CITED4

Summary

CITED4 (Cbp/p300 interacting transactivator with ED-rich tail 4, HGNC:18696) is a protein-coding gene on chromosome 1p34.2, encoding Cbp/p300-interacting transactivator 4 (Q96RK1). Acts as a transcriptional coactivator for TFAP2/AP-2.

The protein encoded by this intronless gene belongs to the CITED family of transcriptional coactivators that bind to several proteins, including CREB-binding protein (CBP) and p300, via a conserved 32 aa C-terminal motif, and regulate gene transcription. This protein also interacts with transcription factor AP2 (TFAP2), and thus may function as a co-activator for TFAP2. Hypermethylation and transcriptional downregulation of this gene has been observed in oligodendroglial tumors with deletions of chromosomal arms 1p and 19q, and associated with longer recurrence-free and overall survival of patients with oligodendroglial tumors.

Source: NCBI Gene 163732 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 50 total
• MANE Select transcript: NM_133467

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18696
Approved symbol	CITED4
Name	Cbp/p300 interacting transactivator with ED-rich tail 4
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000179862
Ensembl biotype	protein_coding
OMIM	606815
Entrez	163732

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000372638

RefSeq mRNA: 1 — MANE Select: NM_133467 NM_133467

CCDS: CCDS458

Canonical transcript exons

ENST00000372638 — 1 exons

Exon	Start	End
ENSE00001458283	40861054	40862363

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 94.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.0925 / max 1332.3055, expressed in 1666 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11940	27.9940	1663
11939	1.0985	623

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	94.46	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.24	gold quality
apex of heart	UBERON:0002098	92.12	gold quality
lower esophagus mucosa	UBERON:0035834	91.66	gold quality
skin of leg	UBERON:0001511	90.48	gold quality
skin of abdomen	UBERON:0001416	89.25	gold quality
body of pancreas	UBERON:0001150	88.89	gold quality
upper arm skin	UBERON:0004263	88.63	gold quality
zone of skin	UBERON:0000014	88.28	gold quality
minor salivary gland	UBERON:0001830	87.64	gold quality
mammary duct	UBERON:0001765	87.33	gold quality
epithelium of mammary gland	UBERON:0003244	87.20	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	87.18	silver quality
mouth mucosa	UBERON:0003729	86.27	gold quality
right lobe of liver	UBERON:0001114	86.24	gold quality
pigmented layer of retina	UBERON:0001782	86.19	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.03	gold quality
gastrocnemius	UBERON:0001388	85.65	gold quality
heart left ventricle	UBERON:0002084	85.53	gold quality
saliva-secreting gland	UBERON:0001044	85.45	gold quality
cardiac ventricle	UBERON:0002082	85.28	gold quality
muscle of leg	UBERON:0001383	85.01	gold quality
body of tongue	UBERON:0011876	84.92	gold quality
spleen	UBERON:0002106	84.66	gold quality
ascending aorta	UBERON:0001496	84.12	gold quality
thoracic aorta	UBERON:0001515	83.94	gold quality
right testis	UBERON:0004534	83.92	gold quality
monocyte	CL:0000576	83.91	gold quality
esophagus mucosa	UBERON:0002469	83.83	gold quality
left testis	UBERON:0004533	83.70	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	47.85
E-MTAB-10553	yes	26.43
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting CITED4, 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-4692	100.00	67.32	2066
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-6826-3P	98.19	66.32	1153
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-7973	96.48	65.54	502

Literature-anchored findings (GeneRIF, showing 9)

• CITED4 functions as a transactivator when artificially targeted to a promoter element. CITED4 physically interacts with all TFAP2 isoforms in vitro and strongly co-activates all TFAP2 isoforms in Hep3B cells. (PMID:11744733)
• Results show that breast cancer development is characterized by either nuclear loss or cytoplasmic translocation of CITED4, with consequent loss of hypoxia-inducible factor-1alpha transcriptional antagonist activity. (PMID:15342390)
• The interaction and functional cooperation between FHL2, CITED4, and CTNNB were studied. (PMID:15572674)
• CITED4 is epigenetically silenced in the vast majority of oligodendroglial tumours with 1p and 19q deletions. (PMID:17311001)
• mutational study of CITED4 in 24 glial tumors (22 primary glioblastomas, 1 low-grade astrocytoma & its recurrent secondary glioblastoma) (PMID:18722883)
• Demethylation and histone modification can potentially reactivate CITED4 gene expression in some breast cancers and lead to changes in tumour behaviour. (PMID:21755341)
• Upregulation of CITED4 is associated with colorectal cancer. (PMID:26243458)
• Studies indicate that CCAAT enhancer binding protein beta (C/EBPB)-transcription factor CITED4 (CITED4) signaling is a pathway in cardioprotection mediating benefits of exercise in heart. (PMID:29098625)
• CITED4 enhances the metastatic potential of lung adenocarcinoma. (PMID:33759374)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cited4a	ENSDARG00000035990
danio_rerio	cited4b	ENSDARG00000101009
mus_musculus	Cited4	ENSMUSG00000070803
rattus_norvegicus	Cited4	ENSRNOG00000046607

Paralogs (2): CITED1 (ENSG00000125931), CITED2 (ENSG00000164442)

Protein

Protein identifiers

Cbp/p300-interacting transactivator 4 — Q96RK1 (reviewed: Q96RK1)

Alternative names: MSG1-related protein 2

All UniProt accessions (1): Q96RK1

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional coactivator for TFAP2/AP-2. Enhances estrogen-dependent transactivation mediated by estrogen receptors. May function as an inhibitor of transactivation by HIF1A by disrupting HIF1A interaction with CREBBP. May be involved in regulation of gene expression during development and differentiation of blood cells, endothelial cells and mammary epithelial cells.

Subunit / interactions. Interacts via its C-terminal region with the CH1 domain of CREBBP and EP300. Interacts with all TFAP2/AP-2 isoforms.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in most tissues examined with highest levels of expression in heart, liver, skeletal muscle and pancreas. Also expressed in bladder cell line ECV-304 and in various breast cancer cell lines. Also detected in both in situ and invasive breast tumors where its expression is down-regulated and mostly restricted to the cytoplasm of malignant epithelium. Down-regulation of expression is associated with elevated levels of HIF1A and increased tumor growth and angiogenesis.

Similarity. Belongs to the CITED family.

RefSeq proteins (1): NP_597724* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007576	CITED	Family

Pfam: PF04487

UniProt features (5 total): region of interest 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RK1-F1	60.74	0.14

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8866907	Activation of the TFAP2 (AP-2) family of transcription factors

MSigDB gene sets: 106 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, TTGCWCAAY_CEBPB_02, MODULE_205, chr1p34, GOBP_RESPONSE_TO_ESTROGEN, GOBP_RESPONSE_TO_HORMONE, NKX22_01, RYTTCCTG_ETS2_B, P53_DECAMER_Q2, CTGAGCC_MIR24, STAT5A_01, STAT5A_02, RAY_TUMORIGENESIS_BY_ERBB2_CDC25A_DN, GATA_C

GO Biological Process (3): response to estrogen (GO:0043627), regulation of DNA-templated transcription (GO:0006355), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (1): transcription coactivator activity (GO:0003713)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	2
cellular anatomical structure	2
response to hormone	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CITED4	EP300	Q09472	884
CITED4	TFAP2A	P05549	752
CITED4	CREBBP	Q92793	677
CITED4	CEBPB	P17676	491
CITED4	FERD3L	Q96RJ6	416
CITED4	ARHGEF3	Q9NR81	380
CITED4	PERP	Q96FX8	369
CITED4	CAMK2A	Q9UQM7	368
CITED4	NOPCHAP1	Q8N5I9	356
CITED4	CCDC71	Q8IV32	343
CITED4	KLHDC7A	Q5VTJ3	342
CITED4	MANEAL	Q5VSG8	335
CITED4	HMBOX1	Q6NT76	333
CITED4	ZNF684	Q5T5D7	322
CITED4	NRG4	Q8WWG1	322

IntAct

0 interactions, top by confidence:

BioGRID (8): CITED4 (Affinity Capture-RNA), CITED4 (Affinity Capture-Western), EP300 (Affinity Capture-Western), CITED4 (Reconstituted Complex), CITED4 (Two-hybrid), TFAP2A (Reconstituted Complex), TFAP2B (Reconstituted Complex), TFAP2C (Reconstituted Complex)

ESM2 similar proteins: A2A9A2, A6NEQ2, A6NJT0, A6QQ94, A7MB34, A8MYZ6, B5RHS5, E9PZZ1, O02754, O02755, O02756, O35392, O60548, O70220, O88470, P05554, P17676, P21272, P28033, P35713, P49715, P49716, P50548, P53566, P58012, P79765, Q12952, Q13461, Q14526, Q4VUF1, Q60843, Q61345, Q63244, Q6BEB4, Q6VFT5, Q6VFT6, Q6VFT7, Q6ZQN5, Q70KY4, Q8MIP2

Diamond homologs: A1YFU7, O35740, P97769, Q0VCT9, Q2HJ78, Q5XGW7, Q6NX30, Q96RK1, Q99966, Q99967, Q99MA0, Q9BDI3, Q9I8K7, Q9WUL8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

106 predictions. Top by Δscore:

Variant	Effect	Δscore
1:40862299:CGCA:C	donor_loss	0.9600
1:40862300:GCAC:G	donor_loss	0.9600
1:40862302:ACC:A	donor_loss	0.9600
1:40862338:A:AT	donor_gain	0.9400
1:40862145:C:CC	acceptor_gain	0.9100
1:40862145:CTGCG:C	acceptor_loss	0.9100
1:40862146:T:C	acceptor_loss	0.9100
1:40862147:G:C	acceptor_loss	0.9000
1:40862155:A:T	acceptor_loss	0.8800
1:40862141:CTGC:C	acceptor_gain	0.8600
1:40862337:C:CT	donor_gain	0.8400
1:40862149:GGGGA:G	acceptor_loss	0.8200
1:40862163:GTGGT:G	acceptor_loss	0.8100
1:40862304:C:G	donor_loss	0.8100
1:40862154:C:CT	acceptor_loss	0.7900
1:40862142:TGC:T	acceptor_gain	0.7700
1:40862335:CGCA:C	donor_gain	0.7600
1:40862148:CGGGG:C	acceptor_loss	0.7500
1:40862165:GGTCA:G	acceptor_loss	0.7500
1:40862166:GTCAG:G	acceptor_loss	0.7500
1:40862293:C:CT	donor_gain	0.7300
1:40862294:T:TT	donor_gain	0.7300
1:40862150:GGGA:G	acceptor_loss	0.6900
1:40862295:A:AC	donor_gain	0.6900
1:40862296:C:CC	donor_gain	0.6900
1:40862168:CAGCG:C	acceptor_loss	0.6800
1:40862302:A:AC	donor_gain	0.6800
1:40862303:C:CC	donor_gain	0.6800
1:40862315:AG:A	donor_gain	0.6500
1:40862167:T:C	acceptor_loss	0.6300

AlphaMissense

1151 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:40861627:G:C	F167L	0.990
1:40861627:G:T	F167L	0.990
1:40861629:A:G	F167L	0.990
1:40861694:A:G	L145P	0.986
1:40861676:A:G	L151P	0.985
1:40861703:A:G	L142P	0.985
1:40861718:A:T	I137N	0.982
1:40861682:A:G	L149P	0.981
1:40861694:A:T	L145Q	0.980
1:40861680:C:A	G150W	0.978
1:40861658:A:G	L157P	0.975
1:40861676:A:T	L151Q	0.975
1:40861703:A:T	L142Q	0.975
1:40861649:A:G	L160P	0.974
1:40861679:C:A	G150V	0.972
1:40861655:G:T	P158H	0.971
1:40861680:C:G	G150R	0.970
1:40861680:C:T	G150R	0.970
1:40861649:A:T	L160H	0.969
1:40861578:A:G	C184R	0.968
1:40861718:A:C	I137S	0.968
1:40861628:A:G	F167S	0.966
1:40861645:G:C	F161L	0.962
1:40861645:G:T	F161L	0.962
1:40861647:A:G	F161L	0.962
1:40861686:C:T	E148K	0.962
1:40861628:A:C	F167C	0.961
1:40861715:T:A	D138V	0.960
1:40861579:G:C	S183R	0.957
1:40861579:G:T	S183R	0.957

dbSNP variants (sampled 300 via entrez): RS1000739326 (1:40862603 C>G), RS1001233353 (1:40863485 G>A,T), RS1001767702 (1:40863222 A>G), RS1002099850 (1:40862205 T>C), RS1002169413 (1:40864205 A>C,G), RS1003240565 (1:40860772 C>A,T), RS1004259871 (1:40861164 G>C), RS1006366424 (1:40861390 C>G), RS1007578471 (1:40864148 C>G,T), RS1007609437 (1:40863920 G>C), RS1007913063 (1:40861585 G>A,T), RS1009137218 (1:40862308 C>G,T), RS1009329080 (1:40862403 C>A), RS1009439144 (1:40862278 C>T), RS1009492724 (1:40862424 C>A)

Disease associations

OMIM: gene MIM:606815 | 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

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	3
sodium arsenite	decreases expression, increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Cadmium Chloride	decreases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	decreases expression	1
afuresertib	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
terbufos	increases methylation	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
zinc chromate	decreases expression, increases abundance	1
ferrous chloride	decreases expression	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
pentanal	increases expression	1
avobenzone	increases expression	1
chromium hexavalent ion	increases abundance, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
jinfukang	decreases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
MT19c compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Sunitinib	decreases expression	1
Troglitazone	decreases expression	1
Aldehydes	increases expression	1
Calcitriol	increases expression	1

Clinical trials (associated diseases)

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