LDOC1

Summary

LDOC1 (LDOC1 regulator of NFKB signaling, HGNC:6548) is a protein-coding gene on chromosome Xq27.1, encoding Protein LDOC1 (O95751). May have an important role in the development and/or progression of some cancers.

The protein encoded by this gene contains a leucine zipper-like motif and a proline-rich region that shares marked similarity with an SH3-binding domain. The protein localizes to the nucleus and is down-regulated in some cancer cell lines. It is thought to regulate the transcriptional response mediated by the nuclear factor kappa B (NF-kappaB). The gene has been proposed as a tumor suppressor gene whose protein product may have an important role in the development and/or progression of some cancers.

Source: NCBI Gene 23641 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 21 total
• MANE Select transcript: NM_012317

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6548
Approved symbol	LDOC1
Name	LDOC1 regulator of NFKB signaling
Location	Xq27.1
Locus type	gene with protein product
Status	Approved
Aliases	Mar7, Mart7, SIRH7, RTL7
Ensembl gene	ENSG00000182195
Ensembl biotype	protein_coding
OMIM	300402
Entrez	23641

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000370526, ENST00000460721, ENST00000670989

RefSeq mRNA: 1 — MANE Select: NM_012317 NM_012317

CCDS: CCDS14672

Canonical transcript exons

ENST00000370526 — 1 exons

Exon	Start	End
ENSE00001452951	141173235	141177129

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 98.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 69.7934 / max 793.7565, expressed in 1443 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200744	51.1540	1424
200745	5.9669	1247
200737	3.5767	1093
200742	3.0501	933
200736	2.9764	1012
200735	0.6828	365
200734	0.5015	293
200740	0.3976	208
200739	0.3758	192
209845	0.2581	142

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
descending thoracic aorta	UBERON:0002345	98.99	gold quality
blood vessel layer	UBERON:0004797	98.96	gold quality
thoracic aorta	UBERON:0001515	98.73	gold quality
ascending aorta	UBERON:0001496	98.69	gold quality
right coronary artery	UBERON:0001625	98.57	gold quality
aorta	UBERON:0000947	98.33	gold quality
popliteal artery	UBERON:0002250	98.10	gold quality
tibial artery	UBERON:0007610	98.09	gold quality
adenohypophysis	UBERON:0002196	97.96	gold quality
prefrontal cortex	UBERON:0000451	97.40	gold quality
left coronary artery	UBERON:0001626	97.25	gold quality
pituitary gland	UBERON:0000007	97.19	gold quality
coronary artery	UBERON:0001621	97.19	gold quality
right frontal lobe	UBERON:0002810	97.14	gold quality
frontal cortex	UBERON:0001870	96.54	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.54	gold quality
cortical plate	UBERON:0005343	96.47	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.47	gold quality
nucleus accumbens	UBERON:0001882	96.40	gold quality
hypothalamus	UBERON:0001898	96.36	gold quality
endometrium epithelium	UBERON:0004811	96.29	gold quality
neocortex	UBERON:0001950	96.27	gold quality
cingulate cortex	UBERON:0003027	96.21	gold quality
amygdala	UBERON:0001876	96.19	gold quality
anterior cingulate cortex	UBERON:0009835	96.15	gold quality
ganglionic eminence	UBERON:0004023	96.08	gold quality
cerebral cortex	UBERON:0000956	96.00	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.97	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.86	gold quality
forebrain	UBERON:0001890	95.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.70

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1

miRNA regulators (miRDB)

39 targeting LDOC1, 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-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-4473	98.89	69.10	652
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051

Literature-anchored findings (GeneRIF, showing 19)

• These observations suggest that LDOC1 is a novel regulator of NF-kappaB that can affect the PMA or TNF-alpha-mediated pathway to apoptosis through inhibition of NF-kappaB activation in BxPC3 pancreatic cancer cells. (PMID:12712434)
• MZF-1 was revealed to interact with LDOC1 and enhance the activity of LDOC1 for inducing apoptosis (PMID:15670815)
• LDOC1 is dramatically down-regulated in mutated chronic lymphocytic leukemia cases compared with unmutated cases, and have identified a new splice variant, LDOC1S (PMID:21310924)
• Over expression of LDOC1 may explain the clinical manifestation found in patients with cryptochidism and Digeorge anomaly. (PMID:21547351)
• Letter/Case Report: LDOC1/PARP1 are down-regulated in melanoma with repeated in-transit metastases. (PMID:21986234)
• The aim of this study was to evaluate the possible differential expression of LDOC1 mRNA in leucocytes of peripheral blood of Down’s syndrome subjects. compared with the normal population. (PMID:22546831)
• Silencing of BEX1 and LDOC1 by promoter hypermethylation might represent a critical event in the molecular pathogenesis of oral squamous cell carcinoma (OSCC) and the male predominance of OSCC occurrence. (PMID:23362108)
• It has potential roles in apoptosis of well differentiated carcinoma without metastases and in neurodegeneration of Alzheimer’s disease. (PMID:23775301)
• Silencing of LDOC1 is a frequent event in cervical cancer and may be of interest as a molecular marker in cervical cancer. (PMID:24125169)
• Cigarette smoke-induced promoter methylation may contribute to LDOC1 downregulation, thereby conferring oncogenic features to oral cells. (PMID:26317789)
• LDOC1 inhibits proliferation and promotes apoptosis by repressing NF-kappaB activation in papillary thyroid carcinoma (PMID:26637328)
• These finding of this study suggested that the hypothesize that LDOC1 gene upregulation may play a role in the spermatogenesis derangement observed in patients with Klinefelter Syndrome. (PMID:27076087)
• GNL3L-LDOC1 interplay regulates cell proliferation through the modulation of NF-kappaB pathway during tumorigenesis. (PMID:27764577)
• data show that LDOC1 is a tumor suppressor in osteosarcoma, and that it regulates metastasis of osteosarcoma cells. Furthermore, LDOC1 might be a valuable prognostic marker in osteosarcomas. (PMID:28240050)
• that epigenetic silencing of LDOC1 in high-risk Group A ependymoma regulates tumor biology and drives inflammatory immune phenotype (PMID:28510691)
• LDOC1 is a tumor suppressor in Colorectal cancer (CRC) and it inhibits cell proliferation and promotes cell apoptosis. Additionally, it inhibits CRC cell metastasis by downregulating the Wnt/betacatenin signaling pathway. (PMID:31002361)
• Acute myeloid leukemia cells secrete microRNA-4532-containing exosomes to mediate normal hematopoiesis in hematopoietic stem cells by activating the LDOC1-dependent STAT3 signaling pathway. (PMID:31842997)
• LDOC1 is differentially expressed in thyroid cancer and display tumor-suppressive function in papillary thyroid carcinoma. (PMID:31889386)
• LDOC1 as Negative Prognostic Marker for Vulvar Cancer Patients. (PMID:33291445)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ldoc1	ENSMUSG00000057615
rattus_norvegicus	Ldoc1	ENSRNOG00000003409

Paralogs (10): RTL8C (ENSG00000134590), RTL3 (ENSG00000179300), RTL4 (ENSG00000187823), RTL6 (ENSG00000188636), RTL8A (ENSG00000203950), RTL8B (ENSG00000212747), RTL10 (ENSG00000215012), PEG10 (ENSG00000242265), RTL5 (ENSG00000242732), RTL1 (ENSG00000254656)

Protein

Protein identifiers

Protein LDOC1 — O95751 (reviewed: O95751)

Alternative names: Leucine zipper protein down-regulated in cancer cells

All UniProt accessions (1): O95751

UniProt curated annotations — full annotation on UniProt →

Function. May have an important role in the development and/or progression of some cancers.

Subunit / interactions. Interacts with NOD2.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed with high levels in brain ant thyroid and low expression in placenta, liver and leukocytes. Expressed as well in six of the seven human breast cancer cell lines examined.

Induction. Down-regulated by muramyl-dipeptide and lipopolysaccharide.

Similarity. Belongs to the LDOC1 family.

RefSeq proteins (1): NP_036449* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR032549	RTL1/1-8/LDOC_capsid-like	Domain

Pfam: PF16297

UniProt features (1 total): chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95751-F1	90.65	0.78

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 124 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, FAELT_B_CLL_WITH_VH_REARRANGEMENTS_DN, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOZGIT_ESR1_TARGETS_DN, HASLINGER_B_CLL_WITH_MUTATED_VH_GENES, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, CTATGCA_MIR153, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_MURAMYL_DIPEPTIDE, MODULE_66, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (5): maternal placenta development (GO:0001893), negative regulation of cell population proliferation (GO:0008285), maternal process involved in parturition (GO:0060137), cellular response to lipopolysaccharide (GO:0071222), cellular response to muramyl dipeptide (GO:0071225)

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

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to oxygen-containing compound	2
nuclear lumen	2
placenta development	1
developmental process involved in reproduction	1
anatomical structure development	1
maternal process involved in female pregnancy	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
parturition	1
multicellular organismal reproductive process	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
response to muramyl dipeptide	1
cellular response to nitrogen compound	1
binding	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

822 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LDOC1	RTL4	Q6ZR62	653
LDOC1	RTL9	Q8NET4	599
LDOC1	CREB3	O43889	515
LDOC1	SPANXD	Q9BXN6	400
LDOC1	GNL3L	Q9NVN8	395
LDOC1	PNMA5	Q96PV4	391
LDOC1	PWWP4	A0A494C071	367
LDOC1	PTCD1	O75127	351
LDOC1	SEPTIN10	Q9P0V9	349
LDOC1	PNMA6A	P0CW24	348
LDOC1	RAB40C	Q96S21	346
LDOC1	VGLL3	A8MV65	334
LDOC1	RAB40B	Q12829	333
LDOC1	SPANXA1	Q9NS26	322
LDOC1	SPANXC	Q9NY87	310

IntAct

467 interactions, top by confidence:

A	B	Type	Score
LDOC1	PRPF31	psi-mi:“MI:0915”(physical association)	0.850
LDOC1	HGS	psi-mi:“MI:0915”(physical association)	0.850
PRPF31	LDOC1	psi-mi:“MI:0915”(physical association)	0.850
HGS	LDOC1	psi-mi:“MI:0915”(physical association)	0.850
ATF4	LDOC1	psi-mi:“MI:0915”(physical association)	0.800
LDOC1	ATF4	psi-mi:“MI:0915”(physical association)	0.800
LDOC1	PSMA1	psi-mi:“MI:0915”(physical association)	0.790
ZBTB24	LDOC1	psi-mi:“MI:0915”(physical association)	0.780
DPPA4	LDOC1	psi-mi:“MI:0915”(physical association)	0.780
LENG1	LDOC1	psi-mi:“MI:0915”(physical association)	0.780
LDOC1	BARD1	psi-mi:“MI:0915”(physical association)	0.780
SH2D4A	LDOC1	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (176): LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid), LDOC1 (Two-hybrid)

ESM2 similar proteins: A6QLK5, A6ZKI3, D2HBJ8, O15519, O94955, O95751, P0CW24, P10272, Q0V9G5, Q17QF6, Q17RB0, Q1JQ94, Q2TBA3, Q5RD56, Q5RER6, Q5XGZ2, Q63053, Q6NTR6, Q6P5G6, Q6SEH4, Q6SEH5, Q70Z35, Q7JV70, Q7K1U0, Q7LC44, Q7TPY9, Q86TG7, Q8AWC3, Q8C1C8, Q8CA95, Q8N165, Q8N635, Q8ND90, Q8QZR7, Q8TCU6, Q8VHZ4, Q8WNV3, Q96PV4, Q9BWD3, Q9BYG7

Diamond homologs: A6NKG5, A6ZKI3, O95751, Q17QF6, Q17RB0, Q1JQ94, Q52QI2, Q5DTZ0, Q5HYW3, Q6SEH4, Q6SEH5, Q7M732, Q7TPY9, Q9BWD3, Q505G4, Q6ICC9, Q7TN75, Q86TG7, Q8N8U3, Q32KG4, Q5DTT4, Q5R6M8, Q7L3V2, Q6P1Y1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

129 predictions. Top by Δscore:

Variant	Effect	Δscore
X:141176591:T:TA	donor_gain	0.9900
X:141176594:T:TA	donor_gain	0.9900
X:141176590:AT:A	donor_gain	0.9800
X:141176590:ATCCT:A	donor_gain	0.9800
X:141176600:T:TA	donor_gain	0.8900
X:141176755:C:CT	donor_gain	0.7800
X:141176587:ATCAT:A	donor_gain	0.7700
X:141176754:C:CT	donor_gain	0.7700
X:141176591:T:C	donor_gain	0.7100
X:141176595:C:CA	donor_gain	0.6500
X:141176888:CGTA:C	donor_loss	0.6300
X:141176889:GTAC:G	donor_loss	0.6300
X:141176890:TACCT:T	donor_loss	0.6300
X:141176892:C:A	donor_loss	0.6300
X:141176887:ACGT:A	donor_loss	0.6200
X:141176450:G:GT	acceptor_gain	0.5700
X:141176829:G:GT	acceptor_gain	0.5400
X:141176886:GACGT:G	donor_loss	0.5400
X:141176405:ATTC:A	acceptor_loss	0.5300
X:141176409:C:CG	acceptor_loss	0.5300
X:141176410:T:G	acceptor_loss	0.5300
X:141176583:A:AC	donor_gain	0.5200
X:141176597:T:TA	donor_gain	0.5200
X:141176411:G:C	acceptor_loss	0.5100
X:141176416:A:T	acceptor_loss	0.5100
X:141176555:C:A	donor_gain	0.5000
X:141176709:C:CT	donor_gain	0.4900
X:141176727:C:A	donor_gain	0.4900
X:141176823:ACTCG:A	acceptor_gain	0.4900
X:141176404:TATTC:T	acceptor_gain	0.4800

AlphaMissense

977 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:141176776:G:C	F82L	1.000
X:141176776:G:T	F82L	1.000
X:141176778:A:G	F82L	1.000
X:141176659:G:C	F121L	0.999
X:141176659:G:T	F121L	0.999
X:141176660:A:G	F121S	0.999
X:141176661:A:G	F121L	0.999
X:141176713:C:A	W103C	0.999
X:141176713:C:G	W103C	0.999
X:141176715:A:G	W103R	0.999
X:141176715:A:T	W103R	0.999
X:141176749:G:C	F91L	0.999
X:141176749:G:T	F91L	0.999
X:141176750:A:G	F91S	0.999
X:141176751:A:G	F91L	0.999
X:141176777:A:G	F82S	0.999
X:141176821:A:C	F67L	0.999
X:141176821:A:T	F67L	0.999
X:141176822:A:G	F67S	0.999
X:141176823:A:G	F67L	0.999
X:141176846:C:A	G59V	0.999
X:141176851:A:C	F57L	0.999
X:141176851:A:T	F57L	0.999
X:141176853:A:G	F57L	0.999
X:141176862:G:A	P54S	0.999
X:141176635:A:C	F129L	0.998
X:141176635:A:T	F129L	0.998
X:141176637:A:G	F129L	0.998
X:141176735:A:G	L96P	0.998
X:141176738:A:G	L95P	0.998

dbSNP variants (sampled 300 via entrez): RS1000799503 (X:141174805 G>A), RS1002496237 (X:141173357 T>A,C), RS1002790442 (X:141173883 T>G), RS1005843391 (X:141177447 G>A), RS1006133654 (X:141178046 A>G), RS1006678838 (X:141176845 G>T), RS1008233792 (X:141175356 G>A), RS1009798863 (X:141174364 C>T), RS1012903003 (X:141178117 T>C), RS1013481315 (X:141176446 G>A,C), RS1013620856 (X:141178472 C>G), RS1013643443 (X:141176042 C>G), RS1017150639 (X:141178058 C>A), RS1017343314 (X:141177458 G>A), RS1018466920 (X:141176496 G>A)

Disease associations

OMIM: gene MIM:300402 | 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
Estradiol	decreases expression, affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
manganese chloride	increases abundance, decreases expression	1
potassium chromate(VI)	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
Resveratrol	decreases expression, affects cotreatment	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Manganese	decreases expression, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	1
Dronabinol	increases expression	1
Valproic Acid	increases expression	1
Vanadates	increases expression	1
Mifepristone	decreases expression	1
Cyclosporine	decreases expression	1
Sodium Selenite	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Lactic Acid	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

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