PAGE4

Summary

PAGE4 (PAGE family member 4, HGNC:4108) is a protein-coding gene on chromosome Xp11.23, encoding P antigen family member 4 (O60829). Intrinsically disordered protein that potentiates the transcriptional activator activity of JUN.

This gene is a member of the GAGE family. The GAGE genes are expressed in a variety of tumors and in some fetal and reproductive tissues. This gene is strongly expressed in prostate and prostate cancer. It is also expressed in other male and female reproductive tissues including testis, fallopian tube, uterus, and placenta, as well as in testicular cancer and uterine cancer. The protein encoded by this gene shares sequence similarity with other GAGE/PAGE proteins, and also belongs to a family of CT (cancer-testis) antigens. The protein may play a role in benign and malignant prostate diseases. A related pseudogene is located on chromosome 7. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 9506 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 17 total
• MANE Select transcript: NM_007003

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4108
Approved symbol	PAGE4
Name	PAGE family member 4
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	PAGE-4, CT16.7
Ensembl gene	ENSG00000101951
Ensembl biotype	protein_coding
OMIM	300287
Entrez	9506

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000218068, ENST00000376141, ENST00000474146, ENST00000478785, ENST00000715210, ENST00000715211, ENST00000912014, ENST00000912015, ENST00000912016, ENST00000967044

RefSeq mRNA: 2 — MANE Select: NM_007003 NM_001318877, NM_007003

CCDS: CCDS35274

Canonical transcript exons

ENST00000218068 — 5 exons

Exon	Start	End
ENSE00001149637	49829303	49829351
ENSE00001728871	49830399	49830506
ENSE00003536107	49830997	49831084
ENSE00003540446	49832525	49832650
ENSE00003891832	49833846	49834264

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 99.70.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.0036 / max 837.2316, expressed in 105 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196334	1.6823	87
196335	0.2401	21
196333	0.0559	27
196336	0.0253	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.70	gold quality
cauda epididymis	UBERON:0004360	99.61	gold quality
caput epididymis	UBERON:0004358	99.55	gold quality
placenta	UBERON:0001987	98.90	gold quality
prostate gland	UBERON:0002367	93.16	gold quality
seminal vesicle	UBERON:0000998	90.35	gold quality
left uterine tube	UBERON:0001303	86.98	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.97	gold quality
smooth muscle tissue	UBERON:0001135	80.89	gold quality
endometrium	UBERON:0001295	80.16	gold quality
body of uterus	UBERON:0009853	79.02	gold quality
uterus	UBERON:0000995	74.82	gold quality
myometrium	UBERON:0001296	72.78	gold quality
cervix squamous epithelium	UBERON:0006922	70.38	gold quality
right testis	UBERON:0004534	69.63	gold quality
gastrocnemius	UBERON:0001388	69.52	gold quality
left testis	UBERON:0004533	69.21	gold quality
testis	UBERON:0000473	68.59	gold quality
germinal epithelium of ovary	UBERON:0001304	68.56	gold quality
muscle of leg	UBERON:0001383	68.27	gold quality
superficial temporal artery	UBERON:0001614	67.90	gold quality
metanephros cortex	UBERON:0010533	66.15	gold quality
muscle organ	UBERON:0001630	65.71	gold quality
adult organism	UBERON:0007023	65.23	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	63.86	gold quality
sperm	CL:0000019	63.85	silver quality
female reproductive system	UBERON:0000474	63.72	gold quality
male germ cell	CL:0000015	63.48	silver quality
right adrenal gland cortex	UBERON:0035827	63.28	gold quality
right adrenal gland	UBERON:0001233	62.43	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	15156.95
E-HCAD-24	yes	11640.47
E-HCAD-23	yes	8330.88
E-HCAD-38	yes	2165.23
E-ANND-3	no	2.43

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF

miRNA regulators (miRDB)

29 targeting PAGE4, 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-4668-3P	100.00	68.74	2635
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-4531	99.99	69.70	3181
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-4501	98.72	67.19	921
HSA-MIR-384	98.71	67.34	1229
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-5571-3P	97.80	66.07	640
HSA-MIR-3157-5P	97.41	67.61	998
HSA-MIR-6816-3P	95.05	66.08	459
HSA-MIR-7109-3P	94.23	67.19	743

Literature-anchored findings (GeneRIF, showing 11)

• PAGE4 mRNA is expressed only in the cytoplasm of epithelial cells of normal and prostate-cancer specimens (PMID:12489849)
• These results suggest that GAGE gene might have an important role in the development and progression of intestinal type of stomach cancer and the detection of GAGE mRNA may be eligible to the panel of molecular markers for aggressive behavior. (PMID:15362791)
• PAGE4 is a highly intrinsically disordered protein with an anti-apoptotic function (PMID:21357425)
• Dysregulation of epithelial PAGE4 modulates AR signaling. (PMID:22885105)
• Data suggest that disrupting prostate-associated gene 4 (PAGE4)/c-Jun interaction using small molecules could be a novel strategy to treat prostate cancer. (PMID:24263171)
• PAGE4, a regulator of c-Jun transactivation, is phosphorylated by homeodomain-interacting protein kinase 1. (PMID:24559171)
• phosphorylation of PAGE4 leads to conformational shifts (PMID:26242913)
• PAGE4 protects PCa cells from DNA damage and apoptosis under oxidative stress by modulating MAPK signalling pathway. PAGE4 expression may serve as a prognostic biomarker for clinical applications. (PMID:30658679)
• Stromal-epithelial interactions in prostate cancer: Overexpression of PAGE4 in stromal cells inhibits the invasive ability of epithelial cells. (PMID:32003504)
• Tissue-Specific Regulation of the Wnt/beta-Catenin Pathway by PAGE4 Inhibition of Tankyrase. (PMID:32698014)
• The Prostate-Associated Gene 4 (PAGE4) Could Play a Role in the Development of Benign Prostatic Hyperplasia under Oxidative Stress. (PMID:35633887)

Cross-species orthologs

0 orthologs

Paralogs (22): PAGE1 (ENSG00000068985), XAGE2 (ENSG00000155622), PAGE5 (ENSG00000158639), XAGE3 (ENSG00000171402), XAGE5 (ENSG00000171405), GAGE2A (ENSG00000189064), PAGE3 (ENSG00000204279), XAGE1A (ENSG00000204379), XAGE1B (ENSG00000204382), GAGE1 (ENSG00000205777), GAGE12G (ENSG00000215269), GAGE10 (ENSG00000215274), GAGE12E (ENSG00000216649), GAGE12J (ENSG00000224659), GAGE12H (ENSG00000224902), GAGE12D (ENSG00000227488), PAGE2 (ENSG00000234068), GAGE12F (ENSG00000236362), GAGE12C (ENSG00000237671), PAGE2B (ENSG00000238269), GAGE13 (ENSG00000274274), GAGE2E (ENSG00000275113)

Protein

Protein identifiers

P antigen family member 4 — O60829 (reviewed: O60829)

Alternative names: G antigen family C member 1, PAGE-1

All UniProt accessions (1): O60829

UniProt curated annotations — full annotation on UniProt →

Function. Intrinsically disordered protein that potentiates the transcriptional activator activity of JUN. Protects cells from stress-induced apoptosis by inhibiting reactive oxygen species (ROS) production and via regulation of the MAPK signaling pathway.

Subunit / interactions. Interacts with JUN.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion.

Tissue specificity. Expressed at basal lvels in the adult normal prostate gland but is highly up-regulated in the fetal prostate and prostate cancer cells. Preferentially expressed in normal male and female reproductive tissues, testis, fallopian tube, uterus, and placenta, as well as in testicular cancer, uterine cancer, cervical cancer and kidney cancer.

Post-translational modifications. HIPK1-mediated phosphorylation at Thr-51 leads to the compaction of its intrinsically disordered conformation and is critical for its ability to potentiate the transcriptional activator activity of JUN inspite of a reduced interaction with JUN. CLK2-mediated phosphorylation at multiple Ser and Thr residues attenuates its ability to potentiate JUN transcriptional activator activity.

Induction. Up-regulated in response to a variety of stress factors.

Similarity. Belongs to the GAGE family.

RefSeq proteins (2): NP_001305806, NP_008934* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008625	GAGE_fam	Family
IPR031320	GAGE	Domain

Pfam: PF05831

UniProt features (13 total): modified residue 8, compositionally biased region 2, chain 1, region of interest 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6URQ	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60829-F1	63.09	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 (8): 85, 94, 7, 9, 51, 71, 73, 79

Mutagenesis-validated functional residues (1):

Position	Phenotype
51	loss of phosphorylation and its ability to potentiate jun transcriptional activator activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 50 (showing top): GOBP_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GOBP_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GNF2_KISS1, CHIANG_LIVER_CANCER_SUBCLASS_INTERFERON_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_STRESS, GOBP_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, GOBP_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, GOBP_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, CHIANG_LIVER_CANCER_SUBCLASS_CTNNB1_UP, GOBP_RESPONSE_TO_STARVATION, TGGAAA_NFAT_Q4_01

GO Biological Process (6): regulation of stress-activated MAPK cascade (GO:0032872), intracellular signal transduction (GO:0035556), response to starvation (GO:0042594), negative regulation of apoptotic process (GO:0043066), negative regulation of reactive oxygen species biosynthetic process (GO:1903427), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (4): nucleic acid binding (GO:0003676), DNA binding (GO:0003677), transcription coactivator activity (GO:0003713), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
binding	2
intracellular membrane-bounded organelle	2
regulation of MAPK cascade	1
stress-activated MAPK cascade	1
regulation of stress-activated protein kinase signaling cascade	1
signal transduction	1
response to stress	1
response to nutrient levels	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
negative regulation of biosynthetic process	1
reactive oxygen species biosynthetic process	1
regulation of reactive oxygen species biosynthetic process	1
negative regulation of reactive oxygen species metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
nucleic acid binding	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
cellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

886 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAGE4	CLK2	P49760	584
PAGE4	HIPK1	Q86Z02	577
PAGE4	JUN	P05412	561
PAGE4	AR	P10275	541
PAGE4	GAGE2A	Q6NT46	507
PAGE4	XAGE1B	Q9HD64	480
PAGE4	FMR1NB	Q8N0W7	464
PAGE4	CTAG2	O75638	418
PAGE4	NXF2B	Q9GZY0	413
PAGE4	KRTAP2-1	Q9BYU5	394
PAGE4	CST5	P28325	392
PAGE4	DUSP21	Q9H596	389
PAGE4	MAGEB1	P43366	374
PAGE4	DCD	P58461	374
PAGE4	SPANXA1	Q9NS26	370

IntAct

4 interactions, top by confidence:

A	B	Type	Score
PAGE4	JUN	psi-mi:“MI:0407”(direct interaction)	0.440
PAGE4	TNKS	psi-mi:“MI:0914”(association)	0.350

BioGRID (258): TNKS (Affinity Capture-MS), ACLY (Affinity Capture-MS), RCC2 (Affinity Capture-MS), UBA1 (Affinity Capture-MS), IARS (Affinity Capture-MS), BUB3 (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), ENO1 (Affinity Capture-MS), PAICS (Affinity Capture-MS), HUWE1 (Affinity Capture-MS), HSP90B1 (Affinity Capture-MS), MYH9 (Affinity Capture-MS), GART (Affinity Capture-MS), CSE1L (Affinity Capture-MS), GMDS (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RQG5, A1L429, A6NDE8, A6NER3, A6NGK3, E1AZ71, O08664, O60829, O75459, O76087, P0C2W7, P0CL80, P0CL81, P0CL82, P0DSO3, P0DTW1, P52651, P62521, P86478, P86479, P86480, P86481, P86496, Q13066, Q13069, Q13070, Q17QW4, Q28181, Q2T9P9, Q32PA2, Q4V321, Q4V326, Q5JQC4, Q5U2Y8, Q62100, Q63803, Q64256, Q6NT46, Q6X7S9, Q7Z2X7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HIPK1	“up-regulates activity”	PAGE4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

637 predictions. Top by Δscore:

Variant	Effect	Δscore
X:49830397:A:AG	acceptor_gain	1.0000
X:49830397:AGTCT:A	acceptor_loss	1.0000
X:49830398:G:GT	acceptor_gain	1.0000
X:49830398:GT:G	acceptor_gain	1.0000
X:49830398:GTC:G	acceptor_gain	1.0000
X:49830398:GTCT:G	acceptor_gain	1.0000
X:49830398:GTCTT:G	acceptor_gain	1.0000
X:49830502:TGGCT:T	donor_gain	1.0000
X:49830503:GGCT:G	donor_gain	1.0000
X:49830503:GGCTG:G	donor_gain	1.0000
X:49830504:GCT:G	donor_gain	1.0000
X:49830504:GCTG:G	donor_gain	1.0000
X:49830506:TGTG:T	donor_loss	1.0000
X:49830507:G:GA	donor_loss	1.0000
X:49830507:G:GG	donor_gain	1.0000
X:49830508:T:A	donor_loss	1.0000
X:49830968:T:TA	acceptor_gain	1.0000
X:49830971:A:AG	acceptor_gain	1.0000
X:49830972:T:G	acceptor_gain	1.0000
X:49830975:A:AG	acceptor_gain	1.0000
X:49830976:C:G	acceptor_gain	1.0000
X:49830985:A:AG	acceptor_gain	1.0000
X:49830986:C:G	acceptor_gain	1.0000
X:49830992:A:AG	acceptor_gain	1.0000
X:49830993:A:G	acceptor_gain	1.0000
X:49830994:A:AG	acceptor_gain	1.0000
X:49830995:A:AC	acceptor_loss	1.0000
X:49830995:A:G	acceptor_gain	1.0000
X:49830995:AGCCC:A	acceptor_gain	1.0000
X:49830996:G:GA	acceptor_gain	1.0000

AlphaMissense

659 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:49830448:C:T	S7L	0.871
X:49830446:A:C	R6S	0.821
X:49830446:A:T	R6S	0.821
X:49830432:A:C	S2R	0.782
X:49830434:T:A	S2R	0.782
X:49830434:T:G	S2R	0.782
X:49830464:A:C	R12S	0.757
X:49830464:A:T	R12S	0.757
X:49830458:A:C	R10S	0.749
X:49830458:A:T	R10S	0.749
X:49830454:C:T	S9F	0.729
X:49830445:G:C	R6T	0.723
X:49830445:G:T	R6I	0.700
X:49830457:G:T	R10I	0.682
X:49830452:A:C	R8S	0.671
X:49830452:A:T	R8S	0.671
X:49830459:G:A	G11R	0.658
X:49830459:G:C	G11R	0.658
X:49830498:T:C	F24L	0.619
X:49830500:C:A	F24L	0.619
X:49830500:C:G	F24L	0.619
X:49830433:G:T	S2I	0.609
X:49830447:T:C	S7P	0.591
X:49830457:G:C	R10T	0.586
X:49830454:C:A	S9Y	0.577
X:49830454:C:G	S9C	0.570

dbSNP variants (sampled 300 via entrez): RS1000298716 (X:49831168 T>C), RS1000581813 (X:49832916 C>T), RS1000627866 (X:49831538 C>A,T), RS1001803350 (X:49827310 C>T), RS1003070202 (X:49829228 C>A), RS1003553222 (X:49828936 A>G), RS1005842234 (X:49834667 G>T), RS1007333736 (X:49830062 G>A), RS1009338281 (X:49834395 T>A), RS1011778224 (X:49829254 T>A,G), RS1013244663 (X:49832466 A>T), RS1013754491 (X:49832785 G>A), RS1015008203 (X:49832138 A>T), RS1016282742 (X:49834671 A>G), RS1017007344 (X:49828171 G>A)

Disease associations

OMIM: gene MIM:300287 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	3
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	decreases expression	2
methyleugenol	decreases expression	1
terbufos	increases methylation	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Carbamazepine	affects expression	1
Chenodeoxycholic Acid	affects cotreatment, increases expression	1
Cytarabine	decreases expression	1
Deoxycholic Acid	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Fonofos	increases methylation	1
Glycochenodeoxycholic Acid	increases expression, affects cotreatment	1
Glycocholic Acid	increases expression, affects cotreatment	1
Glycodeoxycholic Acid	affects cotreatment, increases expression	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Selenium	decreases expression	1
Mifepristone	decreases expression	1
Cyclosporine	decreases expression	1
beta-Naphthoflavone	decreases expression	1

Clinical trials (associated diseases)

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