BCL3

Last updated

BCL3
Protein BCL3 PDB 1k1a.png
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
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

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

Contents

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:

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/

Related Research Articles

<span class="mw-page-title-main">NF-κB</span> Family of transcription factor protein complexes

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.

Zbtb7, whose protein product is also known as Pokemon, is a gene that functions as a regulator of cellular growth and a proto oncogene.

<span class="mw-page-title-main">Protein c-Fos</span> Mammalian protein found in Homo sapiens

Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the FOS gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV. It is a part of a bigger Fos family of transcription factors which includes c-Fos, FosB, Fra-1 and Fra-2. It has been mapped to chromosome region 14q21→q31. c-Fos encodes a 62 kDa protein, which forms heterodimer with c-jun, resulting in the formation of AP-1 complex which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression. It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers.

<span class="mw-page-title-main">Transcription factor Jun</span> Mammalian protein found in Homo sapiens

Transcription factor Jun is a protein that in humans is encoded by the JUN gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the JUN gene. c-jun was the first oncogenic transcription factor discovered. The proto-oncogene c-Jun is the cellular homolog of the viral oncoprotein v-jun. The viral homolog v-jun was discovered in avian sarcoma virus 17 and was named for ju-nana, the Japanese word for 17. The human JUN encodes a protein that is highly similar to the viral protein, which interacts directly with specific target DNA sequences to regulate gene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.

<span class="mw-page-title-main">IKK2</span> Protein-coding gene in the species Homo sapiens

IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the IKBKB gene.

<span class="mw-page-title-main">NFKB1</span> Protein-coding gene in the species Homo sapiens

Nuclear factor NF-kappa-B p105 subunit is a protein that in humans is encoded by the NFKB1 gene.

The IκB kinase is an enzyme complex that is involved in propagating the cellular response to inflammation, specifically the regulation of lymphocytes.

<span class="mw-page-title-main">IκBα</span> Protein-coding gene in the species Homo sapiens

IκBα is one member of a family of cellular proteins that function to inhibit the NF-κB transcription factor. IκBα inhibits NF-κB by masking the nuclear localization signals (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm. In addition, IκBα blocks the ability of NF-κB transcription factors to bind to DNA, which is required for NF-κB's proper functioning.

<span class="mw-page-title-main">RELA</span> Protein-coding gene in the species Homo sapiens

Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the RELA gene.

<span class="mw-page-title-main">NFKB2</span> Protein-coding gene in the species Homo sapiens

Nuclear factor NF-kappa-B p100 subunit is a protein that in humans is encoded by the NFKB2 gene.

<span class="mw-page-title-main">CHUK</span> Protein-coding gene in humans

Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a protein kinase that in humans is encoded by the CHUK gene. IKK-α is part of the IκB kinase complex that plays an important role in regulating the NF-κB transcription factor. However, IKK-α has many additional cellular targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.

<span class="mw-page-title-main">RELB</span> Protein-coding gene in the species Homo sapiens

Transcription factor RelB is a protein that in humans is encoded by the RELB gene.

<span class="mw-page-title-main">REL</span> Protein-coding gene in the species Homo sapiens

The proto-oncogene c-Rel is a protein that in humans is encoded by the REL gene. The c-Rel protein is a member of the NF-κB family of transcription factors and contains a Rel homology domain (RHD) at its N-terminus and two C-terminal transactivation domains. c-Rel is a myeloid checkpoint protein that can be targeted for treating cancer. c-Rel has an important role in B-cell survival and proliferation. The REL gene is amplified or mutated in several human B-cell lymphomas, including diffuse large B-cell lymphoma and Hodgkin's lymphoma.

<span class="mw-page-title-main">BTRC (gene)</span> Protein-coding gene in the species Homo sapiens

F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC gene.

<span class="mw-page-title-main">BCL2-related protein A1</span> Protein-coding gene in the species Homo sapiens

Bcl-2-related protein A1 is a protein in humans which is encoded by the BCL2A1 gene.

<span class="mw-page-title-main">MAP3K14</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 14 also known as NF-kappa-B-inducing kinase (NIK) is an enzyme that in humans is encoded by the MAP3K14 gene.

<span class="mw-page-title-main">MAP3K8</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the MAP3K8 gene.

<span class="mw-page-title-main">NFKBIZ</span> Protein-coding gene in the species Homo sapiens

NF-kappa-B inhibitor zeta (IκBζ) is a protein that in humans is encoded by the NFKBIZ gene. This gene is a member of the ankyrin-repeat family and is induced by lipopolysaccharide (LPS). The C-terminal portion of the encoded product which contains the ankyrin repeats, shares high sequence similarity with the I kappa B family of proteins. The latter are known to play a role in inflammatory responses to LPS by their interaction with NF-κB proteins through ankyrin-repeat domains. Studies in mouse indicate that this gene product is one of the nuclear I kappa B proteins and an activator of IL-6 production. Two transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">PIR (gene)</span> Protein-coding gene in the species Homo sapiens

Pirin is a protein that in humans is encoded by the PIR gene.

<span class="mw-page-title-main">NFKBID</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, delta also known as IκBNS is a protein in humans that is encoded by the NFKBID gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000069399 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 4 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. 1 2 3 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. 1 2 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. 1 2 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. 1 2 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. 1 2 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.

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