ID4 (inhibitor of DNA binding 4, dominant negative helix-loop-helix protein)
2008-04-01 Jean-Loup Huret AffiliationGenetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
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).
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
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).
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 ID | Last Year | Title | Authors |
|---|---|---|---|
| 10066362 | 1999 | Id4 expression induces apoptosis in astrocytic cultures and is down-regulated by activation of the cAMP-dependent signal transduction pathway. | Andres-Barquin PJ et al |
| 15882580 | 2005 | Id4 is required for the correct timing of neural differentiation. | Bedford L et al |
| 11136250 | 2001 | Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach. | Beger C et al |
| 12969807 | 2003 | Id4 is deregulated by a t(6;14)(p22;q32) chromosomal translocation in a B-cell lineage acute lymphoblastic leukemia. | Bellido M et al |
| 14534543 | 2003 | Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma. | Chan AS et al |
| 11316735 | 2001 | Hormonal regulation and differential actions of the helix-loop-helix transcriptional inhibitors of differentiation (Id1, Id2, Id3, and Id4) in Sertoli cells. | Chaudhary J et al |
| 17510533 | 2007 | Frequent DNA methylation but not mutation of the ID4 gene in malignant lymphoma. | Hagiwara K et al |
| 16018821 | 2005 | Id4 and FABP7 are preferentially expressed in cells with astrocytic features in oligodendrogliomas and oligoastrocytomas. | Liang Y et al |
| 10611221 | 2000 | Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. | Massari ME et al |
| 16682435 | 2006 | Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome. | Peddada S et al |
| 11840323 | 2001 | The regulation and function of the Id proteins in lymphocyte development. | Rivera R et al |
| 16582598 | 2006 | Tumoral expression of BRCA1, estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer. | Roldán G et al |
| 17940204 | 2008 | t(6;14)(p22;q32): a new recurrent IGH@ translocation involving ID4 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). | Russell LJ et al |
| 14633621 | 2003 | Id4 regulates mammary epithelial cell growth and differentiation and is overexpressed in rat mammary gland carcinomas. | Shan L et al |
| 15897910 | 2005 | Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer. | Umetani N et al |
| 15569977 | 2004 | Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis. | Umetani N et al |
| 15876350 | 2005 | Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer. | Wu Q et al |
| 15723065 | 2005 | Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. | Yu L et al |
| 15469968 | 2004 | Id4 regulates neural progenitor proliferation and differentiation in vivo. | Yun K et al |
| 16867866 | 2006 | Id4 messenger RNA and estrogen receptor expression: inverse correlation in human normal breast epithelium and carcinoma. | de Candia P et al |
Other Information
Locus ID:
NCBI: 3400
MIM: 600581
HGNC: 5363
Ensembl: ENSG00000172201
Variants:
dbSNP: 3400
ClinVar: 3400
TCGA: ENSG00000172201
COSMIC: ID4
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000172201 | ENST00000378700 | P47928 |
Expression (GTEx)
Pathways
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38188675 | 2023 | ELK3-ID4 axis governs the metastatic features of triple negative breast cancer. | 0 |
| 38188675 | 2023 | ELK3-ID4 axis governs the metastatic features of triple negative breast cancer. | 0 |
| 35094293 | 2022 | CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors. | 1 |
| 35656024 | 2022 | Upregulated circTMEM59 Inhibits Cell Growth and Metastasis by miR-668-3p/ID4 Axis in Colorectal Cancer. | 7 |
| 35908351 | 2022 | Osteoglycin (OGN) promotes tumorigenesis of pancreatic cancer cell via targeting ID4. | 0 |
| 35094293 | 2022 | CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors. | 1 |
| 35656024 | 2022 | Upregulated circTMEM59 Inhibits Cell Growth and Metastasis by miR-668-3p/ID4 Axis in Colorectal Cancer. | 7 |
| 35908351 | 2022 | Osteoglycin (OGN) promotes tumorigenesis of pancreatic cancer cell via targeting ID4. | 0 |
| 33993270 | 2021 | ID4 predicts poor prognosis and promotes BDNF-mediated oncogenesis of colorectal cancer. | 7 |
| 34723712 | 2021 | miR-9-5p Promotes Lung Adenocarcinoma Cell Proliferation, Migration and Invasion by Targeting ID4. | 6 |
| 33993270 | 2021 | ID4 predicts poor prognosis and promotes BDNF-mediated oncogenesis of colorectal cancer. | 7 |
| 34723712 | 2021 | miR-9-5p Promotes Lung Adenocarcinoma Cell Proliferation, Migration and Invasion by Targeting ID4. | 6 |
| 32054109 | 2020 | Paracrine Signaling from Breast Cancer Cells Causes Activation of ID4 Expression in Tumor-Associated Macrophages. | 7 |
| 32527287 | 2020 | Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer. | 6 |
| 32574963 | 2020 | UVB 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/id4
