB2-driven mammary tumors . Cancer Research . 73 . 2 . 745–755 . January 2013 . 23149915 . 10.1158/0008-5472.CAN-12-1321 . 342425 .
  15. Urban BC, Collard TJ, Eagle CJ, Southern SL, Greenhough A, Hamdollah-Zadeh M, Ghosh A, Poulsom R, Paraskeva C, Silver A, Williams AC . 6 . BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling . Gut . 65 . 7 . 1151–1164 . July 2016 . 26033966 . 4941180 . 10.1136/gutjnl-2014-308270 .
  16. Legge DN, Shephard AP, Collard TJ, Greenhough A, Chambers AC, Clarkson RW, Paraskeva C, Williams AC . 6 . BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells . Disease Models & Mechanisms . 12 . 3 . dmm037697 . March 2019 . 30792270 . 6451435 . 10.1242/dmm.037697 .
  17. Collard TJ, Fallatah HM, Greenhough A, Paraskeva C, Williams AC . BCL‑3 promotes cyclooxygenase‑2/prostaglandin E2 signalling in colorectal cancer . International Journal of Oncology . 56 . 5 . 1304–1313 . May 2020 . 32319612 . 10.3892/ijo.2020.5013 . 216073785 . free . 1983/bef31cac-06ce-4c40-99ed-d8e0ac1d04e1 . free .
  18. Parker C, Chambers AC, Flanagan DJ, Ho JW, Collard TJ, Ngo G, Baird DM, Timms P, Morgan RG, Sansom OJ, Williams AC . 6 . BCL-3 loss sensitises colorectal cancer cells to DNA damage by targeting homologous recombination . DNA Repair . 115 . 103331 . July 2022 . 35468497 . 10.1016/j.dnarep.2022.103331 . 10618080 . 1983/a562c74f-57b8-47be-b70e-d9e1984cfa3d . 248220856 .
  19. Legge DN, Chambers AC, Parker CT, Timms P, Collard TJ, Williams AC . 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 . May 2020 . 31930327 . 7221501 . 10.1093/carcin/bgaa003 .
  20. Chen X, Cao X, Sun X, Lei R, Chen P, Zhao Y, Jiang Y, Yin J, Chen R, Ye D, Wang Q, Liu Z, Liu S, Cheng C, Mao J, Hou Y, Wang M, Siebenlist U, Eugene Chin Y, Wang Y, Cao L, Hu G, Zhang X . 6 . Bcl-3 regulates TGFβ signaling by stabilizing Smad3 during breast cancer pulmonary metastasis . Cell Death & Disease . 7 . 12 . e2508 . December 2016 . 27906182 . 5261001 . 10.1038/cddis.2016.405 .
  21. Wu J, Li L, Jiang G, Zhan H, Wang N . 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 . December 2016 . 27748795 . 10.3892/ijo.2016.3729 . free .
  22. Zhao H, Wang W, Zhao Q, Hu G, Deng K, Liu Y . BCL3 exerts an oncogenic function by regulating STAT3 in human cervical cancer . OncoTargets and Therapy . 9 . 6619–6629 . Oct 2016 . 27822067 . 5087794 . 10.2147/OTT.S118184 . free .
  23. Wu L, Bernal GM, Cahill KE, Pytel P, Fitzpatrick CA, Mashek H, Weichselbaum RR, Yamini B . 6 . BCL3 expression promotes resistance to alkylating chemotherapy in gliomas . Science Translational Medicine . 10 . 448 . eaar2238 . July 2018 . 29973405 . 6613219 . 10.1126/scitranslmed.aar2238 .
  24. Zou Y, Uddin MM, Padmanabhan S, Zhu Y, Bu P, Vancura A, Vancurova I . 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 . October 2018 . 30135206 . 6177577 . 10.1074/jbc.RA118.004084 . free .
  25. Soukupová J, Bordoni C, Turnham DJ, Yang WW, Seaton G, Gruca A, French R, Lee KY, Varnava A, Piggott L, Clarkson RW, Westwell AD, Brancale A . 6 . The Discovery of a Novel Antimetastatic Bcl3 Inhibitor . Molecular Cancer Therapeutics . 20 . 5 . 775–786 . May 2021 . 33649105 . 10.1158/1535-7163.MCT-20-0283 . 232088625 . free .

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