TFAP4

Summary

TFAP4 (transcription factor AP-4, HGNC:11745) is a protein-coding gene on chromosome 16p13.3, encoding Transcription factor AP-4 (Q01664). Transcription factor that activates both viral and cellular genes by binding to the symmetrical DNA sequence 5’-CAGCTG-3’. It is a selective cancer dependency (DepMap: 25.6% of cell lines).

Transcription factors of the basic helix-loop-helix-zipper (bHLH-ZIP) family contain a basic domain, which is used for DNA binding, and HLH and ZIP domains, which are used for oligomerization. Transcription factor AP4 activates both viral and cellular genes by binding to the symmetrical DNA sequence CAGCTG (Mermod et al., 1988 [PubMed 2833704]; Hu et al., 1990 [PubMed 2123466]).

Source: NCBI Gene 7023 — RefSeq curated summary.

At a glance

• GWAS associations: 50
• Clinical variants (ClinVar): 48 total
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Cancer dependency (DepMap): dependent in 25.6% of screened cell lines
• Transcription factor: yes — 41 downstream targets (CollecTRI)
• MANE Select transcript: NM_003223

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11745
Approved symbol	TFAP4
Name	transcription factor AP-4
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	AP-4, bHLHc41
Ensembl gene	ENSG00000090447
Ensembl biotype	protein_coding
OMIM	600743
Entrez	7023

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000204517, ENST00000572393, ENST00000573476, ENST00000574639, ENST00000575300, ENST00000575320, ENST00000575672, ENST00000880819, ENST00000880820, ENST00000880821, ENST00000880822

RefSeq mRNA: 1 — MANE Select: NM_003223 NM_003223

CCDS: CCDS10510

Canonical transcript exons

ENST00000204517 — 7 exons

Exon	Start	End
ENSE00001739113	4257186	4258249
ENSE00003496563	4260455	4260595
ENSE00003522917	4262536	4262701
ENSE00003589979	4272658	4273023
ENSE00003603254	4262324	4262422
ENSE00003663272	4260090	4260245
ENSE00003788859	4261779	4261949

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 93.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2350 / max 434.1932, expressed in 1651 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156071	7.6023	1568
156073	2.3741	1025
156072	1.2156	735
156076	0.6298	297
156074	0.3402	119
156075	0.0731	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	93.91	silver quality
type B pancreatic cell	CL:0000169	91.17	silver quality
vena cava	UBERON:0004087	87.31	silver quality
tongue squamous epithelium	UBERON:0006919	86.43	silver quality
sural nerve	UBERON:0015488	85.90	gold quality
endometrium epithelium	UBERON:0004811	85.71	gold quality
ganglionic eminence	UBERON:0004023	84.56	gold quality
diaphragm	UBERON:0001103	84.25	gold quality
cortical plate	UBERON:0005343	83.83	gold quality
cerebellar hemisphere	UBERON:0002245	83.06	gold quality
cerebellar cortex	UBERON:0002129	82.98	gold quality
lateral nuclear group of thalamus	UBERON:0002736	82.81	silver quality
subthalamic nucleus	UBERON:0001906	82.62	silver quality
nasal cavity epithelium	UBERON:0005384	82.58	silver quality
right hemisphere of cerebellum	UBERON:0014890	82.57	gold quality
cerebellum	UBERON:0002037	82.27	gold quality
ventricular zone	UBERON:0003053	82.26	gold quality
dorsal plus ventral thalamus	UBERON:0001897	81.76	silver quality
inferior vagus X ganglion	UBERON:0005363	81.54	silver quality
ventral tegmental area	UBERON:0002691	81.52	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	81.47	silver quality
hair follicle	UBERON:0002073	81.36	silver quality
pylorus	UBERON:0001166	80.84	silver quality
calcaneal tendon	UBERON:0003701	80.71	gold quality
pharyngeal mucosa	UBERON:0000355	80.53	silver quality
body of pancreas	UBERON:0001150	80.50	gold quality
cervix squamous epithelium	UBERON:0006922	80.50	gold quality
superior vestibular nucleus	UBERON:0007227	80.50	gold quality
tongue	UBERON:0001723	80.49	silver quality
cardia of stomach	UBERON:0001162	80.35	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.21
E-GEOD-99795	no	17.61

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

41 targets.

Target	Regulation
AGT
APP
BGLAP
CAT
CD4	Unknown
CD44
CD8A
CDH1
CDKN1A	Activation
CEBPA
CLCN5	Unknown
CLDN1
CLDN4
CLDN7
DBH
FN1
GNAS
IER3	Repression
IFNG	Unknown
IKZF3	Repression
IL1B
LCP1
LGR5	Repression
LTA	Repression
MAPK8
MDM2	Repression
MUC4	Unknown
NF1
OGG1
PENK	Activation

JASPAR motifs

Motif	Name	Family
MA0691.1	TFAP4	bHLH-ZIP
MA1570.1	TFAP4	bHLH-ZIP
MA1966.1	TFAP4::ETV1	bHLH-ZIP::Ets-related
MA1966.2	TFAP4::ETV1	bHLH-ZIP::Ets-related
MA1967.1	TFAP4::FLI1	bHLH-ZIP::Ets-related
MA1967.2	TFAP4::FLI1	bHLH-ZIP::Ets-related

JASPAR matrix evidence (PMIDs): PMID:18818310, PMID:9741833, PMID:24218641

Upstream regulators (CollecTRI, top): MYC, TBP, TFAP4, TGFB1, USF1, USF2

miRNA regulators (miRDB)

91 targeting TFAP4, 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-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-371A-3P	99.99	66.77	91
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 25.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 33)

• Docking studies showed that the ATF4 DpSGIXXpSXE motif fits the binding pocket of beta-TrCP through an S-turning conformation. (PMID:18052253)
• Activator protein-4 expression was associated with the expression of matrix metalloproteinase-9 and vascular endothelial growth factor in the advanced colorectal cancer. (PMID:18480385)
• c-MYC directly regulates the expression of AP4 via CACGTG motifs in the first intron of the AP4 gene. (PMID:18818310)
• AP-4 participates in a transcriptional-regulating complex at the HDM2-P2 promoter in response to DNA damage. (PMID:19505873)
• Overexpression of AP-4 is associated with gastric carcinoma. (PMID:21336989)
• in serum- or IGF-1-stimulated breast cancer MCF-7 cells, JNK induces SHP1 expression through the binding of AP-4 and RFX-1 transcription factors to the epithelial tissue-specific SHP1 promoter. (PMID:21719561)
• The expression of AP-4 was silenced by the siRNAs transfection. (PMID:22615908)
• findings provide evidence that a high expression level of AP-4 serves as a biomarker for poor prognosis for hepatocellular carcinoma (PMID:23055200)
• Elevated AP4 expression in primary colorectal cancer (CRC) significantly correlated with liver metastasis and poor patient survival. Findings imply AP4 as a new regulator of epithelial-mesenchymal transition that contributes to metastatic processes in CRC (PMID:23752226)
• Senescence caused by AP4-deficiency was prevented by depletion of p16 and/or p21, demonstrating that these factors mediate senescence caused by AP4 loss. (PMID:23949224)
• the 16 SNP variants studied in the genes encoding the four units of AP-4 do not have a major role in overall CP, but SNP rs1217401 of AP4B1 is significantly associated with the risk of CP as a sequela of neonatal HIE in the Chinese population. (PMID:24065543)
• betaTrCP-dependent degradation of TFAP4 is required for the fidelity of mitotic division (PMID:24500709)
• results indicate that AP4 is a central mediator and coordinator of cell cycle progression (PMID:25261373)
• Data show that transcription factor activating enhancer binding protein-4 (TFAP4) is a direct transcriptional target of MYCN in neuroblastoma and that high levels of this transcription factor are associated with poor clinical outcome in this disease. (PMID:27448979)
• Depletion of either Arl5b or AP4 results in the accumulation of APP. (PMID:28000370)
• Results show that AP4 is overexpressed in primary carcinoma compared with the non-cancerous mucosa and is up-regulated in EMT in colorectal cancer (CRC) cells. Its overexpression is correlated with liver metastasis in CRC and poor outcome. Also, The study show that USP22 binds to the promoter region of AP4 to activate its transcription. (PMID:28427243)
• these findings support a plausible mechanism by which the AP4/L-plastin axis is regulated by the PI3K/AKT pathway in human prostate cancer (PCa)and may represent a novel therapeutic target in PCa treatment. (PMID:28981098)
• Findings identify LAPTM4B as a direct AP4 target gene and the interaction of AP4 and LAPTM4B plays an important role in breast cancer progression.Implications: This study demonstrates that AP4 promotes cell growth, migration, invasion, and cisplatin resistance through upregulation of LAPTM4B expression. (PMID:29378908)
• TFAP4 is a key regulator of MYCN-amplified neuroblastom (PMID:29880876)
• These results provide new insight into the mechanisms underlying hyperactivation of the Wnt/beta-catenin pathway in hepatocellular carcinoma, as well the oncogenic ability of TFAP4 to enhance the tumor-forming ability of hepatocellular carcinoma cells via its binding to the promoters of DVL1 (dishevelled segment polarity protein 1) and LEF1 (lymphoid enhancer binding factor 1). (PMID:30026867)
• AP4-associated signatures are conserved between murine adenomas and human colorectal cancer samples. Results establish Ap4 as rate-limiting mediator of adenoma initiation, as well as regulator of intestinal and colonic stem cell and Paneth cell homeostasis. (PMID:30177706)
• TRIB2 suppresses cellular senescence through interaction with AP4 to down-regulate p21 expression. (PMID:30541550)
• TFAP4 promotes hepatocellular carcinoma invasion and metastasis by inducing epithelial-mesenchymal transition and regulating MMP-9 expression via activating the PI3K/AKT signaling pathway. (PMID:31281549)
• The polymorphic variant rs1800734 influences methylation acquisition and allele-specific TFAP4 binding in the MLH1 promoter leading to differential mRNA expression. (PMID:31530880)
• TFAP4-66aa-uORF inhibited the TFAP4/LINC00520/miR-520f-3p feedback loop. (PMID:31943575)
• An integrated pan-cancer analysis of TFAP4 aberrations and the potential clinical implications for cancer immunity. (PMID:33373169)
• Unexpected suppression of tumorigenesis by c-MYC via TFAP4-dependent restriction of stemness in B lymphocytes. (PMID:34283887)
• Upregulating microRNA-373-3p promotes apoptosis and inhibits metastasis of hepatocellular carcinoma cells. (PMID:34983307)
• Inhibitory effect of CC chemokine ligand 23 (CCL23)/ transcription factor activating enhancer binding protein 4 (TFAP4) on cell proliferation, invasion and angiogenesis in hepatocellular carcinoma. (PMID:35001801)
• Tribbles Pseudokinase 2 Promotes the Proliferation, Migration, and Invasion of Osteosarcoma through Modulating AP4/p21 Pathway. (PMID:35777810)
• TFAP4 Activates IGF2BP1 and Promotes Progression of Non-Small Cell Lung Cancer by Stabilizing TK1 Expression through m6A Modification. (PMID:36074102)
• Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis. (PMID:36894688)
• Downregulation of miR-144 blocked the proliferation and invasion of nerve cells in Hirschsprung disease by regulating Transcription Factor AP 4 (TFAP4). (PMID:37610449)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tfap4	ENSDARG00000103923
mus_musculus	Tfap4	ENSMUSG00000005718
rattus_norvegicus	Tfap4	ENSRNOG00000005227
drosophila_melanogaster	crp	FBGN0001994
caenorhabditis_elegans		WBGENE00001955

Paralogs (3): MLXIPL (ENSG00000009950), MLX (ENSG00000108788), MLXIP (ENSG00000175727)

Protein

Protein identifiers

Transcription factor AP-4 — Q01664 (reviewed: Q01664)

Alternative names: Activating enhancer-binding protein 4, Class C basic helix-loop-helix protein 41

All UniProt accessions (4): Q01664, I3L254, I3L301, I3L4L6

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that activates both viral and cellular genes by binding to the symmetrical DNA sequence 5’-CAGCTG-3'.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Homodimer.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_003214* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR052207	Max-like/E-box_TFs	Family

Pfam: PF00010

UniProt features (15 total): cross-link 4, region of interest 4, modified residue 3, chain 1, domain 1, sequence variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q01664-F1	73.88	0.33

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 (7): 147, 187, 189, 285, 123, 124, 139

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 360 (showing top): AHRARNT_01, E2F_Q4, FREAC2_01, PAX4_01, TGCGCANK_UNKNOWN, E2F4DP1_01, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GCANCTGNY_MYOD_Q6, GOBP_HOST_MEDIATED_ACTIVATION_OF_VIRAL_TRANSCRIPTION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (15): regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of cell population proliferation (GO:0008285), negative regulation of gene expression (GO:0010629), DNA damage response, signal transduction by p53 class mediator (GO:0030330), positive regulation of apoptotic process (GO:0043065), negative regulation of DNA binding (GO:0043392), host-mediated suppression of viral transcription (GO:0043922), host-mediated activation of viral transcription (GO:0043923), negative regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0045736), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), protein-containing complex assembly (GO:0065003), cellular response to dexamethasone stimulus (GO:0071549), regulation of mitotic cell cycle phase transition (GO:1901990), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (12): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), protein homodimerization activity (GO:0042803), histone deacetylase binding (GO:0042826), sequence-specific DNA binding (GO:0043565), E-box binding (GO:0070888), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), transcription repressor complex (GO:0017053)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
DNA binding	2
host-mediated perturbation of viral transcription	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
negative regulation of binding	1
regulation of DNA binding	1
host-mediated suppression of viral proces	1
host-mediated activation of viral process	1
regulation of cyclin-dependent protein serine/threonine kinase activity	1
cyclin-dependent protein serine/threonine kinase activity	1
negative regulation of cell cycle	1
negative regulation of protein serine/threonine kinase activity	1
negative regulation of cyclin-dependent protein kinase activity	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
cellular component assembly	1
protein-containing complex organization	1
cellular response to glucocorticoid stimulus	1
response to dexamethasone	1
cellular response to ketone	1
regulation of mitotic cell cycle	1
mitotic cell cycle phase transition	1
regulation of cell cycle phase transition	1
positive regulation of DNA-templated transcription	1

Protein interactions and networks

STRING

892 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TFAP4	HBS1L	Q9Y450	762
TFAP4	HBG1	P02096	749
TFAP4	DCLRE1A	Q6PJP8	718
TFAP4	PRM1	P04553	710
TFAP4	CCL23	P55773	665
TFAP4	A0A0J9YYA3	A0A0J9YYA3	639
TFAP4	MIPEP	Q99797	497
TFAP4	USF2	Q15853	494
TFAP4	MYC	P01106	440
TFAP4	GATA1	P15976	436
TFAP4	TAF6L	Q9Y6J9	435
TFAP4	GMNN	O75496	428
TFAP4	RPRD2	Q5VT52	425
TFAP4	PAX5	Q02548	424
TFAP4	L3MBTL2	Q969R5	422

IntAct

94 interactions, top by confidence:

A	B	Type	Score
GOLGA2	TFAP4	psi-mi:“MI:0915”(physical association)	0.720
TRAF1	TFAP4	psi-mi:“MI:0915”(physical association)	0.720
EXOSC8	TFAP4	psi-mi:“MI:0915”(physical association)	0.720
TFAP4	TRAF1	psi-mi:“MI:0915”(physical association)	0.720
TFAP4	EXOSC8	psi-mi:“MI:0915”(physical association)	0.720
TFAP4	GOLGA2	psi-mi:“MI:0915”(physical association)	0.720
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
TFAP4	FBXW11	psi-mi:“MI:0914”(association)	0.640
TFAP4		psi-mi:“MI:0915”(physical association)	0.580
TFAP4	NDUFB7	psi-mi:“MI:0915”(physical association)	0.560
NDUFB7	TFAP4	psi-mi:“MI:0915”(physical association)	0.560
TFAP4	VMAC	psi-mi:“MI:0915”(physical association)	0.560
TFAP4	SFMBT2	psi-mi:“MI:0915”(physical association)	0.560
TFAP4	AJUBA	psi-mi:“MI:0915”(physical association)	0.560
TFAP4	TEKT4	psi-mi:“MI:0915”(physical association)	0.560
TFAP4	TRAF4	psi-mi:“MI:0915”(physical association)	0.560
PTPN3	TFAP4	psi-mi:“MI:0915”(physical association)	0.560
TFAP4	INCA1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (231): TFAP4 (Affinity Capture-MS), TFAP4 (Two-hybrid), TRAF1 (Two-hybrid), EXOSC8 (Two-hybrid), TFAP4 (Affinity Capture-MS), TFAP4 (Affinity Capture-MS), TFAP4 (Affinity Capture-MS), TFAP4 (Affinity Capture-MS), SNRNP200 (Co-fractionation), TFAP4 (Co-fractionation), TFAP4 (Proximity Label-MS), TFAP4 (Two-hybrid), TFAP4 (Affinity Capture-MS), TFAP4 (Affinity Capture-MS), TFAP4 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GXY6, A0A8I3QA39, A0M8S4, A1YB07, A2A6T1, B6RSP1, B8A5S6, E1BEQ5, F1MRK3, G3V735, O75334, O75335, O94876, P39880, P53564, P53565, Q01664, Q07DV1, Q07DW4, Q07DX4, Q07DY4, Q07E41, Q09YG9, Q09YI1, Q09YJ3, Q09YK4, Q09YM8, Q108T9, Q13136, Q2IBF8, Q2QLF8, Q3UIL6, Q5RDH2, Q5U4W1, Q69ZZ6, Q6DIS8, Q6IQ23, Q6NZT2, Q6P402, Q8BHS8

Diamond homologs: A8E5T6, B6VQA1, D2CLZ9, O09029, O09105, O13125, O13126, O16867, O35437, O42202, O42606, O43680, O57598, O60682, O88940, O96642, P13903, P26687, P34555, P41894, P46581, P48985, P48986, P48987, P57102, P59101, P70447, P70595, P70660, P70661, P79765, P79766, P79782, P79920, P97831, Q01664, Q08DI0, Q0V9X5, Q10574, Q13516

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
TFAP4	“up-regulates activity”	NFIA	binding
TFAP4	“up-regulates activity”	HDAC1	binding
TFAP4	“up-regulates activity”	SP1	binding
TFAP4	“down-regulates quantity by repression”	MDM2	“transcriptional regulation”
TFAP4	“up-regulates quantity by expression”	SALL2	“transcriptional regulation”
TGFB1	“down-regulates quantity by repression”	TFAP4	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 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
Regulation of PLK1 Activity at G2/M Transition	5	13.8×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
chromatin organization	7	11.0×	4e-04
transcription by RNA polymerase II	8	8.9×	4e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — BL, NHL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1267 predictions. Top by Δscore:

Variant	Effect	Δscore
16:4258246:TTGC:T	acceptor_gain	1.0000
16:4258248:GCC:G	acceptor_loss	1.0000
16:4258250:CT:C	acceptor_loss	1.0000
16:4260085:GGTAC:G	donor_loss	1.0000
16:4260086:GTAC:G	donor_loss	1.0000
16:4260087:TA:T	donor_loss	1.0000
16:4260088:A:AG	donor_loss	1.0000
16:4260241:AGAAG:A	acceptor_gain	1.0000
16:4260242:GAAG:G	acceptor_gain	1.0000
16:4260244:AG:A	acceptor_gain	1.0000
16:4260245:GCT:G	acceptor_loss	1.0000
16:4260246:C:CC	acceptor_gain	1.0000
16:4260450:CTCA:C	donor_loss	1.0000
16:4260453:A:AC	donor_gain	1.0000
16:4260453:ACCTG:A	donor_loss	1.0000
16:4260454:C:CC	donor_gain	1.0000
16:4260454:C:T	donor_loss	1.0000
16:4260591:CGCAC:C	acceptor_gain	1.0000
16:4260592:GCAC:G	acceptor_gain	1.0000
16:4260593:CAC:C	acceptor_gain	1.0000
16:4260593:CACC:C	acceptor_gain	1.0000
16:4260594:AC:A	acceptor_gain	1.0000
16:4260595:CC:C	acceptor_gain	1.0000
16:4260596:C:CC	acceptor_gain	1.0000
16:4260597:T:A	acceptor_loss	1.0000
16:4261774:CTCA:C	donor_loss	1.0000
16:4261776:CAC:C	donor_loss	1.0000
16:4261778:CCTG:C	donor_gain	1.0000
16:4261947:CTC:C	acceptor_gain	1.0000
16:4261948:TCCTG:T	acceptor_loss	1.0000

AlphaMissense

2208 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:4258245:A:C	I276S	1.000
16:4258245:A:G	I276T	1.000
16:4258245:A:T	I276N	1.000
16:4258249:C:G	A275P	1.000
16:4260097:A:C	I272S	1.000
16:4260097:A:G	I272T	1.000
16:4260097:A:T	I272N	1.000
16:4260106:A:G	L269P	1.000
16:4260106:A:T	L269Q	1.000
16:4261789:A:G	L172P	1.000
16:4261798:C:G	R169P	1.000
16:4261807:C:G	R166P	1.000
16:4261811:C:T	E165K	1.000
16:4261819:A:G	L162P	1.000
16:4261828:C:G	R159P	1.000
16:4261831:A:G	L158P	1.000
16:4261894:A:T	I137K	1.000
16:4261898:C:G	G136R	1.000
16:4262340:A:G	L113P	1.000
16:4262352:T:G	Q109P	1.000
16:4262361:A:G	L106P	1.000
16:4262382:A:G	L99P	1.000
16:4262391:A:T	I96N	1.000
16:4262400:G:T	A93D	1.000
16:4262401:C:G	A93P	1.000
16:4262403:G:A	T92I	1.000
16:4262406:T:G	Q91P	1.000
16:4262409:T:G	Q90P	1.000
16:4262412:A:C	L89R	1.000
16:4262412:A:G	L89P	1.000

dbSNP variants (sampled 300 via entrez): RS1000191770 (16:4274039 G>C), RS1000363655 (16:4263705 G>C), RS1000416546 (16:4269310 A>G), RS1000696021 (16:4264804 C>G), RS1000893653 (16:4258949 G>A,C,T), RS1000978318 (16:4265078 T>A,C), RS1001080723 (16:4264972 A>G), RS1001238441 (16:4259594 C>G), RS1001702853 (16:4268572 T>G), RS1001705427 (16:4265492 T>G), RS1001800645 (16:4273679 A>G), RS1001846198 (16:4274383 GCTTA>G), RS1002313091 (16:4269819 AAAC>A), RS1002416648 (16:4259414 T>A), RS1002434791 (16:4269631 G>A)

Disease associations

OMIM: gene MIM:600743 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

50 associations (top):

Study	Trait	p-value
GCST004093_40	Prostate-specific antigen levels	1.000000e-09
GCST008481_8	Lung function (FEV1/FVC)	7.000000e-06
GCST010703_267	Brain morphology (MOSTest)	4.000000e-13
GCST010796_100	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_26	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_27	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-10
GCST010796_28	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_29	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_30	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-09
GCST010796_31	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-10
GCST010796_32	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_33	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010796_34	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_35	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-10
GCST010796_356	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_36	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-10
GCST010796_37	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_38	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_39	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_40	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_41	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_42	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-10
GCST010796_43	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-10
GCST010796_44	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-10
GCST010796_45	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_46	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-09
GCST010796_47	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_48	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_49	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_50	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0004346	neuroimaging measurement
EFO:0004327	electrocardiography
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004309	platelet count
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
bisphenol A	increases expression	2
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Estradiol	increases expression	2
Tretinoin	decreases expression	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
alpha phellandrene	decreases expression	1
trichostatin A	affects expression	1
afimoxifene	decreases reaction, increases expression	1
tanshinone	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	increases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Atrazine	increases expression	1
Caffeine	affects phosphorylation	1
Calcitriol	decreases expression, affects cotreatment	1
Cocaine	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Estrogens	decreases reaction, increases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7H3	SEES3-1V human TFAP4, clone1	Embryonic stem cell	Male
CVCL_A7H4	SEES3-1V human TFAP4, clone2	Embryonic stem cell	Male
CVCL_A7H5	SEES3-1V human TFAP4, clone3	Embryonic stem cell	Male
CVCL_B2ID	Abcam HeLa TFAP4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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