ID4 (inhibitor of DNA binding 4, dominant negative helix-loop-helix protein)

2008-04-01   Jean-Loup Huret  

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Identity

HGNC
ID4
LOCATION
6p22.3
LOCUSID
3400
ALIAS
IDB4,bHLHb27
FUSION GENES
Show Gene Fusions

DNA/RNA

Description

The gene spans 3,3 kb on plus strand.

Transcription

3 exons; mRNA 2,343 bp.

Proteins

Description

161 amino acids; 16.6 KDa; contains a poly-Ala (from amino acid 39 to 48), a helix-loop-helix motif (65 to 105), and a poly-Pro (118 to 124).

Expression

Expressed in various tissues.

Function

ID4 is one of the members of the ID gene family : "Inhibitors of DNA binding". They are transcription factors which act as transcription inhibitory proteins. They are basic helix-loop-helix (bHLH) proteins which contain the bHLH dimerization domain, but lack the DNA binding domain. They are able to form heterodimers with other bHLH proteins, but inhibit the DNA binding, inactivating the process. Since bHLH proteins act as transcription factors, ID genes are transcription repressors, modulating various functions.
ID proteins play critical roles in early embryonic processes, growth, differentiation, senescence and apoptosis; they are also involved in angiogenesis.
ID4 is expressed in the central nervous system. ID4 is required for G1-S transition and enhance proliferation in early cortical progenitors. On the other hand, ID4 enhances RB1 -mediated inhibition of proliferation of differenciating neurons, either by direct interaction or through interaction with other molecules of the cell cycle machinery. Other ID genes are not redondant with ID4 during telencephalic development, supporting the idea that ID4 function is unique in this context (Yun et al, 2004). In immature neurons with high expression of ID proteins, heterodimers of bHLH-ID prevent DNA binding and expression of differentiation associated genes.
ID4 may play an important suppressive role in tumor progression, and its silencing by hypermethylation favours tumorogenesis (see below).

Implicated in

Entity name
B-cell acute lymphoblastic leukaemia (B-ALL) with t(6;14)(p22;q32) --> ID4 - IGH
Note
ID4 was juxtaposed to the IGH enhancer, leading to ID4 overexpression. (Bellido et al 2003, Russell et al 2008).
Prognosis
Prognosis in this disease looks fair.
Entity name
Non Hodgkin lymphoma
Note
ID4 promoter was found hypermethylated in follicular lymphomas, diffuse large B-cell lymphomas, as well as lymphoid cell lines (Hagiwara K et al 2007).
Entity name
Brain tumours
Note
In oligodendroglial tumours and glioblastomas, ID4 is expressed in neoplastic astrocytes but not in neoplastic oligodendrocytes (Liang et al, 2005).
Entity name
Breast cancer
Note
Hypermethylation of ID4 promoter and ID4 mRNA suppression was found in breast cancer cell lines as well as in primary breast cancers. In one study, it was a significant risk factor for nodal metastasis (Umetani et al, 2006). In another study, BRCA1, ER (estrogen receptor), and ID4 were found expressed in breast cancer specimens from patients with invasive carcinomas. Most of the patients who expressed BRCA1 also expressed ER, but were negative for ID4, and vice versa. BRCA1-ER and ID4 are linked in a negative correlation (Roldan et al 2006). Id4 regulates BRCA1 expression and may be involved in hormone-dependent regulation of BRCA1 homeostasis (de Candia et al 2004). ID4 is constitutively expressed in the normal human mammary epithelium but is suppressed in ER-.
Positive breast carcinomas and preneoplastic lesions. ER-negative carcinomas are Id4 positive (de Candia et al 2006).
These results support a possible role of Id4 as a tumor suppressor factor in the human breast and suggest that the expression of Id4 in the mammary ductal epithelium may be regulated by estrogen (de Candia et al 2006).
Entity name
Bladder cancer
Note
ID4 is part of the 6p22.3 amplicon frequently observed in advanced stage bladder cancer. ID4, as well as E2F3 and DEK, was overexpressed in bladder cancer cell lines. This overexpression was correlated with the copy number. However, ID4 expression was equivalent in fresh cancer tissues and normal urothelium (Wu et al, 2005).
Entity name
Gastric cancer
Note
ID4 promoter is hypermethylated and showed a low level of expression in 30% of gastric adenocarcinomas and in most gastric cancer cell lines, while its expression was high in normal gastric mucosa. Furthermore, there was a significant association of ID4 promoter hypermethylation / ID4 down regulation and that of hMLH1 and microsatellite instability (Chan et al 2003).
Entity name
Colorectal cancer
Note
ID4 is silenced in colorectal cancer: Hypermethylation was found in half of the primary colorectal cancer specimens tested (and in cell lines as well), in 3/4 of liver metastases of colorectal cancer specimens tested, but not in normal epitheliums nor in adenomas. Moreover, the methylation status was correlated with the histopathological grade, and hypermethylation of ID4 was identified as a significant independant risk factor of poor prognosis (Umetani et al 2005).
Entity name
Rett syndrome
Note
A significantly increased protein expression of ID genes was found in human brain tissue of Rett syndrome patients, compared to controls (Peddada et al 2006). Rett syndrome is a X-linked neurodevelopmental disorder resembling autism, and due to MECP2 (Xq28 ) mutations in most cases, more rarely due to mutations of CDKL5 (Xp22) or, much less convaincingly, NTNG1 (1p13).

Article Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 3400
MIM: 600581
HGNC: 5363
Ensembl: ENSG00000172201

Variants:

dbSNP: 3400
ClinVar: 3400
TCGA: ENSG00000172201
COSMIC: ID4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000172201ENST00000378700P47928

Expression (GTEx)

0
50
100
150
200
250
300
350
400
450
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
TGF-beta signaling pathwayKEGGko04350
TGF-beta signaling pathwayKEGGhsa04350
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550

References

Pubmed IDYearTitleCitations
381886752023ELK3-ID4 axis governs the metastatic features of triple negative breast cancer.0
381886752023ELK3-ID4 axis governs the metastatic features of triple negative breast cancer.0
350942932022CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors.1
356560242022Upregulated circTMEM59 Inhibits Cell Growth and Metastasis by miR-668-3p/ID4 Axis in Colorectal Cancer.7
359083512022Osteoglycin (OGN) promotes tumorigenesis of pancreatic cancer cell via targeting ID4.0
350942932022CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors.1
356560242022Upregulated circTMEM59 Inhibits Cell Growth and Metastasis by miR-668-3p/ID4 Axis in Colorectal Cancer.7
359083512022Osteoglycin (OGN) promotes tumorigenesis of pancreatic cancer cell via targeting ID4.0
339932702021ID4 predicts poor prognosis and promotes BDNF-mediated oncogenesis of colorectal cancer.7
347237122021miR-9-5p Promotes Lung Adenocarcinoma Cell Proliferation, Migration and Invasion by Targeting ID4.6
339932702021ID4 predicts poor prognosis and promotes BDNF-mediated oncogenesis of colorectal cancer.7
347237122021miR-9-5p Promotes Lung Adenocarcinoma Cell Proliferation, Migration and Invasion by Targeting ID4.6
320541092020Paracrine Signaling from Breast Cancer Cells Causes Activation of ID4 Expression in Tumor-Associated Macrophages.7
325272872020Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer.6
325749632020UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes.17

Citation

Jean-Loup Huret

ID4 (inhibitor of DNA binding 4, dominant negative helix-loop-helix protein)

Atlas Genet Cytogenet Oncol Haematol. 2008-04-01

Online version: http://atlasgeneticsoncology.org/gene/40916/gene-explorer/favicon/css/template-nav.css