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
• GTEx eGene: eQTL in 15 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.05 (LoF-tolerant), LOEUF 1.29 (unconstrained)
• MANE Select transcript: NM_014417
• Notable: 62 clinical variants but no curated precision-oncology (CIViC) evidence yet

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: 15 — 13 protein_coding, 2 retained_intron

MANE Select: ENST00000439096

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 1

ENST00000439096, ENST00000300880, ENST00000341983, ENST00000449228, ENST00000598636, ENST00000601438, ENST00000899307, ENST00000899308, ENST00000899309, ENST00000899310, ENST00000899311, ENST00000919804, ENST00000919805, ENST00000919806, ENST00001139961

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.

Highest expression (Bgee): type B pancreatic cell, vena cava, olfactory bulb, pancreatic ductal cell, parotid gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

BBC3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 15 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

16 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	9.8e-07	+0.13	19:47158236:G:A
Skin Sun Exposed Lower leg	eqtl	1.4e-06	-0.17	19:47193369:C:T
Nerve Tibial	eqtl	2.5e-06	-0.20	19:47193369:C:T
Artery Tibial	eqtl	7.3e-06	-0.16	19:47196450:G:A
Brain Frontal Cortex BA9	eqtl	1.6e-05	-0.34	19:47216835:T:C
Brain Cerebellum	eqtl	6.9e-05	-0.30	19:47216835:T:C
Brain Anterior cingulate cortex BA24	eqtl	1.9e-04	-0.39	19:47216835:T:C
Brain Cortex	eqtl	2.2e-04	-0.30	19:47213090:T:A
Brain Cerebellar Hemisphere	eqtl	1.4e-03	-0.24	19:47213090:T:A
Thyroid	eqtl	2.2e-03	-0.19	19:47213090:T:A
Whole Blood	eqtl	7.3e-03	-0.08	19:47196450:G:A
Testis	eqtl	1.8e-02	+0.25	19:47800940:A:T
Colon Transverse	sqtl	1.9e-02	-0.30	19:47232959:T:C
Adipose Subcutaneous	eqtl	2.1e-02	+0.16	19:47164069:T:A
Lung	eqtl	2.6e-02	-0.13	19:47216835:T:C
Brain Spinal cord cervical c-1	eqtl	4.9e-02	+0.23	19:47158236:G:A

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

showing 100 of 275 tissues 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
substantia nigra pars reticulata	UBERON:0001966	84.59	silver quality
superior vestibular nucleus	UBERON:0007227	84.38	gold quality
superior surface of tongue	UBERON:0007371	84.34	silver quality
blood	UBERON:0000178	84.26	gold quality
globus pallidus	UBERON:0001875	83.57	silver quality
leukocyte	CL:0000738	83.38	gold quality
monocyte	CL:0000576	83.32	gold quality
mononuclear cell	CL:0000842	83.22	gold quality
diaphragm	UBERON:0001103	82.97	gold quality
trachea	UBERON:0003126	82.80	gold quality
middle temporal gyrus	UBERON:0002771	82.67	silver quality
medial globus pallidus	UBERON:0002477	82.61	gold quality
mucosa of transverse colon	UBERON:0004991	82.12	gold quality
skeletal muscle tissue	UBERON:0001134	81.94	gold quality
Brodmann (1909) area 46	UBERON:0006483	81.75	silver quality
cerebellar vermis	UBERON:0004720	81.67	silver quality
cerebellar hemisphere	UBERON:0002245	81.64	gold quality
cerebellar cortex	UBERON:0002129	81.62	gold quality
trigeminal ganglion	UBERON:0001675	81.51	silver quality
renal medulla	UBERON:0000362	81.41	silver quality
right hemisphere of cerebellum	UBERON:0014890	81.41	gold quality
male germ cell	CL:0000015	81.25	gold quality
cerebellum	UBERON:0002037	81.10	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	81.07	gold quality
apex of heart	UBERON:0002098	81.06	gold quality
buccal mucosa cell	CL:0002336	80.85	silver quality
right lung	UBERON:0002167	80.66	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	80.66	silver quality
right uterine tube	UBERON:0001302	80.35	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	80.29	silver quality
sperm	CL:0000019	80.20	gold quality
cortical plate	UBERON:0005343	80.02	gold quality
muscle tissue	UBERON:0002385	80.00	gold quality
cervix squamous epithelium	UBERON:0006922	79.89	gold quality
nipple	UBERON:0002030	79.88	silver quality
skin of abdomen	UBERON:0001416	79.56	gold quality
entorhinal cortex	UBERON:0002728	79.56	silver quality
skin of leg	UBERON:0001511	79.44	gold quality
body of pancreas	UBERON:0001150	79.26	gold quality
parietal lobe	UBERON:0001872	79.25	silver quality
cartilage tissue	UBERON:0002418	79.14	gold quality
bone marrow	UBERON:0002371	78.86	gold quality
bone marrow cell	CL:0002092	78.66	gold quality
Brodmann (1909) area 23	UBERON:0013554	78.60	silver quality
muscle organ	UBERON:0001630	78.53	gold quality
gastrocnemius	UBERON:0001388	78.52	gold quality
upper lobe of left lung	UBERON:0008952	78.46	gold quality
saliva-secreting gland	UBERON:0001044	78.42	gold quality
dorsal root ganglion	UBERON:0000044	78.40	silver quality
transverse colon	UBERON:0001157	78.39	gold quality
superior frontal gyrus	UBERON:0002661	78.38	gold quality
stromal cell of endometrium	CL:0002255	78.22	gold quality
postcentral gyrus	UBERON:0002581	78.16	silver quality
upper lobe of lung	UBERON:0008948	77.99	gold quality
mammalian vulva	UBERON:0000997	77.92	silver quality
mucosa of stomach	UBERON:0001199	77.78	gold quality
zone of skin	UBERON:0000014	77.69	gold quality
lower esophagus muscularis layer	UBERON:0035833	77.63	gold quality
lower esophagus	UBERON:0013473	77.57	gold quality
muscle of leg	UBERON:0001383	77.55	gold quality
spleen	UBERON:0002106	77.54	gold quality
right adrenal gland cortex	UBERON:0035827	77.54	gold quality
left ventricle myocardium	UBERON:0006566	77.50	gold quality
occipital lobe	UBERON:0002021	77.26	gold quality
hindlimb stylopod muscle	UBERON:0004252	77.10	gold quality
mucosa of urinary bladder	UBERON:0001259	77.08	silver quality
minor salivary gland	UBERON:0001830	77.08	gold quality
hair follicle	UBERON:0002073	77.06	silver quality
esophagogastric junction muscularis propria	UBERON:0035841	77.03	gold quality
mouth mucosa	UBERON:0003729	76.96	gold 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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Pancreas	tissue	4.7	high
Bone marrow	tissue	4.6	medium
Locus coeruleus	tissue	4.4
Postcentral gyrus	tissue	4.0
Hippocampus	tissue	3.9	low
Olfactory bulb	tissue	3.9
Skin 1	tissue	3.8	high
Thymus	tissue	3.7
Colon	tissue	3.6	high
Choroid plexus	tissue	3.6
Vagina	tissue	3.2	high
Stomach 1	tissue	3.1	low
Salivary gland	tissue	3.0	medium
Skeletal muscle	tissue	2.9	medium
Lymph node	tissue	2.6	medium
Cerebellum	tissue	2.6	high
Lung	tissue	2.6	high
Spleen	tissue	2.6	not detected
Small intestine	tissue	2.6	medium
Spinal cord	tissue	2.4
Duodenum	tissue	2.3	medium
Hippocampal formation	tissue	2.3
Cerebral cortex	tissue	2.2	low
Nucleus accumbens	tissue	2.2
Hypothalamus	tissue	2.2
Superior colliculi	tissue	2.2
Insular cortex	tissue	2.2
Pituitary gland	tissue	2.1
Frontal cortex	tissue	2.1
Substantia nigra	tissue	2.1
Prefrontal cortex	tissue	2.0
Endometrium 1	tissue	2.0	medium
Somatosensory cortex	tissue	2.0
Temporal cortex	tissue	2.0
Pons	tissue	1.9
Parathyroid gland	tissue	1.9	not detected
Motor cortex	tissue	1.9
Gallbladder	tissue	1.9	medium
Entorhinal cortex	tissue	1.9
Appendix	tissue	1.9	low
Amygdala	tissue	1.8
Fallopian tube	tissue	1.8	medium
Septum	tissue	1.8
Retrosplenial cortex	tissue	1.8
Rectum	tissue	1.7	high
Urinary bladder	tissue	1.7	not detected
Midbrain	tissue	1.7
Medulla oblongata	tissue	1.7
Thalamus	tissue	1.7
Placenta	tissue	1.7	low
Retrosplenial and cingulate cortex	tissue	1.7
Periaqueductal gray	tissue	1.7
Ovary	tissue	1.6	medium
Adipose tissue	tissue	1.6	not detected
Liver	tissue	1.6	not detected
Occipital cortex	tissue	1.6
Cervix	tissue	1.5	high
Heart muscle	tissue	1.3	medium
Ventral forebrain	tissue	1.3
Seminal vesicle	tissue	1.2	not detected

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Flocculonodular lobe (8.5), Vermis (8.5), Cerebellar cortex (8.0), Periaquaductal grey, anterior (7.8), Area parastriata, superior (7.1).

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)

Targeting BBC3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 40 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 0.0515, LOEUF 1.29, missense Z -0.972 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000439096 — one region, missense o/e 0.83.

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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2181667) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 14 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased cellular sensitivity to gamma-irradiation	2
abnormal neuron physiology	2
increased leukocyte cell number	1
abnormal cell death	1
decreased myocardial infarct size	1
abnormal nervous system physiology	1
increased left ventricle developed pressure	1
abnormal CD8-positive, alpha-beta T cell physiology	1
decreased lactate dehydrogenase level	1
decreased apoptosis	1
increased CD8-positive, alpha-beta T cell number	1
abnormal splenic cell ratio	1
decreased sensitivity to induced cell death	1
abnormal heart left ventricle pressure	1

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR3190	ncRNA	100422899
SAE1	protein-coding	10055
ZC3H4	protein-coding	23211
INAFM1	protein-coding	255783
CCDC9	protein-coding	26093
MIR3191	ncRNA	100422832
TMEM160	protein-coding	54958
C5AR1	protein-coding	728
NPAS1	protein-coding	4861
C5AR2	protein-coding	27202

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 by resolution:

PDB	Title	Method	Resolution (Å)
5UUL	Human Bfl-1 in complex with PUMA BH3	X-RAY DIFFRACTION	1.33
4BPJ	Mcl-1 bound to alpha beta Puma BH3 peptide 3	X-RAY DIFFRACTION	1.6
4BPK	Bcl-xL bound to alpha beta Puma BH3 peptide 5	X-RAY DIFFRACTION	1.76
6TQP	Structural insight into tanapoxvirus mediated inhibition of apoptosis	X-RAY DIFFRACTION	1.85
6QG8	Structure of human Bcl-2 in complex with PUMA BH3 peptide	X-RAY DIFFRACTION	1.9
4BPI	Mcl-1 bound to alpha beta Puma BH3 peptide 2	X-RAY DIFFRACTION	1.98
6QFM	Structure of human Mcl-1 in complex with PUMA BH3 peptide	X-RAY DIFFRACTION	2
7P9W	Epstein-Barr virus encoded apoptosis regulator BHRF1 in complex with Puma BH3	X-RAY DIFFRACTION	2
7QTX	Kaposi sarcoma associated herpes virus (KSHV) encoded apoptosis inhibitor, KsBcl-2 in …	X-RAY DIFFRACTION	2.12
7P0S	ORF virus encoded Bcl-2 homolog ORFV125 in complex with Puma BH3 peptide	X-RAY DIFFRACTION	2.5
7DVD	The crystal structure of p53 DNA binding domain and PUMA complex	X-RAY DIFFRACTION	2.59
4HNJ	Crystallographic structure of BCL-xL domain-swapped dimer in complex with PUMA BH3 …	X-RAY DIFFRACTION	2.9
2M04	Solution structure of BCL-xL in complex with PUMA BH3 peptide	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH approved · IF approved

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)

Type	Positions
Phosphoserine	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

4 curated (TAS) of 14; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

14 pathways:

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

MSigDB gene sets: 0 (showing top):

GO Biological Process (18): 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), positive regulation of neuron apoptotic process (GO:0043525), positive regulation of thymocyte apoptotic process (GO:0070245), cellular response to hypoxia (GO:0071456), 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 IRE1-mediated unfolded protein response (GO:1903896), positive regulation of apoptotic process (GO:0043065)

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

10 top-level categories:

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

48 GO namespaces:

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
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron 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
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
positive regulation of intrinsic apoptotic signaling pathway	1
IRE1-mediated unfolded protein response	1
positive regulation of endoplasmic reticulum unfolded protein response	1
regulation of IRE1-mediated unfolded protein response	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
enzyme binding	1
binding	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1
cellular anatomical structure	1
lytic vacuole	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 13 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

13 experimentally-supported GO terms:

GO term	NS	Evidence
apoptotic process	BP	mutant phenotype
apoptotic signaling pathway	BP	direct assay
cellular response to hypoxia	BP	expression pattern
execution phase of apoptosis	BP	direct assay
intrinsic apoptotic signaling pathway	BP	direct assay
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	BP	direct assay
positive regulation of intrinsic apoptotic signaling pathway	BP	mutant phenotype
positive regulation of protein-containing complex assembly	BP	direct assay
positive regulation of release of cytochrome c from mitochondria	BP	genetic interaction
release of cytochrome c from mitochondria	BP	direct assay
response to endoplasmic reticulum stress	BP	direct assay
mitochondrion	CC	direct assay
ATPase binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,148 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BBC3	PMAIP1	Q13794	859
BBC3	TP53	P04637	831
BBC3	BAX	P55269	797
BBC3	CDKN1A	P38936	784
BBC3	BCL2L1	Q07817	752
BBC3	BCL2L11	O43521	718
BBC3	BCL2	P10415	716
BBC3	MDM2	Q00987	658
BBC3	BID	P55957	653
BBC3	BAK1	Q16611	649
BBC3	HRK	O00198	639
BBC3	MCL1	Q07820	621
BBC3	RTL10	Q7L3V2	621
BBC3	BIK	Q13323	611
BBC3	CASP3	P42574	610

IntAct

Human interaction partners of BBC3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
FHL5	physical association	0.560	3
HGS	physical association	0.560	3
HSD17B13	physical association	0.560	3
MYPOP	physical association	0.560	3
NDUFAB1	physical association	0.560	3
UBASH3B	physical association	0.560	3
WDR5	physical association	0.560	3
ZNF438	physical association	0.560	3

BioGRID (66 interactions; top human partners by supporting records): MCL1 (Protein-peptide; 13 records), BCL2L1 (Protein-peptide; 7 records), BCL2 (Protein-peptide; 5 records), FBXL20 (Affinity Capture-Western; 5 records), BAX (Affinity Capture-Western; 2 records), BCL2L2 (Affinity Capture-MS; 2 records), CHUK (Biochemical Activity; 2 records), MAP1LC3A (Affinity Capture-Western; 2 records), SQSTM1 (Affinity Capture-Western; 2 records), ALB (Affinity Capture-MS), BAD (Negative Genetic), BCL2A1 (Protein-peptide), BCL2L13 (Negative Genetic), BNIP3 (Negative Genetic), BRCA2 (Positive Genetic)

SIGNOR signaling

6 signaling 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”

Disease & clinical

Genetic variants

Variant evidence for BBC3: 62 ClinVar records (0 pathogenic / likely pathogenic); 3 GWAS associations.

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 452):

Position(s)	Effect	Δscore	Sites
19:47226756	acceptor_gain	1.0000
19:47221919–47221920	acceptor_loss	0.9900	6
19:47226562–47226563	donor_loss	0.9900	5
19:47226755–47226756	acceptor_loss	0.9900	5
19:47230927–47230928	donor_loss	0.9700	6
19:47230979–47230980	donor_gain	0.9600	2
19:47228156–47228157	donor_loss	0.9500	5
19:47230924	donor_loss	0.9300
19:47226562	donor_loss	0.9200
19:47228156	donor_loss	0.9200

AlphaMissense

15 missense substitutions predicted likely pathogenic (of 1,194 scored), across 8 residues. Top 8 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
S221	3	0.612	0.612
G204	2	0.722	0.757
G218	2	0.675	0.686
Q227	2	0.629	0.629
Q207	2	0.612	0.612
W113	2	0.607	0.607
G211	1	0.696	0.696
E203	1	0.593	0.593

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Bladder Urothelial Carcinoma (TCGA)	favorable	0.000295

Disease associations

OMIM: gene MIM:605854 | disease phenotypes:

GWAS associations

3 associations:

Study	Trait	p-value
GCST90000025_109	Appendicular lean mass	2e-33
GCST004625_218	Monocyte count	3e-9
GCST90002407_500	White blood cell count	4e-9

EFO canonical traits (from GWAS)

2 canonical traits:

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 (CPIC guideline: no)

PubChem BioAssay actives

1 with measured affinity, of 4 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	increases reaction, affects cotreatment, decreases response to substance, decreases reaction, affects 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	decreases reaction, affects reaction, increases response to substance, affects cotreatment, decreases expression (+2 more)	7
sodium arsenite	increases abundance, increases reaction, affects binding, increases expression, affects cotreatment (+1 more)	6
Doxorubicin	decreases reaction, increases expression, increases phosphorylation, affects cotreatment, increases reaction (+3 more)	6
pifithrin	decreases reaction, increases expression, decreases activity, increases reaction	5
nutlin 3	affects cotreatment, increases expression, increases reaction, affects reaction	5
Resveratrol	decreases expression, increases expression, increases reaction, affects cotreatment	5
cobaltous chloride	increases activity, increases expression, increases phosphorylation, affects cotreatment, decreases expression (+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	increases localization, increases response to substance, increases expression, increases reaction, decreases reaction (+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)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for BBC3 across ~30M SureChEMBL compounds — explore on Sugi Predict.