BCL3

Summary

BCL3 (BCL3 transcription coactivator, HGNC:998) is a protein-coding gene on chromosome 19q13.32, encoding B-cell lymphoma 3 protein (P20749). Contributes to the regulation of transcriptional activation of NF-kappa-B target genes.

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 co-activator 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.

Source: NCBI Gene 602 — RefSeq curated summary.

At a glance

• GWAS associations: 41
• Clinical variants (ClinVar): 80 total
• Druggable target: yes
• Transcription factor: yes — 36 downstream targets (CollecTRI)
• MANE Select transcript: NM_005178

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:998
Approved symbol	BCL3
Name	BCL3 transcription coactivator
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000069399
Ensembl biotype	protein_coding
OMIM	109560
Entrez	602

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 retained_intron, 2 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000164227, ENST00000403534, ENST00000444487, ENST00000464319, ENST00000473468, ENST00000473473, ENST00000474300, ENST00000477832, ENST00000487394

RefSeq mRNA: 1 — MANE Select: NM_005178 NM_005178

CCDS: CCDS12642

Canonical transcript exons

ENST00000164227 — 9 exons

Exon	Start	End
ENSE00001549617	44759428	44760044
ENSE00001823746	44748708	44749046
ENSE00003534157	44757646	44757723
ENSE00003550473	44758246	44758413
ENSE00003592913	44751227	44751380
ENSE00003600591	44757017	44757221
ENSE00003605392	44756232	44756340
ENSE00003639612	44757327	44757415
ENSE00003669599	44758724	44758841

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 98.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 57.7402 / max 3472.1535, expressed in 1793 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176281	35.8178	1687
176282	9.6397	1112
176278	3.9183	1110
176280	2.3440	1228
176291	1.3368	524
176293	1.1734	632
176279	0.9631	195
176285	0.7540	353
176294	0.7468	412
176284	0.3993	190

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left uterine tube	UBERON:0001303	98.30	gold quality
right lobe of liver	UBERON:0001114	98.05	gold quality
upper lobe of left lung	UBERON:0008952	97.03	gold quality
mucosa of stomach	UBERON:0001199	96.73	gold quality
lower esophagus mucosa	UBERON:0035834	96.71	gold quality
mucosa of transverse colon	UBERON:0004991	96.61	gold quality
spleen	UBERON:0002106	96.50	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.46	gold quality
esophagus mucosa	UBERON:0002469	96.45	gold quality
omental fat pad	UBERON:0010414	96.42	gold quality
peritoneum	UBERON:0002358	96.37	gold quality
apex of heart	UBERON:0002098	96.33	gold quality
upper lobe of lung	UBERON:0008948	96.24	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.15	gold quality
transverse colon	UBERON:0001157	95.87	gold quality
left adrenal gland cortex	UBERON:0035825	95.82	gold quality
right lung	UBERON:0002167	95.79	gold quality
minor salivary gland	UBERON:0001830	95.73	gold quality
body of stomach	UBERON:0001161	95.66	gold quality
left adrenal gland	UBERON:0001234	95.55	gold quality
vena cava	UBERON:0004087	95.38	gold quality
esophagus	UBERON:0001043	95.29	gold quality
left lobe of thyroid gland	UBERON:0001120	95.25	gold quality
granulocyte	CL:0000094	95.18	gold quality
right coronary artery	UBERON:0001625	95.17	gold quality
adrenal cortex	UBERON:0001235	95.15	gold quality
small intestine	UBERON:0002108	94.98	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.91	gold quality
right lobe of thyroid gland	UBERON:0001119	94.88	gold quality
right adrenal gland	UBERON:0001233	94.87	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.90

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

36 targets.

Target	Regulation
ADRB2
BCL2	Activation
BCL3
CAMP	Activation
CCND1	Activation
CDKN2A
CEL
CRTC3	Repression
CTCF	Repression
CXCL8	Unknown
EGFR	Activation
GNAS
IFNG	Unknown
IL10
IL2
IL23A	Repression
IL6
IRF6
LCK
MDM2	Activation
MMP1
MYB	Unknown
NFKB	Repression
NFKB1	Repression
NOS2
PDK4	Activation
PDLIM7
PTHLH
RB1
RELA	Unknown

Upstream regulators (CollecTRI, top): AP1, BCL3, DMTF1, MYC, NFKB1, NFKB, NKX6-3, RELA, STAT3, TP53

miRNA regulators (miRDB)

47 targeting BCL3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-4324	99.04	70.14	1569

Literature-anchored findings (GeneRIF, showing 40)

• High-level expression of BCL3 differentiates t(2;5)(p23;q35)-positive anaplastic large cell lymphoma from Hodgkin disease. (PMID:12456498)
• BCL3 is downregulated by p53 to repress cyclin D1 and has a role in regulation of cell cycle progression (PMID:12808109)
• The relatively high frequency of BCL-3 expression in some non-Hodgkin and Hodgkin lymphoma types raises the possibility that BCL-3 is involved in the pathogenesis of these tumors, and may be a target of new therapies. (PMID:15105810)
• Supported by IL-12 signals, Bcl-3 enhances survival and clonal expansion of transgenic OT-1 CD8 T cells. (PMID:15634875)
• Bcl-3 might participate in oncogenic pathways involving Lck (PMID:16099425)
• (p52)2/Bcl-3P ternary complex, which is specifically induced in CD30-stimulated anaplasstic larage cell lymphoma, can modulate expression of apoptosis-related genes regulated by NF-kappaB. (PMID:16108830)
• elevated Bcl-3 expression has an important function in classical Hodgkin lymphoma and peripheral T-cell non-Hodgkin lymphoma, in particular anaplastic large-cell lymphomas (PMID:16123212)
• overexpression of BCL3 increases apoptosis, whereas BCL3-specific siRNA does not affect the viability of INA-6 cells suggesting that BCL3 is not essential for the survival of these cells (PMID:16732314)
• HBx and NF-kappaB2/BCL3 mediated-cyclin D1 up-regulation might play an important role in the HBx-mediated HCC development and progression (PMID:16940298)
• study indicates that BCL3 translocations are not restricted to B-cell chronic lymphocytic leukemia but present in a heterogeneous group of B-cell malignancies (PMID:17495977)
• BCL3 functions as a repressor of HTLV-1 LTR-mediated transcription through interactions with TORC3 (PMID:17644518)
• induction of p50/p50/Bcl-3 complexes by latent membrane protein 1 (LMP1) C-terminal activating region 1 mediates LMP1-induced epidermal growth factor receptor upregulation (PMID:17881446)
• Bcl-3 is rapidly induced following the expression of Epstein-Barr virus LMP1. (PMID:17963943)
• demonstrated that HCCs almost universally overexpress Bcl-3 and preferentially express nuclear p52 and p50, with little evidence of p65 activation. (PMID:18025803)
• Buthionine sulfoximine activates a noncanonical, inhibitory NF-kappaB- and p65-independent NF-kappaB pathway via a multistep process leading to the up-regulation of Bcl-2 (PMID:18796561)
• BCL2 or BCL3 are recurrent translocation partners of the IGH locus in cHL (classical Hodgkin lymphomas). (PMID:18940474)
• BCL3 is a common target gene for several growth-promoting cytokines in myeloma cells and high expression of BCL3 at the time of diagnosis is associated with poor prognosis of patients with multiple myeloma (PMID:19191868)
• Characterization of the mouse BCL3 ortholog and comparison to the human gene. (PMID:1923524)
• Bcl-3 as an important modulator of cutaneous innate immune responses and its possible therapeutic role in atopic dermatitis (AD). (PMID:19282837)
• elevated lung levels of IL-10 may impair MTb-mediated alveolar macrophage apoptosis in HIV through a BCL-3-dependent mechanism (PMID:19383626)
• Transcriptional profiling demonstrated that Bcl3 activates genes involved in diverse pathways including a subset involved in cellular energy metabolism known to be regulated by PGC-1alpha, ERRalpha, and a second nuclear receptor, PPARalpha. (PMID:19451226)
• activation of p52/Bcl-3 complexes in monocyte-derived macrophages (MDM) and p50/p65 heterodimers in fibroblasts in response to HCMV infection might explain the low-level growth of the virus in MDMs vs efficient growth in fibroblasts (PMID:19494302)
• adiponectin augmented the expression of A20, suppressor of cytokine signaling (SOCS) 3, B-cell CLL/lymphoma (BCL) 3, TNF receptor-associated factor (TRAF) 1, and TNFAIP3-interacting protein (TNIP) 3. (PMID:19617629)
• JNK2 suppression of a novel JNK1/c-Jun/Bcl-3 apoptotic network hasa role in basal cancer cell survival (PMID:19806201)
• Bcl-3 interacts with the pleckstrin homology domain and the phosphotyrosine binding domain of IRS-3, and that IRS-3 interacts with the ankyrin repeat domain of Bcl-3. (PMID:20226764)
• NF-kB and Bcl-3 activation are prognostic in metastatic colorectal cancer (PMID:20414006)
• Human T cell leukemia virus type 1 (HTLV-1) oncoprotein Tax increases Bcl3 expression, which is associated with enhanced growth of HTLV-1-infected T cells. (PMID:20471052)
• Biochemical purification of interacting partners of BCL-3 led to the identification of CtBP as a molecule required for the ability of BCL-3 to repress gene transcription. (PMID:20547759)
• Data defined a unique motif of BCL-3 that is needed for its recruitment to the proteasome and identified PSMB1 as a key protein required for the proteasome-mediated degradation of a nuclear and oncogenic IkappaB protein. (PMID:20558726)
• Genetic variations of UBE2L3 and BCL3 are potential new risk genes for Crohn’s disease. (PMID:20601676)
• inhibitory effect on OC cell growth was mediated by miR-125b inhibition of the translation of an mRNA encoding a proto-oncogene, BCL3 (PMID:20658525)
• found that depleting Bcl-3 protein using shRNAs induce a decrease of proliferation and clonogenic survival associated with the induction of multinucleation and increased ploidy (PMID:20731879)
• COX-2 inhibitor can inhibit the expression of BCL-3 and cyclin D1 in a dose-dependent manner human colon cancer cell line SW480. (PMID:20737317)
• this study reveals a novel combinatorial role for Bcl3 and CtBP1, providing an explanation for the acquisition of resistance to apoptosis in cancer cells, which is a major requirement for cancer development. (PMID:20800578)
• We validated STAT3 as a bona fide target of BCL3 in a cervical cancer cell line by additional interference RNA and in silico analyses of previously reported lymphoma patients. (PMID:20974051)
• a novel mechanism for regulatory control of CTCF in UV stress-induced human corneal epithelial cells, which requires activation and formation of Bcl-3/p50 complex through a noncanonical NF-kappaB pathway (PMID:21912613)
• using Bcl-3 knockdown in prostate cancer cells, identified the inhibitor of DNA-binding (Id) family of helix-loop-helix proteins as potential Bcl-3-regulated genes (PMID:22580608)
• acute alcohol treatment induces molecular signatures of TLR4/LPS tolerance through the induction of Bcl-3 (PMID:22782967)
• Carriers of BCL3 allele rs7257231T had longer posterior cranial bases than noncarriers, and in the familial-based association test showed the statistically strongest relationship to phenotype. (PMID:23115114)
• These results indicate for the first time a cell-autonomous disease-modifying role for Bcl3 in vivo, affecting metastatic disease progression rather than primary tumor growth. (PMID:23149915)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	bcl3	ENSDARG00000087832
mus_musculus	Bcl3	ENSMUSG00000053175
rattus_norvegicus	Bcl3	ENSRNOG00000043416

Paralogs (16): NFKBIE (ENSG00000146232), POTED (ENSG00000166351), POTEC (ENSG00000183206), POTEG (ENSG00000187537), POTEE (ENSG00000188219), POTEA (ENSG00000188877), POTEF (ENSG00000196604), POTEI (ENSG00000196834), POTEH (ENSG00000198062), POTEM (ENSG00000222036), POTEJ (ENSG00000222038), POTEB2 (ENSG00000230031), POTEB (ENSG00000233917), (ENSG00000276760), (ENSG00000277630), POTEB3 (ENSG00000278522)

Protein

Protein identifiers

B-cell lymphoma 3 protein — P20749 (reviewed: P20749)

Alternative names: Proto-oncogene BCL3

All UniProt accessions (2): P20749, H7C0A2

UniProt curated annotations — full annotation on UniProt →

Function. Contributes to the regulation of transcriptional activation of NF-kappa-B target genes. In the cytoplasm, inhibits the nuclear translocation of the NF-kappa-B p50 subunit. In the nucleus, acts as transcriptional activator that promotes transcription of NF-kappa-B target genes. Contributes to the regulation of cell proliferation.

Subunit / interactions. Component of a complex consisting of the NF-kappa-B p52-p52 homodimer and BCL3. Component of a complex consisting of the NF-kappa-B p50-p50 homodimer and BCL3. Interacts with N4BP2, COPS5 and PIR. Interacts with CYLD.

Subcellular location. Nucleus. Cytoplasm. Perinuclear region.

Post-translational modifications. Polyubiquitinated. Ubiquitination via ‘Lys-63’-linked ubiquitin chains is required for nuclear accumulation. Deubiquitinated by CYLD, which acts on ‘Lys-63’-linked ubiquitin chains. Deubiquitination by CYLD prevents nuclear accumulation. Activated by phosphorylation.

Disease relevance. A chromosomal aberration involving BCL3 may be a cause of B-cell chronic lymphocytic leukemia (B-CLL). Translocation t(14;19)(q32;q13.1) with immunoglobulin gene regions.

RefSeq proteins (1): NP_005169* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR051070	NF-kappa-B_inhibitor	Family

Pfam: PF00023, PF12796

UniProt features (35 total): helix 13, repeat 7, compositionally biased region 6, modified residue 4, turn 2, region of interest 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1K1A	X-RAY DIFFRACTION	1.86
1K1B	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20749-F1	71.86	0.51

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 41, 374, 402, 406

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 441 (showing top): GOBP_RESPONSE_TO_UV_C, CREL_01, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, CAR_TNFRSF25, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, MCLACHLAN_DENTAL_CARIES_UP, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, SCHWAB_TARGETS_OF_BMYB_POLYMORPHIC_VARIANTS_DN, GOBP_B_CELL_ACTIVATION, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, SP3_Q3, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, ROVERSI_GLIOMA_COPY_NUMBER_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (39): follicular dendritic cell differentiation (GO:0002268), marginal zone B cell differentiation (GO:0002315), humoral immune response mediated by circulating immunoglobulin (GO:0002455), germinal center formation (GO:0002467), protein import into nucleus (GO:0006606), DNA damage response (GO:0006974), canonical NF-kappaB signal transduction (GO:0007249), response to virus (GO:0009615), response to UV-C (GO:0010225), antimicrobial humoral response (GO:0019730), extracellular matrix organization (GO:0030198), DNA damage response, signal transduction by p53 class mediator (GO:0030330), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), negative regulation of interleukin-8 production (GO:0032717), negative regulation of tumor necrosis factor production (GO:0032720), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-10 production (GO:0032733), T-helper 1 type immune response (GO:0042088), defense response to bacterium (GO:0042742), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), defense response to protozoan (GO:0042832), regulation of apoptotic process (GO:0042981), negative regulation of apoptotic process (GO:0043066), T-helper 2 cell differentiation (GO:0045064), positive regulation of translation (GO:0045727), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426), spleen development (GO:0048536), regulation of DNA binding (GO:0051101), T cell apoptotic process (GO:0070231), negative regulation of T cell apoptotic process (GO:0070233), regulation of non-canonical NF-kappaB signal transduction (GO:1901222), negative regulation of cytokine production (GO:0001818), apoptotic process (GO:0006915), response to stress (GO:0006950), positive regulation of gene expression (GO:0010628), response to other organism (GO:0051707)

GO Molecular Function (7): transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), protein-macromolecule adaptor activity (GO:0030674), histone deacetylase binding (GO:0042826), DNA-binding transcription factor binding (GO:0140297), transcription coregulator activity (GO:0003712), protein binding (GO:0005515)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), midbody (GO:0030496), protein-containing complex (GO:0032991), Bcl3-Bcl10 complex (GO:0032996), Bcl3/NF-kappaB2 complex (GO:0033257), ciliary basal body (GO:0036064), perinuclear region of cytoplasm (GO:0048471)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
humoral immune response	2
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	2
positive regulation of cytokine production	2
transcription coregulator activity	2
cytoplasm	2
follicular dendritic cell activation	1
cell differentiation	1
mature B cell differentiation involved in immune response	1
immunoglobulin mediated immune response	1
anatomical structure formation involved in morphogenesis	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cellular response to stress	1
intracellular signaling cassette	1
response to other organism	1
response to UV	1
defense response to symbiont	1
extracellular structure organization	1
external encapsulating structure organization	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
negative regulation of cytokine production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
defense response	1
response to bacterium	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
intrinsic apoptotic signaling pathway by p53 class mediator	1
positive regulation of DNA-templated transcription	1
negative regulation of DNA-templated transcription	1

Protein interactions and networks

STRING

3016 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BCL3	NFKB2	Q00653	985
BCL3	NFKB1	P19838	984
BCL3	PIR	O00625	966
BCL3	REL	Q04864	936
BCL3	RELA	Q04206	925
BCL3	RELB	Q01201	882
BCL3	HDAC1	Q13547	812
BCL3	CD40	P25942	804
BCL3	FOS	P01100	795
BCL3	CYLD	Q9NQC7	738
BCL3	COPS5	Q92905	731
BCL3	IL6	P05231	722
BCL3	IL1B	P01584	657
BCL3	KAT5	Q92993	657
BCL3	IKBKG	Q9Y6K9	654

IntAct

17 interactions, top by confidence:

A	B	Type	Score
LCK	BCL3	psi-mi:“MI:0915”(physical association)	0.590
BCL3	LCK	psi-mi:“MI:0915”(physical association)	0.590
NUP58	BCL3	psi-mi:“MI:0915”(physical association)	0.560
BCL3	BCL10	psi-mi:“MI:0915”(physical association)	0.520
BCL10	BCL3	psi-mi:“MI:0915”(physical association)	0.520
CTBP2	BCL3	psi-mi:“MI:0915”(physical association)	0.510
BCL3	CTBP2	psi-mi:“MI:0915”(physical association)	0.510
PIR	BCL3	psi-mi:“MI:0407”(direct interaction)	0.440
BCL3	FYN	psi-mi:“MI:0915”(physical association)	0.400
BCL3	HSPA6	psi-mi:“MI:0914”(association)	0.350
CUL4A	DDX39A	psi-mi:“MI:0914”(association)	0.350
BCL3	ANKRD28	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (99): BCL3 (Two-hybrid), NCOA1 (Reconstituted Complex), BARD1 (Two-hybrid), BCL3 (Biochemical Activity), BCL3 (Biochemical Activity), BCL3 (Biochemical Activity), NFKB2 (Reconstituted Complex), NFKB1 (Affinity Capture-Western), NFKB1 (Co-localization), NFKB1 (Reconstituted Complex), NFKB1 (Co-purification), NFKB1 (Affinity Capture-Western), BCL3 (Co-localization), RELB (Co-localization), N4BP2 (Two-hybrid)

ESM2 similar proteins: A2AKB9, A2AWP8, A4FV57, D3YYI7, G3V9M2, O09112, O43189, O60347, O77638, O94827, O95644, P20749, P22681, P22682, P30291, P49797, P98201, Q01201, Q04863, Q09YL6, Q0GA42, Q13202, Q13387, Q3TZ87, Q3UR85, Q3V1H9, Q5XI70, Q66T02, Q6A039, Q6RFZ7, Q6ZN18, Q70EL4, Q7Z6J2, Q86YJ5, Q8BUM9, Q8CE64, Q8N554, Q8N6N2, Q8R4T5, Q8TC41

Diamond homologs: A0A096LNW5, A2RUV0, B4DH59, G3I6Z6, O35474, O35516, O75095, O89019, P07207, P0DPK3, P0DPK4, P13508, P20749, P21783, P31695, P46530, P46531, P82279, Q01705, Q04721, Q07008, Q20911, Q499M5, Q502K3, Q5RBP1, Q61982, Q6UXI9, Q6UY11, Q7Z3S9, Q810B6, Q8AVH7, Q8IUX8, Q91V88, Q99466, Q9FY48, Q9JJZ5, Q9P2R3, Q9QW30, Q9QXT5, Q9R172

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
BCL3	up-regulates	HDAC1	binding
BCL3	up-regulates	HDAC3	binding
BCL3	“up-regulates quantity by expression”	MDM2	“transcriptional regulation”
BCL3	up-regulates	NFKB2	binding
BCL3	up-regulates	NFKB2
CYLD	down-regulates	BCL3	deubiquitination
CRTC3	up-regulates	BCL3	binding
TBL1XR1	down-regulates	BCL3	ubiquitination
BCL3	“down-regulates quantity by repression”	CTCF	“transcriptional regulation”
BCL3	“up-regulates activity”	NFKB1	binding
GSK3A	“down-regulates quantity by destabilization”	BCL3	phosphorylation
DMTF1	“up-regulates quantity by expression”	BCL3	“transcriptional regulation”
AKT1	“up-regulates quantity by stabilization”	BCL3	phosphorylation
AKT2	“up-regulates quantity by stabilization”	BCL3	phosphorylation
MAPK1	“up-regulates activity”	BCL3	phosphorylation
CHUK	“up-regulates activity”	BCL3	phosphorylation
IKBKB	“up-regulates activity”	BCL3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

80 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	58
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1146 predictions. Top by Δscore:

Variant	Effect	Δscore
19:44751376:GACAC:G	donor_gain	1.0000
19:44751381:G:GG	donor_gain	1.0000
19:44756228:CCA:C	acceptor_loss	1.0000
19:44756230:A:AG	acceptor_gain	1.0000
19:44756230:A:AT	acceptor_loss	1.0000
19:44756231:G:GC	acceptor_gain	1.0000
19:44756231:GGC:G	acceptor_gain	1.0000
19:44756231:GGCCT:G	acceptor_gain	1.0000
19:44756336:GGCAG:G	donor_gain	1.0000
19:44756337:GCAG:G	donor_gain	1.0000
19:44756337:GCAGG:G	donor_gain	1.0000
19:44756338:C:T	donor_gain	1.0000
19:44756339:AGG:A	donor_loss	1.0000
19:44756341:GTGAG:G	donor_loss	1.0000
19:44757011:CCCCA:C	acceptor_loss	1.0000
19:44757012:CCCA:C	acceptor_loss	1.0000
19:44757014:CA:C	acceptor_loss	1.0000
19:44757015:A:AG	acceptor_gain	1.0000
19:44757016:G:GC	acceptor_loss	1.0000
19:44757016:G:GG	acceptor_gain	1.0000
19:44757016:GA:G	acceptor_gain	1.0000
19:44757016:GAC:G	acceptor_gain	1.0000
19:44757016:GACA:G	acceptor_gain	1.0000
19:44757016:GACAC:G	acceptor_gain	1.0000
19:44757057:T:TA	acceptor_gain	1.0000
19:44757062:C:CA	acceptor_gain	1.0000
19:44757069:T:TA	acceptor_gain	1.0000
19:44757217:TGACG:T	donor_gain	1.0000
19:44757218:GACG:G	donor_gain	1.0000
19:44757218:GACGG:G	donor_gain	1.0000

AlphaMissense

2889 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:44758370:A:T	N339I	1.000
19:44758371:C:A	N339K	1.000
19:44758371:C:G	N339K	1.000
19:44757102:A:T	D202V	0.999
19:44757668:C:A	P279Q	0.999
19:44757668:C:G	P279R	0.999
19:44757671:T:A	L280H	0.999
19:44757679:G:C	A283P	0.999
19:44757716:T:C	L295P	0.999
19:44758280:G:T	G309V	0.999
19:44758289:C:A	A312D	0.999
19:44758292:T:C	L313P	0.999
19:44758301:C:A	A316E	0.999
19:44758337:T:A	L328Q	0.999
19:44758337:T:C	L328P	0.999
19:44758388:C:A	P345Q	0.999
19:44758388:C:G	P345R	0.999
19:44756328:C:A	N169K	0.998
19:44756328:C:G	N169K	0.998
19:44757021:C:G	P175R	0.998
19:44757030:T:C	L178P	0.998
19:44757129:T:C	L211P	0.998
19:44757384:T:C	L261S	0.998
19:44757646:G:C	D272H	0.998
19:44757647:A:T	D272V	0.998
19:44757659:G:A	G276D	0.998
19:44757659:G:T	G276V	0.998
19:44757671:T:C	L280P	0.998
19:44757680:C:A	A283D	0.998
19:44757716:T:A	L295Q	0.998

dbSNP variants (sampled 300 via entrez): RS1000394143 (19:44748435 C>A,G,T), RS1000758818 (19:44754331 C>T), RS1000886222 (19:44748854 G>A), RS1000916991 (19:44748988 G>T), RS1000989591 (19:44750423 C>T), RS1001286834 (19:44754413 A>G), RS1001346837 (19:44750282 C>T), RS1001574256 (19:44750868 C>T), RS1002166889 (19:44749698 C>T), RS1002281711 (19:44756170 G>A,C,T), RS1002295226 (19:44756543 G>A), RS1002731351 (19:44758667 TG>T), RS1002842004 (19:44752288 T>C), RS1002888832 (19:44745981 C>T), RS1002995457 (19:44753233 G>C)

Disease associations

OMIM: gene MIM:109560 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

41 associations (top):

Study	Trait	p-value
GCST001947_2	Alzheimer’s disease (late onset)	5.000000e-39
GCST002422_1	Alzheimer’s disease	9.000000e-116
GCST004600_110	Eosinophil percentage of white cells	8.000000e-09
GCST005950_15	Body mass index x sex x age interaction (4df test)	2.000000e-10
GCST005951_56	Body mass index	1.000000e-06
GCST005952_8	Body mass index (age>50)	9.000000e-12
GCST005954_4	Body mass index x age interaction	2.000000e-07
GCST007320_13	Alzheimer’s disease or family history of Alzheimer’s disease	3.000000e-57
GCST007320_15	Alzheimer’s disease or family history of Alzheimer’s disease	3.000000e-44
GCST007320_82	Alzheimer’s disease or family history of Alzheimer’s disease	3.000000e-10
GCST007600_3	Alzheimer’s disease	4.000000e-06
GCST007600_76	Alzheimer’s disease	2.000000e-06
GCST007826_2	Alzheimer’s disease or fasting insulin levels (pleiotropy)	7.000000e-13
GCST007827_17	Alzheimer’s disease or HDL levels (pleiotropy)	3.000000e-12
GCST007827_3	Alzheimer’s disease or HDL levels (pleiotropy)	1.000000e-97
GCST007827_5	Alzheimer’s disease or HDL levels (pleiotropy)	7.000000e-74
GCST007827_6	Alzheimer’s disease or HDL levels (pleiotropy)	7.000000e-54
GCST007827_7	Alzheimer’s disease or HDL levels (pleiotropy)	5.000000e-50
GCST007827_8	Alzheimer’s disease or HDL levels (pleiotropy)	3.000000e-36
GCST008075_187	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	5.000000e-09
GCST008075_39	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-16
GCST008077_5	LDL cholesterol levels	2.000000e-49
GCST008077_58	LDL cholesterol levels	3.000000e-14
GCST008078_136	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-177
GCST008078_53	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-83
GCST008079_102	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-213
GCST008079_31	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-273
GCST008084_205	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-10
GCST008084_5	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-16
GCST008085_95	HDL cholesterol levels in current drinkers	1.000000e-07

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009268	family history of Alzheimer’s disease
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004842	eosinophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523197 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Inhibitors of NF-kappaB (IκB) family proteins

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
BCL3 inhibitor JS6	Inhibition	7.34	pIC50

ChEMBL bioactivities

13 potent at pChembl≥5 of 15 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.16	IC50	6.97	nM	CHEMBL1383390
7.92	IC50	11.95	nM	CHEMBL4562558
7.34	IC50	45.43	nM	CHEMBL4558803
7.21	IC50	61.7	nM	CHEMBL1383390
6.80	IC50	156.6	nM	CHEMBL4558803
6.68	IC50	210.6	nM	CHEMBL4558803
6.62	IC50	237.8	nM	CHEMBL4534875
6.41	IC50	385.5	nM	CHEMBL4558803
6.15	IC50	705.9	nM	CHEMBL4522736
6.00	IC50	988.9	nM	CHEMBL4451393
5.97	IC50	1070	nM	CHEMBL4562558
5.60	IC50	2500	nM	CHEMBL4519964
5.60	IC50	2490	nM	CHEMBL4528261

CTD chemical–gene interactions

93 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases expression	4
Particulate Matter	increases abundance, increases expression, decreases expression, affects cotreatment	4
sodium arsenite	decreases expression, affects reaction, increases expression, affects localization, affects binding (+1 more)	3
(+)-JQ1 compound	decreases expression, decreases reaction, increases expression	3
Nickel	increases expression	3
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	2
Bortezomib	affects cotreatment, decreases expression	2
Resveratrol	affects cotreatment, decreases expression, decreases reaction, increases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	affects expression, increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	increases expression	2
Estradiol	decreases expression, increases expression	2
Hydrogen Peroxide	decreases reaction, affects expression, decreases expression	2
Lipopolysaccharides	decreases reaction, increases expression, affects response to substance, affects cotreatment	2
Oxygen	decreases reaction, increases expression, decreases expression	2
Ozone	affects expression, increases abundance, increases expression	2
Rotenone	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Palmitic Acid	decreases expression, decreases phosphorylation	2
aristolochic acid I	increases expression	1
Glupearl 19S	increases expression	1
dicrotophos	increases expression	1
2-anisidine	affects expression	1
chloroacetaldehyde	decreases expression	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	increases expression	1
hydroxyhydroquinone	decreases reaction, increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
afimoxifene	decreases expression, decreases reaction	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4422027	Binding	Inhibition of FLAG-tagged Bcl-3 (unknown origin) expressed in HEK293 cells assessed as reduction in Bcl3 binding to its cognate protein partner NFKB1 (p50) incubated for 24 hrs by indirect sandwich ELISA	2-benzoylaminobenzamide derivatives as bcl-3 inhibitors

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8BY	Abcam HCT 116 BCL3 KO	Cancer cell line	Male
CVCL_B8SX	Abcam MCF-7 BCL3 KO	Cancer cell line	Female
CVCL_B9E2	Abcam A-549 BCL3 KO	Cancer cell line	Male
CVCL_SE98	HAP1 BCL3 (-) 1	Cancer cell line	Male
CVCL_SE99	HAP1 BCL3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.