BBC3

Summary

BBC3 (BCL2 binding component 3, HGNC:17868) is a protein-coding gene on chromosome 19q13.32, encoding Bcl-2-binding component 3, isoforms 3/4 (Q96PG8). Does not affect cell growth.

This gene encodes a member of the BCL-2 family of proteins. This family member belongs to the BH3-only pro-apoptotic subclass. The protein cooperates with direct activator proteins to induce mitochondrial outer membrane permeabilization and apoptosis. It can bind to anti-apoptotic Bcl-2 family members to induce mitochondrial dysfunction and caspase activation. Because of its pro-apoptotic role, this gene is a potential drug target for cancer therapy and for tissue injury. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 27113 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 62 total
• MANE Select transcript: NM_014417

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17868
Approved symbol	BBC3
Name	BCL2 binding component 3
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	JFY1, PUMA
Ensembl gene	ENSG00000105327
Ensembl biotype	protein_coding
OMIM	605854
Entrez	27113

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 2 retained_intron

ENST00000300880, ENST00000341983, ENST00000439096, ENST00000449228, ENST00000598636, ENST00000601438, ENST00000899307, ENST00000899308, ENST00000899309, ENST00000899310, ENST00000899311, ENST00000919804, ENST00000919805, ENST00000919806

RefSeq mRNA: 4 — MANE Select: NM_014417 NM_001127240, NM_001127241, NM_001127242, NM_014417

CCDS: CCDS12697, CCDS46128, CCDS46129, CCDS46130

Canonical transcript exons

ENST00000439096 — 4 exons

Exon	Start	End
ENSE00001510056	47230929	47231199
ENSE00003536245	47226564	47226754
ENSE00003616225	47228158	47228446
ENSE00003903432	47220824	47221918

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 93.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.4741 / max 192.4691, expressed in 1760 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181732	16.0330	1754
181733	0.2707	99
181728	0.1704	60

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	93.68	silver quality
vena cava	UBERON:0004087	93.55	gold quality
olfactory bulb	UBERON:0002264	93.26	gold quality
pancreatic ductal cell	CL:0002079	91.68	silver quality
parotid gland	UBERON:0001831	90.99	silver quality
body of tongue	UBERON:0011876	90.00	silver quality
pons	UBERON:0000988	89.53	silver quality
pericardium	UBERON:0002407	89.34	gold quality
tongue squamous epithelium	UBERON:0006919	89.22	gold quality
granulocyte	CL:0000094	88.94	gold quality
triceps brachii	UBERON:0001509	87.74	silver quality
tongue	UBERON:0001723	87.51	silver quality
tendon of biceps brachii	UBERON:0008188	87.51	silver quality
subthalamic nucleus	UBERON:0001906	87.47	silver quality
inferior olivary complex	UBERON:0002127	87.22	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	87.13	silver quality
lateral nuclear group of thalamus	UBERON:0002736	87.10	silver quality
saphenous vein	UBERON:0007318	86.89	gold quality
cardia of stomach	UBERON:0001162	86.22	silver quality
dorsal plus ventral thalamus	UBERON:0001897	86.22	silver quality
gluteal muscle	UBERON:0002000	86.01	silver quality
lateral globus pallidus	UBERON:0002476	85.76	silver quality
nasal cavity epithelium	UBERON:0005384	85.72	silver quality
heart right ventricle	UBERON:0002080	85.71	silver quality
medulla oblongata	UBERON:0001896	85.58	silver quality
pylorus	UBERON:0001166	85.42	silver quality
substantia nigra pars compacta	UBERON:0001965	85.20	gold quality
inferior vagus X ganglion	UBERON:0005363	85.14	silver quality
ventral tegmental area	UBERON:0002691	85.01	silver quality
pharyngeal mucosa	UBERON:0000355	84.65	silver quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-99795	yes	15.05
E-ANND-3	yes	3.74
E-GEOD-124858	no	3.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF4, CTBP2, CTCF, DDIT3, DNMT1, E2F1, ESR1, ETV6, FOXC1, FOXO3, HES1, IRF1, JUN, KDM4B, MYC, NKX6-3, NR1I2, NR4A3, PARK7, SMAD3, SMAD4, SOX4, SP1, TCF3, TP53, TP63, TP73, ZNF331

miRNA regulators (miRDB)

40 targeting BBC3, 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-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-LET-7C-3P	99.95	73.42	2862
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-4496	99.88	68.89	2236
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-3180	98.46	64.68	348

Literature-anchored findings (GeneRIF, showing 40)

• role in mediating the apoptotic response to p53 in colorectal cancer cells (PMID:12574499)
• PUMA suppresses tumor cell growth in head/neck cancer, but it does not appear to be a direct target of inactivation in head and neck tumorigenesis. (PMID:12963126)
• PUMA-induced Bax conformational change and Bax translocation to mitochondria can be separate events and the conformational change in Bax is crucial for PUMA-induced mitochondrial dysfunction (PMID:14550297)
• PUMA is an essential mediator of p53-dependent and -independent apoptosis in vivo (PMID:14585351)
• findings demonstrate that p73 protein elicits apoptosis via the mitochondrial pathway using p53 up regulated modulator of apoptosis(PUMA) and Bax protein as mediators (PMID:14634023)
• In the absence of PUMA, there is no HIV apoptosis. (PMID:15143349)
• PUMA expression may be of minor importance in the development of colorectal cancer (PMID:15547745)
• a specific interaction between Bax Halpha1 and their BH3 domains allows Bid and PUMA to function as “death agonists” of Bax (PMID:15574335)
• histones and a ubiquitin conjugate protein UBC9, which are involved in DNA double-strand break (DSB) repair were significantly down-regulated in the PUMA-overexpressing apoptotic cells, suggesting the detection of DSB in the apoptotic process (PMID:15595728)
• degraded during Chlamydia trachomatis infection (PMID:15731037)
• degraded in Chlamydia trachomatis-infected cells. (PMID:15731089)
• Results demonstrate that thapsigargin engages PUMA and Bax for full transduction of apoptotic signals and both PUMA and Bax appear to exist in the same apoptotic pathway in which PUMA may reside upstream of Bax. (PMID:15905879)
• The interaction of PUMA with MCL1 is not sufficient to prevent rapid degradation of MCL1. (PMID:16007132)
• BBC3 mediates fenretinide-induced cell death in neuroblastoma. (PMID:16091745)
• demonstrated that a tripartite nexus between Bcl-xL, cytoplasmic p53, and PUMA coordinates the nuclear and cytoplasmic p53 proapoptotic functions (PMID:16151013)
• interference with the p53/PUMA/Bax cascade is crucial for the antiapoptotic function of the viral E6 oncogene in HPV-positive cancer cells (PMID:16462759)
• PUMA initiates apoptosis in part by dissociating Bax and Bcl-X(L), thereby promoting Bax multimerization and mitochondrial translocation (PMID:16608847)
• p53 activation and the transcriptional induction of its target gene PUMA play an important role in the sensitivity of cancer cells to apoptosis induced by proteasome inhibition (PMID:16983338)
• Differential expression of PUMA between normal and neoplastic gastric cells suggests that regulation of PUMA expression might play a possible role in the development of gastric adenocarcinoma. (PMID:17267315)
• the binding of nuclear p53 to the specific sites within the PUMA promoter is essential for its ability to induce apoptosis and is likely to be required for its tumor suppressive capacity (PMID:17360476)
• findings suggest that PUMA plays an important role in celecoxib-induced mitochondrial dysfunction and the resulting apoptosis (PMID:17368424)
• Expression of BBC3 protein was increased in the colorectal cancer cells and may possibly alter the cell death regulation during colorectal tumorigenesis. (PMID:17393317)
• GADD153 (CHOP) and Bcl-2-binding component 3 (PUMA) and apoptosis are induced by 4-hydroxybenzylretinone in a process that is caspase- dependent and independent of the retinoic acid receptor (PMID:17616685)
• Mcl-1 confers TRAIL resistance by serving as a buffer for Bak, Bim, and Puma, and sorafenib is a potential modulator of TRAIL sensitivity (PMID:17698840)
• Differential expression of PUMA between non-neoplastic and neoplastic hepatocellular cells suggests that regulation of PUMA expression may play a role in development of hepatocellular carcinoma. (PMID:17934815)
• critical involvement of p38 MAPK, PUMA, and Bax in 6-OHDA-induced apoptosis (PMID:17996028)
• PUMA exerts a negative feedback on p53 and p21, leading to p21-dependent growth suppressive and survival changes. (PMID:18215742)
• A p53-upregulated modulator of apoptosis (Puma) protein accumulated significantly in genistein-treated A549 and WI-38 cells. (PMID:18324703)
• Noxa and Puma bind Mcl-1 to release Bak and Bim within 6 hours of arsenic trioxide addition (PMID:18354037)
• PUMA is involved in green tea polyphenol-induced apoptosis in colorectal cancer cell lines (PMID:18367875)
• Puma deletion in the Emu-Myc mouse model of Burkitt lymphoma accelerates lymphomagenesis and that approximately 75% of Emu-Myc lymphomas naturally select against Puma protein expression. (PMID:18573879)
• transcription factors Sp1 and p73 mediate p53-independent induction of PUMA following serum starvation to trigger apoptosis in human cancer cells. (PMID:18579560)
• PUMA (p53-upregulated modulator of apoptosis) plays a role in H2O2-induced apoptosis in colorectal cancer cells. (PMID:18811981)
• These results demonstrate that the level of the Bcl-2 prosurvival family sets the threshold at which Puma is able to indirectly activate Bax or Bak, leading in turn to activation of caspases that cause cell death. (PMID:18835564)
• Up-regulation of miR-34a after irradiation was associated with induction of Bax and p21, but not Puma (PMID:18941118)
• PUMA makes a key contribution to the process whereby kaempferol induces ATM protein phosphorylation. (PMID:19028473)
• loss of Puma only provided transient protection from apoptosis in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells (PMID:19064725)
• Results suggest that Puma is competent to trigger Bax activity by itself, thereby promoting cellular dependence on prosurvival Bcl-2 family members. (PMID:19380879)
• Results suggest that PUMA induction through p73 represents a new mechanism of EGFR inhibitor-induced apoptosis, and provide potential ways for enhancing and predicting the sensitivity to EGFR-targeted therapies in HNSCC. (PMID:19421143)
• Studies create an important conclusion that PUMA promotes Bax translocation both by directly interacting with Bax and by competitive binding to Bcl-X(L) in UV-induced apoptosis. (PMID:19439449)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Bbc3	ENSMUSG00000002083
rattus_norvegicus	Bbc3	ENSRNOG00000062473

Protein

Protein identifiers

Bcl-2-binding component 3, isoforms 3/4 — Q96PG8 (reviewed: Q96PG8, Q9BXH1)

Alternative names: JFY-1, p53 up-regulated modulator of apoptosis

All UniProt accessions (2): Q96PG8, Q9BXH1

UniProt curated annotations — full annotation on UniProt →

Function. Does not affect cell growth.

Subunit / interactions. Does not interact with BCL2.

Domain organisation. Contrary to isoforms 1 and 2, isoforms 3 and 4 do not contain any BH3 motif.

Induction. Up-regulated by TP53.

Isoforms (4)

UniProt ID	Names	Canonical?
Q96PG8-2	4, PUMA gamma	yes
Q96PG8-1	3, PUMA delta
Q9BXH1-1	1, PUMA alpha
Q9BXH1-2	2, PUMA beta

RefSeq proteins (4): NP_001120712, NP_001120713, NP_001120714, NP_055232* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031661	Bbc3	Family

Pfam: PF15826

UniProt features (22 total): compositionally biased region 9, region of interest 3, chain 2, splice variant 2, mutagenesis site 2, turn 1, short sequence motif 1, modified residue 1, helix 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
5UUL	X-RAY DIFFRACTION	1.33
4BPJ	X-RAY DIFFRACTION	1.6
4BPK	X-RAY DIFFRACTION	1.76
6TQP	X-RAY DIFFRACTION	1.85
6QG8	X-RAY DIFFRACTION	1.9
4BPI	X-RAY DIFFRACTION	1.98
6QFM	X-RAY DIFFRACTION	2
7P9W	X-RAY DIFFRACTION	2
7QTX	X-RAY DIFFRACTION	2.12
7P0S	X-RAY DIFFRACTION	2.5
7DVD	X-RAY DIFFRACTION	2.59
4HNJ	X-RAY DIFFRACTION	2.9
2M04	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96PG8-F1	47.60	0.00
AF-Q9BXH1-F1	61.12	0.13

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 (1): 10

Mutagenesis-validated functional residues (2):

Position	Phenotype
133	impairs p53/tp53-dependent apoptosis.
141–143	abolishes blc2-binding. impairs growth inhibitory activity. no effect on mitochondrial subcellular location.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-111453	BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members
R-HSA-139915	Activation of PUMA and translocation to mitochondria
R-HSA-6803204	TP53 Regulates Transcription of Genes Involved in Cytochrome C Release
R-HSA-9614657	FOXO-mediated transcription of cell death genes
R-HSA-109581	Apoptosis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-114452	Activation of BH3-only proteins
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5357801	Programmed Cell Death
R-HSA-5633008	TP53 Regulates Transcription of Cell Death Genes
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9614085	FOXO-mediated transcription

MSigDB gene sets: 0 (showing top):

GO Biological Process (27): release of cytochrome c from mitochondria (GO:0001836), apoptotic process (GO:0006915), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), positive regulation of release of cytochrome c from mitochondria (GO:0090200), execution phase of apoptosis (GO:0097194), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), DNA damage response (GO:0006974), determination of adult lifespan (GO:0008340), positive regulation of protein-containing complex assembly (GO:0031334), response to endoplasmic reticulum stress (GO:0034976), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), positive regulation of neuron apoptotic process (GO:0043525), fibroblast apoptotic process (GO:0044346), T cell apoptotic process (GO:0070231), positive regulation of thymocyte apoptotic process (GO:0070245), cellular response to hypoxia (GO:0071456), cellular response to ionizing radiation (GO:0071479), apoptotic signaling pathway (GO:0097190), intrinsic apoptotic signaling pathway (GO:0097193), positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902237), positive regulation of protein localization to mitochondrion (GO:1903749), positive regulation of IRE1-mediated unfolded protein response (GO:1903896), positive regulation of fibroblast apoptotic process (GO:2000271), positive regulation of apoptotic process (GO:0043065), lymphocyte apoptotic process (GO:0070227), positive regulation of lymphocyte apoptotic process (GO:0070230), positive regulation of T cell apoptotic process (GO:0070234)

GO Molecular Function (2): ATPase binding (GO:0051117), protein binding (GO:0005515)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), lysosome (GO:0005764)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Intrinsic Pathway for Apoptosis	2
Generic Transcription Pathway	2
Activation of BH3-only proteins	1
TP53 Regulates Transcription of Cell Death Genes	1
FOXO-mediated transcription	1
Programmed Cell Death	1
Apoptosis	1
RNA Polymerase II Transcription	1
Transcriptional Regulation by TP53	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic signaling pathway	3
apoptotic process	3
cellular response to stress	3
intrinsic apoptotic signaling pathway	2
cytoplasm	2
apoptotic mitochondrial changes	1
programmed cell death	1
execution phase of apoptosis	1
response to endoplasmic reticulum stress	1
release of cytochrome c from mitochondria	1
positive regulation of organelle organization	1
regulation of release of cytochrome c from mitochondria	1
cellular process	1
bleb assembly	1
positive regulation of intracellular signal transduction	1
positive regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
multicellular organismal process	1
regulation of protein-containing complex assembly	1
positive regulation of cellular component biogenesis	1
positive regulation of cellular component organization	1
protein-containing complex assembly	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
intrinsic apoptotic signaling pathway by p53 class mediator	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
lymphocyte apoptotic process	1
positive regulation of T cell apoptotic process	1
thymocyte apoptotic process	1
regulation of thymocyte apoptotic process	1
response to hypoxia	1
cellular response to decreased oxygen levels	1
response to ionizing radiation	1
cellular response to radiation	1
signal transduction	1
intracellular signal transduction	1
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1
regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1
positive regulation of response to endoplasmic reticulum stress	1

Protein interactions and networks

STRING

1186 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BBC3	BCL2	P10415	994
BBC3	BCL2L1	Q07817	988
BBC3	MCL1	Q07820	949
BBC3	PMAIP1	Q13794	875
BBC3	TP53	P04637	856
BBC3	CDKN1A	P38936	793
BBC3	BAK1	Q16611	770
BBC3	BAX	P55269	763
BBC3	CASP3	P42574	752
BBC3	BCL2L2-PABPN1	Q92843	739
BBC3	BCL2L11	O43521	720
BBC3	MDM2	Q00987	672
BBC3	RTL10	Q7L3V2	660
BBC3	HRK	O00198	637
BBC3	BID	P55957	627

IntAct

33 interactions, top by confidence:

A	B	Type	Score
BCL2	BCL2L11	psi-mi:“MI:0914”(association)	0.930
MCL1	PRKAB2	psi-mi:“MI:0914”(association)	0.640
BBC3	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
HGS	BBC3	psi-mi:“MI:0915”(physical association)	0.560
MYPOP	BBC3	psi-mi:“MI:0915”(physical association)	0.560
WDR5	BBC3	psi-mi:“MI:0915”(physical association)	0.560
FHL5	BBC3	psi-mi:“MI:0915”(physical association)	0.560
UBASH3B	BBC3	psi-mi:“MI:0915”(physical association)	0.560
ZNF438	BBC3	psi-mi:“MI:0915”(physical association)	0.560
HSD17B13	BBC3	psi-mi:“MI:0915”(physical association)	0.560
NDUFAB1	BBC3	psi-mi:“MI:0915”(physical association)	0.560
BCL2L2	SLC27A2	psi-mi:“MI:0914”(association)	0.530
MCL1	PRKAG1	psi-mi:“MI:0914”(association)	0.530
BCL2	ABCB1	psi-mi:“MI:0914”(association)	0.350
CHCHD2	ZNF593	psi-mi:“MI:0914”(association)	0.350
BCL2L1	UBB	psi-mi:“MI:0914”(association)	0.350
HGS	BBC3	psi-mi:“MI:0915”(physical association)	0.000
WDR5	BBC3	psi-mi:“MI:0915”(physical association)	0.000
BBC3	FHL5	psi-mi:“MI:0915”(physical association)	0.000
BBC3	UBASH3B	psi-mi:“MI:0915”(physical association)	0.000
BBC3	ZNF438	psi-mi:“MI:0915”(physical association)	0.000
BBC3	NDUFAB1	psi-mi:“MI:0915”(physical association)	0.000
MYPOP	BBC3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (66): BBC3 (Protein-peptide), BBC3 (Protein-peptide), BCL2L1 (Co-crystal Structure), BBC3 (Protein-peptide), BBC3 (Protein-peptide), BBC3 (Protein-peptide), BBC3 (Protein-peptide), BBC3 (Affinity Capture-MS), BBC3 (Affinity Capture-Western), BBC3 (Affinity Capture-Western), BBC3 (Affinity Capture-Western), BBC3 (Co-localization), BBC3 (Affinity Capture-MS), BBC3 (Affinity Capture-MS), BCL2 (Affinity Capture-Western)

ESM2 similar proteins: A0A1W2PPE3, A0A3B3IS91, A0A6I8MX38, A0A6I8PU40, A8MTW9, B1AH88, B3EWF7, C0HLS1, C0HMD6, H3BQW9, I3L0S3, I3L1E1, O70738, O75638, P03289, P0C880, P0DI83, P11300, P13985, P16807, P29164, P33485, P59091, P80612, Q01480, Q01900, Q3SYB3, Q5JLA7, Q5SY85, Q5T4H9, Q63003, Q6EEV4, Q6VB84, Q86SI9, Q8N1I8, Q8N1X5, Q8N319, Q8N6K4, Q8N6U2, Q8N726

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
E2F1	“up-regulates quantity by expression”	BBC3	“transcriptional regulation”
TCF3	“down-regulates quantity by repression”	BBC3	“transcriptional regulation”
TP73	“up-regulates quantity by expression”	BBC3	“transcriptional regulation”
KDM4B	“down-regulates quantity by repression”	BBC3	“transcriptional regulation”
ERBB2	“down-regulates activity”	BBC3	phosphorylation
ETV6	“up-regulates quantity by expression”	BBC3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
extrinsic apoptotic signaling pathway in absence of ligand	5	117.0×	2e-07
intrinsic apoptotic signaling pathway in response to DNA damage	5	81.0×	6e-07
positive regulation of apoptotic process	5	14.2×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	17
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

801 predictions. Top by Δscore:

Variant	Effect	Δscore
19:47221917:CT:C	acceptor_gain	1.0000
19:47221919:C:CC	acceptor_gain	1.0000
19:47226562:ACCCG:A	donor_gain	1.0000
19:47226563:CCCGC:C	donor_gain	1.0000
19:47226575:A:AC	donor_gain	1.0000
19:47226576:C:CC	donor_gain	1.0000
19:47226756:T:C	acceptor_gain	1.0000
19:47230979:T:TA	donor_gain	1.0000
19:47221915:GTCT:G	acceptor_gain	0.9900
19:47221918:TCT:T	acceptor_loss	0.9900
19:47221919:C:A	acceptor_loss	0.9900
19:47226558:ACTC:A	donor_loss	0.9900
19:47226559:CTCA:C	donor_loss	0.9900
19:47226560:TCAC:T	donor_loss	0.9900
19:47226561:CAC:C	donor_loss	0.9900
19:47226562:A:AC	donor_gain	0.9900
19:47226562:AC:A	donor_gain	0.9900
19:47226563:C:CC	donor_gain	0.9900
19:47226563:CC:C	donor_gain	0.9900
19:47226563:CCCG:C	donor_gain	0.9900
19:47226752:GACC:G	acceptor_loss	0.9900
19:47226753:ACC:A	acceptor_loss	0.9900
19:47226756:T:G	acceptor_loss	0.9900
19:47226756:T:TC	acceptor_gain	0.9900
19:47230927:ACC:A	donor_gain	0.9900
19:47230928:CCC:C	donor_gain	0.9900
19:47226754:CCT:C	acceptor_gain	0.9800
19:47226755:C:CC	acceptor_gain	0.9800
19:47227393:AAGG:A	donor_gain	0.9800
19:47230927:AC:A	donor_gain	0.9800

AlphaMissense

1194 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:47221877:C:G	G204R	0.757
19:47221856:C:A	G211W	0.696
19:47221877:C:A	G204C	0.687
19:47221835:C:G	G218R	0.686
19:47221835:C:A	G218W	0.665
19:47221806:T:A	Q227H	0.629
19:47221806:T:G	Q227H	0.629
19:47221824:G:C	S221R	0.612
19:47221824:G:T	S221R	0.612
19:47221826:T:G	S221R	0.612
19:47221866:T:A	Q207H	0.612
19:47221866:T:G	Q207H	0.612
19:47228196:C:A	W113C	0.607
19:47228196:C:G	W113C	0.607
19:47221879:T:A	E203V	0.593

dbSNP variants (sampled 300 via entrez): RS1000000222 (19:47232491 G>A,C), RS1000181215 (19:47224298 A>C), RS1000253110 (19:47225454 T>A), RS1000489932 (19:47222099 G>C), RS1000543433 (19:47223170 C>T), RS1000646685 (19:47228113 T>C), RS1000980604 (19:47232224 G>A), RS1001097026 (19:47225203 G>A), RS1001179294 (19:47226255 G>A), RS1001190751 (19:47231850 C>G,T), RS1001215661 (19:47223329 G>A), RS1001216586 (19:47221000 C>G,T), RS1001223373 (19:47231553 C>A), RS1001262107 (19:47224856 A>C), RS1001363710 (19:47221374 A>C,G)

Disease associations

OMIM: gene MIM:605854 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004625_218	Monocyte count	3.000000e-09
GCST90000025_571	Appendicular lean mass	2.000000e-33
GCST90002407_632	White blood cell count	4.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PubChem BioAssay actives

1 with measured affinity, of 29 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide	515601: Inhibition of GST-tagged Bcl-xl/FITC-conjugated PUMA interaction by fluorescence polarisation assay	ic50	0.0003	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects cotreatment, decreases expression, decreases response to substance, affects binding, decreases reaction (+4 more)	13
Arsenic Trioxide	affects cotreatment, increases expression, decreases expression, increases reaction, decreases reaction	9
Benzo(a)pyrene	decreases reaction, increases expression, decreases methylation, affects cotreatment, decreases expression (+2 more)	8
Fluorouracil	affects cotreatment, decreases expression, decreases response to substance, increases expression, decreases reaction (+2 more)	7
sodium arsenite	increases reaction, affects binding, increases expression, affects cotreatment, decreases expression (+1 more)	6
Doxorubicin	affects binding, increases phosphorylation, increases reaction, affects reaction, decreases reaction (+3 more)	6
pifithrin	increases expression, decreases activity, increases reaction, decreases reaction	5
nutlin 3	affects cotreatment, increases expression, increases reaction, affects reaction	5
Resveratrol	increases expression, increases reaction, affects cotreatment, decreases expression	5
cobaltous chloride	increases phosphorylation, affects cotreatment, decreases expression, decreases reaction, increases activity (+1 more)	4
Estradiol	decreases reaction, increases expression, affects expression, decreases expression	4
Tunicamycin	increases expression	4
Simvastatin	decreases reaction, increases expression, affects localization	4
Decitabine	affects expression, affects methylation, increases expression	3
Air Pollutants	affects cotreatment, increases abundance, increases expression, affects expression	3
Cadmium	increases abundance, increases expression, decreases reaction, affects reaction	3
Etoposide	increases expression, increases reaction, decreases reaction	3
Paraquat	affects cotreatment, decreases reaction, increases expression	3
bisphenol A	decreases expression, increases expression, affects cotreatment	2
trichostatin A	increases expression, increases reaction	2
sulforaphane	increases expression	2
dioscin	increases expression	2
nickel chloride	increases expression, affects reaction	2
ochratoxin A	decreases expression	2
chromium hexavalent ion	affects reaction, increases abundance, increases expression	2
pyrazolanthrone	decreases reaction, increases expression	2
Celecoxib	decreases reaction, increases activity, increases localization, increases response to substance, increases expression (+1 more)	2
Bortezomib	increases expression	2
Erlotinib Hydrochloride	affects cotreatment, increases expression, increases reaction	2
Vorinostat	increases expression, increases reaction	2

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1L2	Abcam HeLa BBC3 KO	Cancer cell line	Female
CVCL_HD55	DLD-1 BBC3(-/-)	Cancer cell line	Male
CVCL_HD70	HCT 116 BBC3(-/-)	Cancer cell line	Male
CVCL_SE82	HAP1 BBC3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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