CDCA4

Summary

CDCA4 (cell division cycle associated 4, HGNC:14625) is a protein-coding gene on chromosome 14q32.33, encoding Cell division cycle-associated protein 4 (Q9BXL8). May participate in the regulation of cell proliferation through the E2F/RB pathway.

This gene encodes a protein that belongs to the E2F family of transcription factors. This protein regulates E2F-dependent transcriptional activation and cell proliferation, mainly through the E2F/retinoblastoma protein pathway. It also functions in the regulation of JUN oncogene expression. This protein shows distinctive nuclear-mitotic apparatus distribution, it is involved in spindle organization from prometaphase, and may also play a role as a midzone factor involved in chromosome segregation or cytokinesis. Two alternatively spliced transcript variants encoding the same protein have been noted for this gene. Two pseudogenes have also been identified on chromosome 1.

Source: NCBI Gene 55038 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_017955

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14625
Approved symbol	CDCA4
Name	cell division cycle associated 4
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Aliases	SEI-3, TRIP-Br3, FLJ20764, Hepp
Ensembl gene	ENSG00000170779
Ensembl biotype	protein_coding
OMIM	612270
Entrez	55038

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000336219, ENST00000392590, ENST00000896959, ENST00000896960, ENST00000896961, ENST00000912742, ENST00000912743, ENST00000912744, ENST00000912745, ENST00000953396

RefSeq mRNA: 2 — MANE Select: NM_017955 NM_017955, NM_145701

CCDS: CCDS9996

Canonical transcript exons

ENST00000336219 — 2 exons

Exon	Start	End
ENSE00001387259	105009573	105011935
ENSE00002515469	105020999	105021083

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 91.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.6437 / max 129.2983, expressed in 1752 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145161	20.6437	1752

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	91.16	gold quality
oocyte	CL:0000023	90.36	gold quality
gingival epithelium	UBERON:0001949	90.23	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.77	gold quality
buccal mucosa cell	CL:0002336	89.08	gold quality
tongue squamous epithelium	UBERON:0006919	89.01	gold quality
gingiva	UBERON:0001828	88.82	gold quality
ventricular zone	UBERON:0003053	88.14	gold quality
embryo	UBERON:0000922	87.85	gold quality
trabecular bone tissue	UBERON:0002483	87.40	gold quality
oviduct epithelium	UBERON:0004804	87.27	gold quality
bone marrow	UBERON:0002371	87.09	gold quality
skin of leg	UBERON:0001511	86.74	gold quality
upper leg skin	UBERON:0004262	86.69	gold quality
cervix epithelium	UBERON:0004801	86.55	gold quality
hair follicle	UBERON:0002073	86.42	silver quality
squamous epithelium	UBERON:0006914	85.91	gold quality
type B pancreatic cell	CL:0000169	85.85	gold quality
zone of skin	UBERON:0000014	85.75	gold quality
cervix squamous epithelium	UBERON:0006922	85.68	gold quality
upper arm skin	UBERON:0004263	85.66	gold quality
skin of abdomen	UBERON:0001416	85.51	gold quality
ganglionic eminence	UBERON:0004023	85.08	gold quality
esophagus mucosa	UBERON:0002469	84.73	gold quality
lower esophagus mucosa	UBERON:0035834	84.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.61	gold quality
amniotic fluid	UBERON:0000173	84.35	gold quality
epithelium of esophagus	UBERON:0001976	84.23	gold quality
olfactory bulb	UBERON:0002264	84.11	gold quality
placenta	UBERON:0001987	83.92	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	37.29
E-ANND-3	yes	4.94
E-MTAB-7381	no	355.09
E-CURD-11	no	201.10

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, E2F4

miRNA regulators (miRDB)

69 targeting CDCA4, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 16)

• Isolation of the mouse ortholog and comparison to the human protein. (PMID:11482882)
• CDCA4 participates in the regulation of cell proliferation, mainly through the E2F/retinoblastoma protein pathway (PMID:16984923)
• Data suggest that CDCA4 is involved in spindle organization from prometaphase, and when anaphase begins, it may play a different role as a midzone factor involved in chromosome segregation or cytokinesis. (PMID:18498124)
• an important role of CDCA4 in the context of transcriptional regulation and cell fate determination through the JUN oncogene (PMID:18572021)
• High CDCA4 expression is associated with malignant melanoma. (PMID:27492455)
• The results confirmed that CDCA4 RNA interference reduced the percentage of human breast cancer cells to <50%. In addition, RNA interference of CDCA4 resulted in a significant increase in the apoptotic rate of cells. (PMID:29257222)
• Apelin enhances biological functions in lung cancer A549 cells by downregulating exosomal miR-15a-5p. (PMID:32808032)
• Circ_0010220-mediated miR-503-5p/CDCA4 axis contributes to osteosarcoma progression tumorigenesis. (PMID:32827680)
• ELK1-induced upregulation lncRNA LINC02381 accelerates the osteosarcoma tumorigenesis through targeting CDCA4 via sponging miR-503-5p. (PMID:33640603)
• PCOS follicular fluid derived exosomal miR-424-5p induces granulosa cells senescence by targeting CDCA4 expression. (PMID:33930499)
• Implications of cell division cycle associated 4 on the Wilm’s tumor cells viability via AKT/mTOR signaling pathway. (PMID:34723730)
• MiR-497-5p down-regulates CDCA4 to restrains lung squamous cell carcinoma progression. (PMID:34772428)
• A Pan-Cancer Analysis of the Oncogenic Role of Cell Division Cycle-Associated Protein 4 (CDCA4) in Human Tumors. (PMID:35251007)
• STAT1 Mediates the Transcription of CircIFI30 and Promotes the Progression of Triple-Negative Breast Cancer by Up-Regulating CDCA4. (PMID:35378000)
• CDCA4 interacts with IGF2BP1 to regulate lung adenocarcinoma proliferation via the PI3K/AKT pathway. (PMID:36737405)
• ALKBH5 promotes the development of lung adenocarcinoma by regulating the polarization of M2 macrophages through CDCA4. (PMID:37949419)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdca4	ENSDARG00000042319
mus_musculus	Cdca4	ENSMUSG00000047832
rattus_norvegicus	Cdca4	ENSRNOG00000013898
drosophila_melanogaster	tara	FBGN0040071

Paralogs (1): SERTAD2 (ENSG00000179833)

Protein

Protein identifiers

Cell division cycle-associated protein 4 — Q9BXL8 (reviewed: Q9BXL8)

Alternative names: Hematopoietic progenitor protein

All UniProt accessions (1): Q9BXL8

UniProt curated annotations — full annotation on UniProt →

Function. May participate in the regulation of cell proliferation through the E2F/RB pathway. May be involved in molecular regulation of hematopoietic stem cells and progenitor cell lineage commitment and differentiation.

Subcellular location. Nucleus.

Tissue specificity. Highest levels of expression in the pancreas, thymus, testis, spleen, liver, placenta and leukocytes. Relatively low levels in the lung, kidney, prostate, ovary, small intestine and colon. Hardly detectable, if at all, in the brain, skeletal muscle and heart.

Induction. By E2F1.

RefSeq proteins (2): NP_060425, NP_663747 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009263	SERTA_dom	Domain
IPR052262	E2F-SERTA_domain_protein	Family

Pfam: PF06031

UniProt features (3 total): chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXL8-F1	64.15	0.18

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 168 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, MORI_SMALL_PRE_BII_LYMPHOCYTE_DN, FISCHER_DREAM_TARGETS, VERNELL_RETINOBLASTOMA_PATHWAY_UP, KOBAYASHI_EGFR_SIGNALING_24HR_DN, chr14q32, BERENJENO_TRANSFORMED_BY_RHOA_UP, LINDGREN_BLADDER_CANCER_CLUSTER_1_DN, GEORGES_TARGETS_OF_MIR192_AND_MIR215, GOMF_TRANSCRIPTION_COACTIVATOR_ACTIVITY, WANG_RESPONSE_TO_GSK3_INHIBITOR_SB216763_DN, DUTERTRE_ESTRADIOL_RESPONSE_24HR_UP, LINSLEY_MIR16_TARGETS

GO Biological Process (1): positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (2): transcription coactivator activity (GO:0003713), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA-templated transcription	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
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

836 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDCA4	SERTAD1	Q9UHV2	890
CDCA4	CDCA5	Q96FF9	639
CDCA4	CDCA8	Q53HL2	634
CDCA4	E2F2	Q14209	624
CDCA4	SERTAD4	Q9NUC0	595
CDCA4	CDCA2	Q69YH5	571
CDCA4	E2F3	O00716	555
CDCA4	CDCA7	Q9BWT1	545
CDCA4	CCNA1	P78396	532
CDCA4	CCNA2	P20248	529
CDCA4	E2F4	Q16254	525
CDCA4	E2F1	Q01094	521
CDCA4	CDCA3	Q99618	513
CDCA4	SERTAD3	Q9UJW9	484
CDCA4	TP53	P04637	481

IntAct

111 interactions, top by confidence:

A	B	Type	Score
PPP2R2A	PPP2R1A	psi-mi:“MI:2364”(proximity)	0.970
CDCA4	PPP2R1A	psi-mi:“MI:0914”(association)	0.790
PPP2R2C	PPP2R1A	psi-mi:“MI:0914”(association)	0.730
PPP2R2D	YEATS4	psi-mi:“MI:0914”(association)	0.730
PPP2R2B	MYO9A	psi-mi:“MI:0914”(association)	0.640
PPP2R2C	TCP1	psi-mi:“MI:0914”(association)	0.640
PPP2R2D	ENSA	psi-mi:“MI:0914”(association)	0.570
PPP2R2D	ENSA	psi-mi:“MI:2364”(proximity)	0.570
CDCA4	BRL1	psi-mi:“MI:0915”(physical association)	0.560
BRL1	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
MKRN3	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
CDCA4	ENKD1	psi-mi:“MI:0915”(physical association)	0.560
SHC3	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
TXN2	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
FNDC11	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
FARS2	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
BFSP2	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
CDCA4	AIRIM	psi-mi:“MI:0915”(physical association)	0.560
SUOX	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
TCAP	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
FAM222B	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
CDCA4	KLHL42	psi-mi:“MI:0915”(physical association)	0.560
	CDCA4	psi-mi:“MI:0915”(physical association)	0.560
CDCA4	PARD6B	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (79): CDCA4 (Affinity Capture-MS), CDCA4 (Two-hybrid), CDCA4 (Two-hybrid), CDCA4 (Two-hybrid), CDCA4 (Affinity Capture-MS), CDCA4 (Affinity Capture-MS), CDCA4 (Affinity Capture-MS), XIAP (Affinity Capture-Western), CDCA4 (Affinity Capture-Western), PPP2R2D (Affinity Capture-MS), CDCA4 (Affinity Capture-MS), PPP2CA (Affinity Capture-MS), PPP2R1B (Affinity Capture-MS), BDH2 (Affinity Capture-MS), NMNAT1 (Affinity Capture-MS)

ESM2 similar proteins: A0P8Z5, A6NCL1, A8E4V2, B5DF41, D3YN49, D3ZDX9, D6RGH6, F1QN48, F1SLM8, F7BHS0, G3N1S4, O15079, P12841, P20389, P24793, P97432, Q08B36, Q14140, Q14596, Q14DQ1, Q1LWL8, Q3SYW5, Q3U827, Q3UKU1, Q3URY2, Q3UZ45, Q4KMA0, Q4R3X1, Q501R9, Q5R8C5, Q5RC94, Q5RD40, Q64210, Q6P2K3, Q6ZNC4, Q80U23, Q80YE2, Q8NFW9, Q8R0W1, Q96A56

Diamond homologs: Q14140, Q9BXL8, Q9JJG5, Q9JL10, Q9UHV2, Q9CWM2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

327 predictions. Top by Δscore:

Variant	Effect	Δscore
14:105011931:GTGTC:G	acceptor_gain	1.0000
14:105011932:TGTC:T	acceptor_gain	1.0000
14:105011933:GTCC:G	acceptor_loss	1.0000
14:105011936:C:CC	acceptor_gain	1.0000
14:105011936:CT:C	acceptor_loss	1.0000
14:105011939:C:CT	acceptor_gain	1.0000
14:105020994:CTCA:C	donor_loss	1.0000
14:105020995:TCA:T	donor_loss	1.0000
14:105020998:C:CG	donor_loss	1.0000
14:105011933:GTC:G	acceptor_gain	0.9900
14:105011934:TC:T	acceptor_gain	0.9900
14:105011935:CC:C	acceptor_gain	0.9900
14:105011940:A:T	acceptor_gain	0.9900
14:105011946:C:CT	acceptor_gain	0.9900
14:105011946:C:T	acceptor_gain	0.9900
14:105011947:A:T	acceptor_gain	0.9800
14:105020998:CCTGA:C	donor_gain	0.9700
14:105020997:A:AC	donor_gain	0.9600
14:105020998:C:CC	donor_gain	0.9600
14:105020242:A:C	donor_gain	0.9400
14:105021000:TG:T	donor_gain	0.9300
14:105020294:T:C	donor_gain	0.9200
14:105020997:AC:A	donor_gain	0.9200
14:105020998:CC:C	donor_gain	0.9200
14:105021001:G:T	donor_gain	0.9200
14:105013927:T:C	donor_gain	0.9100
14:105013931:CCCT:C	donor_gain	0.9100
14:105020241:A:AC	donor_gain	0.9100
14:105011945:C:CT	acceptor_gain	0.9000
14:105013932:CCTT:C	donor_gain	0.9000

AlphaMissense

1557 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:105011745:A:T	I62N	0.999
14:105011798:C:A	K44N	0.998
14:105011798:C:G	K44N	0.998
14:105011738:G:C	N64K	0.997
14:105011738:G:T	N64K	0.997
14:105011739:T:A	N64I	0.997
14:105011745:A:C	I62S	0.997
14:105011748:A:G	L61P	0.997
14:105011748:A:T	L61H	0.997
14:105011724:A:G	I69T	0.996
14:105011730:C:G	R67P	0.996
14:105011743:C:G	A63P	0.996
14:105011751:A:T	V60D	0.996
14:105011796:A:G	L45S	0.996
14:105011800:T:C	K44E	0.996
14:105011733:A:T	V66D	0.995
14:105011805:A:G	L42P	0.995
14:105011817:A:G	L38P	0.995
14:105011724:A:C	I69S	0.994
14:105011809:A:G	S41P	0.994
14:105011909:C:A	K7N	0.993
14:105011909:C:G	K7N	0.993
14:105011820:A:G	L37P	0.992
14:105011712:A:G	M73T	0.991
14:105011755:A:G	S59P	0.991
14:105011769:G:T	P54H	0.991
14:105011770:G:A	P54S	0.991
14:105011820:A:T	L37H	0.991
14:105011745:A:G	I62T	0.990
14:105011758:G:T	R58S	0.990

dbSNP variants (sampled 300 via entrez): RS1000266643 (14:105015273 G>C), RS1000340928 (14:105015686 T>C), RS1000441134 (14:105020943 C>A,T), RS1000500123 (14:105020393 A>C,G), RS1000572531 (14:105021197 G>A), RS1000848704 (14:105020018 G>A,C), RS1001179624 (14:105020216 T>C,G), RS1001454570 (14:105014847 T>C), RS1001612915 (14:105020767 C>A,T), RS1002512581 (14:105017641 C>A,T), RS1003145456 (14:105013639 C>T), RS1003645072 (14:105018446 G>A), RS1003674790 (14:105018137 A>G), RS1003747888 (14:105021455 G>A), RS1003872002 (14:105012441 C>T)

Disease associations

OMIM: gene MIM:612270 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST007002_7	Cerebrospinal fluid t-tau levels in normal cognition	7.000000e-09
GCST007007_3	Cerebrospinal fluid t-tau levels	7.000000e-06
GCST009856_35	Leukocyte telomere length	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004760	t-tau measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	4
bisphenol A	decreases expression, affects expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	affects expression, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cupric chloride	increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Calcitriol	decreases expression, affects cotreatment	1
Cisplatin	increases expression	1
Coumestrol	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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