PCNP

Summary

PCNP (PEST proteolytic signal containing nuclear protein, HGNC:30023) is a protein-coding gene on chromosome 3q12.3, encoding PEST proteolytic signal-containing nuclear protein (Q8WW12). May be involved in cell cycle regulation. It is a selective cancer dependency (DepMap: 10.8% of cell lines).

Involved in proteasome-mediated ubiquitin-dependent protein catabolic process and protein ubiquitination. Located in nuclear body.

Source: NCBI Gene 57092 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 24 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.8% of screened cell lines
• MANE Select transcript: NM_020357

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30023
Approved symbol	PCNP
Name	PEST proteolytic signal containing nuclear protein
Location	3q12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000081154
Ensembl biotype	protein_coding
OMIM	615210
Entrez	57092

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 3 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000265260, ENST00000460231, ENST00000465366, ENST00000469941, ENST00000470490, ENST00000486406, ENST00000498274, ENST00000627393

RefSeq mRNA: 6 — MANE Select: NM_020357 NM_001320395, NM_001320397, NM_001320398, NM_001320399, NM_001320401, NM_020357

CCDS: CCDS2942

Canonical transcript exons

ENST00000265260 — 5 exons

Exon	Start	End
ENSE00001837860	101574180	101574279
ENSE00003515634	101585437	101585511
ENSE00003588145	101590215	101590270
ENSE00003620981	101579790	101580004
ENSE00003892584	101592627	101594465

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 98.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.1000 / max 709.1135, expressed in 1807 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37642	31.6364	1807
37644	0.3197	116
37643	0.1440	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.74	gold quality
endothelial cell	CL:0000115	98.62	gold quality
cerebellar vermis	UBERON:0004720	98.57	gold quality
upper leg skin	UBERON:0004262	98.54	gold quality
endometrium	UBERON:0001295	98.51	gold quality
skin of hip	UBERON:0001554	98.41	gold quality
mucosa of stomach	UBERON:0001199	98.29	gold quality
ganglionic eminence	UBERON:0004023	98.28	gold quality
monocyte	CL:0000576	98.27	gold quality
ventricular zone	UBERON:0003053	98.25	gold quality
mononuclear cell	CL:0000842	98.23	gold quality
urethra	UBERON:0000057	98.14	gold quality
seminal vesicle	UBERON:0000998	98.14	gold quality
blood vessel layer	UBERON:0004797	98.14	gold quality
popliteal artery	UBERON:0002250	98.13	gold quality
tibial artery	UBERON:0007610	98.13	gold quality
leukocyte	CL:0000738	98.10	gold quality
left ovary	UBERON:0002119	98.08	gold quality
pons	UBERON:0000988	97.98	gold quality
endocervix	UBERON:0000458	97.97	gold quality
ovary	UBERON:0000992	97.97	gold quality
mammary duct	UBERON:0001765	97.97	gold quality
gall bladder	UBERON:0002110	97.97	gold quality
descending thoracic aorta	UBERON:0002345	97.96	gold quality
body of uterus	UBERON:0009853	97.95	gold quality
uterus	UBERON:0000995	97.94	gold quality
smooth muscle tissue	UBERON:0001135	97.94	gold quality
aorta	UBERON:0000947	97.92	gold quality
right lung	UBERON:0002167	97.88	gold quality
right coronary artery	UBERON:0001625	97.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	3.93
E-MTAB-6386	no	363.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

149 targeting PCNP, 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-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• NIRF has ubiquitination activity, the hallmark of a ubiquitin ligase. PCNP was readily ubiquitinated in 293 and COS-7 cells, and NIRF ubiquitinated PCNP in vitro as well as in vivo. (PMID:14741369)
• PCNP mediates the proliferation, migration, and invasion of human neuroblastoma cells through mitogen-activated protein kinase and PI3K/AKT/mTOR signaling pathways, implying that PCNP is a therapeutic target for patients with neuroblastoma. (PMID:29716528)
• PCNP promotes ovarian cancer progression by accelerating beta-catenin nuclear accumulation and triggering EMT transition. (PMID:32548978)
• TIPE2 and PCNP expression abnormalities in peripheral blood mononuclear cells associated with disease activity in rheumatoid arthritis: a meta-analysis. (PMID:33629294)
• PCNP is a novel regulator of proliferation, migration, and invasion in human thyroid cancer. (PMID:35813472)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcnp	ENSDARG00000037713
		ENSDARG00000116774
mus_musculus	Pcnp	ENSMUSG00000071533
rattus_norvegicus	Pcnp	ENSRNOG00000028411

Protein

Protein identifiers

PEST proteolytic signal-containing nuclear protein — Q8WW12 (reviewed: Q8WW12)

All UniProt accessions (3): Q8WW12, A0A0B4J1Z9, G5E9V9

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in cell cycle regulation.

Subunit / interactions. Interacts with UHRF2/NIRF.

Subcellular location. Nucleus.

Post-translational modifications. Ubiquitinated; mediated by UHRF2 and leading to its subsequent proteasomal degradation. N-terminally acetylated in a HYPK-dependent manner by the NatA acetyltransferase complex which is composed of NAA10 and NAA15.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8WW12-1	1	yes
Q8WW12-2	2
Q8WW12-3	3

RefSeq proteins (6): NP_001307324, NP_001307326, NP_001307327, NP_001307328, NP_001307330, NP_065090* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029169	PCNP	Family

Pfam: PF15473

UniProt features (23 total): modified residue 10, compositionally biased region 4, splice variant 3, region of interest 2, sequence conflict 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WW12-F1	63.43	0.00

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 (10): 64, 77, 87, 119, 139, 147, 150, 152, 2, 53

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 140 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, AGGAAGC_MIR5163P, TTTGTAG_MIR520D, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GGGCATT_MIR365, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, MODULE_48, DANG_BOUND_BY_MYC, MODULE_95, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_NUCLEAR_BODY, CGTSACG_PAX3_B, GOBP_PROTEOLYSIS

GO Biological Process (2): protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1054 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCNP	UHRF2	Q96PU4	734
PCNP	HYPK	Q9NX55	519
PCNP	POLI	Q9UNA4	497
PCNP	DNPH1	O43598	487
PCNP	NAA50	Q9GZZ1	465
PCNP	TULP4	Q9NRJ4	461
PCNP	KLHL2	O95198	441
PCNP	HECW2	Q9P2P5	416
PCNP	NPPC	P23582	414
PCNP	UBE3C	Q15386	413
PCNP	CGREF1	Q99674	412
PCNP	MYCBP2	O75592	409
PCNP	NAA10	P41227	403
PCNP	DTYMK	P23919	393
PCNP	ABI3BP	Q7Z7G0	381

IntAct

86 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SNRPD2	GEMIN2	psi-mi:“MI:0914”(association)	0.710
SF3B1	SAP18	psi-mi:“MI:0914”(association)	0.640
PCNP	KLK6	psi-mi:“MI:0915”(physical association)	0.560
N	CAVIN2	psi-mi:“MI:0914”(association)	0.530
PCNP	TERF2IP	psi-mi:“MI:0915”(physical association)	0.510
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
PCNP	HNRNPDL	psi-mi:“MI:0915”(physical association)	0.400
ECE1	PCNP	psi-mi:“MI:0915”(physical association)	0.370
Kifc5b	KPNA3	psi-mi:“MI:0914”(association)	0.350
Mis12		psi-mi:“MI:0914”(association)	0.350
MYO1C	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
PTPN1		psi-mi:“MI:0914”(association)	0.350
Junb	RGPD3	psi-mi:“MI:0914”(association)	0.350
XRCC3	DERL1	psi-mi:“MI:0914”(association)	0.350
EMC2	TBL2	psi-mi:“MI:0914”(association)	0.350
MMGT1	DERL1	psi-mi:“MI:0914”(association)	0.350
USP11	CNOT8	psi-mi:“MI:0914”(association)	0.350
SF1	U2SURP	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
BPNT1	LYN	psi-mi:“MI:0914”(association)	0.350

BioGRID (114): PCNP (Affinity Capture-MS), PCNP (Affinity Capture-RNA), PCNP (Affinity Capture-RNA), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS), PCNP (Affinity Capture-MS)

ESM2 similar proteins: A0A024R1R8, A1A4Q4, A1CMP1, A2R091, A3N0X3, A5DF06, A6R5Z3, A6S6B0, A6ZWL1, A7F9B8, B0BPQ7, B3GXV7, H3BMG3, O31573, P25886, P47915, Q02642, Q05AK9, Q05AX4, Q06DK3, Q0ULD0, Q13442, Q1DI23, Q1HRV4, Q20588, Q28GR1, Q32KU9, Q32LJ0, Q3E764, Q3UHX2, Q4KLG3, Q4P9Y9, Q4SUE2, Q55F75, Q5ASI4, Q5RCI9, Q60QR6, Q62785, Q66654, Q6C2F3

Diamond homologs: Q32PF3, Q5RCI9, Q6P8I4, Q7TP40, Q8WW12

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
UHRF2	“down-regulates quantity by destabilization”	PCNP	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA Splicing	19	25.4×	4e-20
mRNA Splicing - Minor Pathway	9	24.6×	4e-09
mRNA Polyadenylation	22	23.6×	2e-22
Processing of Capped Intron-Containing Pre-mRNA	22	22.0×	5e-22
mRNA Splicing - Major Pathway	29	19.3×	1e-27
SARS-CoV-2 modulates host translation machinery	7	19.1×	3e-06
mRNA 3’-end processing	7	16.8×	7e-06
RNA Polymerase II Transcription Termination	6	16.1×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
U2-type prespliceosome assembly	11	70.1×	6e-16
negative regulation of mRNA splicing, via spliceosome	5	39.1×	2e-05
spliceosomal complex assembly	6	36.9×	2e-06
RNA splicing, via transesterification reactions	5	31.8×	4e-05
mRNA splicing, via spliceosome	23	21.5×	1e-21
RNA splicing	16	14.4×	4e-12
regulation of alternative mRNA splicing, via spliceosome	5	12.5×	3e-03
mRNA processing	15	12.1×	3e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1017 predictions. Top by Δscore:

Variant	Effect	Δscore
3:101574277:G:GT	donor_gain	1.0000
3:101574295:GCGTC:G	donor_gain	1.0000
3:101580003:GT:G	donor_gain	1.0000
3:101580005:G:GG	donor_gain	1.0000
3:101585419:AATAT:A	acceptor_gain	1.0000
3:101585423:T:G	acceptor_gain	1.0000
3:101585508:AGAT:A	donor_gain	1.0000
3:101585508:AGATG:A	donor_loss	1.0000
3:101585509:GAT:G	donor_gain	1.0000
3:101585509:GATG:G	donor_gain	1.0000
3:101585510:AT:A	donor_gain	1.0000
3:101585510:ATGTA:A	donor_loss	1.0000
3:101585511:TGTAA:T	donor_loss	1.0000
3:101585512:G:GA	donor_loss	1.0000
3:101585512:G:GG	donor_gain	1.0000
3:101585513:TAAG:T	donor_loss	1.0000
3:101585514:A:AT	donor_loss	1.0000
3:101590210:TTTA:T	acceptor_loss	1.0000
3:101590211:TTA:T	acceptor_loss	1.0000
3:101590213:A:AG	acceptor_gain	1.0000
3:101590214:G:GG	acceptor_gain	1.0000
3:101590214:GA:G	acceptor_gain	1.0000
3:101590267:G:GT	donor_gain	1.0000
3:101590267:GAAGG:G	donor_loss	1.0000
3:101590268:A:T	donor_gain	1.0000
3:101590268:AAG:A	donor_loss	1.0000
3:101590269:AG:A	donor_loss	1.0000
3:101590270:GGTAT:G	donor_loss	1.0000
3:101590271:G:A	donor_loss	1.0000
3:101592620:A:AG	acceptor_gain	1.0000

AlphaMissense

1162 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:101585494:T:C	F113L	1.000
3:101585495:T:C	F113S	1.000
3:101585496:T:A	F113L	1.000
3:101585496:T:G	F113L	1.000
3:101590231:T:A	M124K	1.000
3:101590231:T:C	M124T	1.000
3:101590231:T:G	M124R	1.000
3:101590233:C:A	P125T	1.000
3:101590233:C:T	P125S	1.000
3:101590234:C:A	P125H	1.000
3:101590234:C:G	P125R	1.000
3:101590242:G:C	A128P	1.000
3:101590247:G:C	K129N	1.000
3:101590247:G:T	K129N	1.000
3:101590249:T:C	M130T	1.000
3:101590251:A:T	R131W	1.000
3:101590252:G:C	R131T	1.000
3:101590252:G:T	R131M	1.000
3:101590253:G:C	R131S	1.000
3:101590253:G:T	R131S	1.000
3:101590254:A:G	M132V	1.000
3:101590255:T:A	M132K	1.000
3:101590255:T:C	M132T	1.000
3:101590255:T:G	M132R	1.000
3:101590256:G:A	M132I	1.000
3:101590256:G:C	M132I	1.000
3:101590256:G:T	M132I	1.000
3:101590257:A:G	K133E	1.000
3:101590258:A:C	K133T	1.000
3:101590259:G:C	K133N	1.000

dbSNP variants (sampled 300 via entrez): RS1000015362 (3:101574011 T>C), RS1000149284 (3:101583272 A>G), RS1000298049 (3:101586056 A>G), RS1000381104 (3:101577042 G>C), RS1000480152 (3:101592359 A>T), RS1000578694 (3:101589601 G>A,C), RS1000676837 (3:101579149 C>T), RS1000713735 (3:101572388 C>T), RS1000989363 (3:101578128 A>G), RS1001016404 (3:101575215 C>G,T), RS1001154748 (3:101584757 C>T), RS1001697177 (3:101590936 T>A), RS1001716455 (3:101573889 C>T), RS1001762013 (3:101586434 A>ACT), RS1001793316 (3:101586204 C>A)

Disease associations

OMIM: gene MIM:615210 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008839_533	Height	7.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067190 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.70	Kd	198.9	nM	CHEMBL5653589
6.70	ED50	198.9	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 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-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148949: Binding affinity to human PCNP incubated for 45 mins by Kinobead based pull down assay	kd	0.1989	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
sodium arsenite	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
manganese chloride	increases abundance, increases expression	1
chloropicrin	affects expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	affects expression, affects methylation	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Aspirin	increases expression	1
Benztropine	increases expression	1
Cadmium	increases expression	1
Caffeine	decreases phosphorylation	1
Clozapine	increases expression	1
Diuron	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	decreases expression	1
Furaldehyde	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Ketoconazole	decreases expression	1
Manganese	increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651991	Binding	Binding affinity to human PCNP incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3DK	Abcam HEK293T PCNP KO	Transformed cell line	Female

Clinical trials (associated diseases)

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