ID1 (inhibitor of DNA binding 1, dominant negative helix-loop-helix protein)

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ID1 (inhibitor of DNA binding 1, dominant negative helix-loop-helix protein)

Written	2012-09	Eduardo Castañón, Ignacio Gil-Bazo
		New target therapies laboratory, Division of Oncology, Center for Applied Medical Research, 31621 Pamplona, Spain

(Note : for Links provided by Atlas : click)

Identity

Other alias	ID
	bHLHb24
LocusID (NCBI)	3397
Atlas_Id	40914
Location	20q11.21 [Link to chromosome band 20q11]
Location_base_pair	Starts at and ends at bp from pter

Fusion genes
(updated 2017)

Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA



Description	DNA contains 1239 bp encoding 2 coding exons.
Transcription	Id1 gene has 2 transcripts, called Id1-001 (or Id1A) and Id-1-002 (or Id1B). mRNA Id1A contains 994 bps whereas mRNA Id1B contains 1233 bps. Id1A is considered the "canonical sequence".

Protein

Description	ID1 belongs to the helix-loop-helix protein family. It is composed by 155 aa. It has a main domain located on 143-155 aa responsible for the helix-loop-helix conformation. Its main motif, encoded by 14 aa is responsible for the nuclear export signaling.
Expression	High levels of ID1 are found in brain, liver, lung, skin and thyroid gland cells. It is also expressed in fetal cells and in the umbilical vein endothelial cell.
Localisation	Nucleus.
Function	Although it does not bind directly to DNA, by binding basic helix-loop-helix transcription factors through its HLH motif, ID1 may control tissue-specific genes related to cell growth, proliferation, differentiation and angiogenesis.
Homology	H.sapiens: ID1; P.troglodytes: ID1; C.lupus: ID1; B.taurus: ID1; M.musculus: Id1; R.norvegicus: Id1; G.gallus: ID1; D.rerio: id1.

Mutations

Germinal	No germinal mutations have been reported.
Somatic	No somatic mutations have been reported.

Implicated in

Note

Entity	Non small cell lung cancer
Note	ID1 levels are correlated with a worse prognosis in lung adenocarcinoma in both, disease free survival and overall survival. A higher expression of Id1 has been reported in squamous cell carcinoma and adenocarcinoma of the lung. ID1 expression are detected in more resistant tumors to either chemo and radiation therapy. When silencing Id1 in in vitro models, a reversal of resistance to the treatment (both chemotherapy and radiation) was observed.


Entity	Gastric cancer
Note	Gastric cancer prognosis has also been linked to ID1 expression levels. Whereas poor differentiated gastric tumors express higher levels of ID1, those gastric cancers with a higher differentiation, and thus, a better prognosis, express a lower quantity of ID1. Nevertheless, the impact of ID1 expression on clinical outcome has not reached statistical significance when a multivariate analysis was carried out.


Entity	Breast cancer
Note	In breast cancer, especially in those node negative tumors, ID1 expression has become an independent prognostic factor. Higher levels of ID1 are related to a worse prognosis (measured by both, overall survival and disease free survival). This may be explained by the possible relation between ID1 and the steroid-receptor, this latter considered a factor which may change therapeutic options in breast cancer patients.


Entity	Prostate cancer
Note	In prostate cancer it has been observed that levels of ID1 are correlated to the grade of differentiation measured by the Gleason score, detecting higher levels of ID1 in those prostate tumors with a higher Gleason score. Comparing prostate cancer with benign prostate hyperplasia, ID1 expression differences may also be seen; ID1 is not expressed in benign prostate hyperplasia (BPH), whereas ID1 expression is remarkably higher in prostate cancer cells.


Entity	Melanoma
Note	In melanoma ID1 is also positively related to tumor thickness and also with overall survival. Also, ID1 is highly expressed in those BRAF mutated melanomas compared to BRAF wild type melanomas. ID1 negative regulates CDKN2A, which has been related to malignant melanoma development. ID1 is expressed in the earliest stages of melanoma.


Entity	Glioblastoma
Note	In recent studies, ID1 has been catalogued as a marker of brain stem cells localized at the perivascular niche. Those stem cells with higher levels of ID1 have a major capability of tumor initiation and therapeutic resistance.


Entity	Hepatocarcinoma
Note	In Hepatitis B virus-induced hepatocarcinoma, levels of ID1 may predict both disease free survival and overall survival, in a negative manner. Also, ID1 has been related to bad prognostic features such as portal vein invasion, lymph node metastasis and a worse Child Pugh grade.


Entity	Anaplastic thyroid tumor
Note	ID1 is highly expressed in anaplastic thyroid tumors rather than in regular thyroid cells; it may be explained by the role ID1 plays on cell growth and differentiation.


Entity	Neurogenesis
Note	Lacking of Id1 alleles (with simultaneous Id3 downregulation) triggers neural differentiation in mice embryos development resulting in a lethal event. It has also been reported that when Id1 and Id3 are not expressed, vascular sprouting in brain does not occur.


Entity	Heart and vessel formation
Note	Id1 has also being related to play a crucial role in heart development, since Id1 knockout mice showed ventricular defects and myocardium trabeculation impairment. ID1 is also expressed in endothelial progenitor cells, and its suppression is related to angiogenesis inhibition and in a blockade of endothelial cells mobilization.


Entity	Hematopoiesis
Note	Higher ID1 levels are found in pro-B cells, whereas it is downregulated in pre-B and mature cells. When blocking Id1 in those cells, B-cell development is disrupted.


Entity	Metastasis
Note	Higher levels of ID1 expression are found in those breast cancers which are more prone to metastasize to the lung. Id1 has been described as part of the genes signature for breast cancer metastasis to the lung.


Entity	Stemcellness and selfrenewal
Note	Satellite cells are muscle stem cells related to injured muscle renewal. ID1 expression has been recently correlated to muscle stem cell self-renewal ability, showing that when ID1 is expressed, a higher capability of self-renewal may be observed. Culture cells with high ID1 expression, may retain selfrenewal ability after several passages comparing to those cells with lower levels of ID1. Stem cells are characterized by their anchorage to an special microenviroment, also known as niche. ID1, by repressing the activation of Rap1GAP (an inhibitor of an important neural cell adhesion protein known as RAP1) assure stem cell joints to the niche. When ID1 is downregulated, neural stem cells detach from the brain stem cell niches, such as the ventricular zone in embryonic brain and the subventricular zone of post-nata brain. This detachment from the niches, may also trigger neuronal and oligodendrogial differentiation.

Bibliography

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PMID 20414347

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PMID 14742319

Id1 restrains p21 expression to control endothelial progenitor cell formation.

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PLoS One. 2007 Dec 19;2(12):e1338.

PMID 18092003

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Overexpressed Id-1 is associated with patient prognosis and HBx expression in hepatitis B virus-related hepatocellular carcinoma.

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PMID 20574154

The gene for the helix-loop-helix protein, Id, is specifically expressed in neural precursors.

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PMID 1426618

Regulation of Id1 expression by SRC: implications for targeting of the bone morphogenetic protein pathway in cancer.

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Cancer Res. 2008 Apr 1;68(7):2250-8.

PMID 18381431

ID genes mediate tumor reinitiation during breast cancer lung metastasis.

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Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19506-11. Epub 2007 Nov 28.

PMID 18048329

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PMID 8294468

Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells.

Jankovic V, Ciarrocchi A, Boccuni P, DeBlasio T, Benezra R, Nimer SD.

Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1260-5. Epub 2007 Jan 16.

PMID 17227850

Inhibition of tumourigenicity of small cell lung cancer cells by suppressing Id3 expression.

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PMID 20664928

Overexpression of Id-1 is significantly associated with tumour angiogenesis in human pancreas cancers.

Lee KT, Lee YW, Lee JK, Choi SH, Rhee JC, Paik SS, Kong G.

Br J Cancer. 2004 Mar 22;90(6):1198-203.

PMID 15026801

Over-expression of Id-1 induces cell proliferation in hepatocellular carcinoma through inactivation of p16INK4a/RB pathway.

Lee TK, Man K, Ling MT, Wang XH, Wong YC, Lo CM, Poon RT, Ng IO, Fan ST.

Carcinogenesis. 2003 Nov;24(11):1729-36. Epub 2003 Aug 29.

PMID 12949053

The multiple roles of Id-1 in cancer progression.

Ling MT, Wang X, Zhang X, Wong YC.

Differentiation. 2006 Dec;74(9-10):481-7.

PMID 17177845

Downregulation of Id1 by small interfering RNA in prostate cancer PC3 cells in vivo and in vitro.

Ling YX, Tao J, Fang SF, Hui Z, Fang QR.

Eur J Cancer Prev. 2011 Jan;20(1):9-17.

PMID 20881502

Expression and prognostic relevance of Id1 in stage III esophageal squamous cell carcinoma.

Liu J, Hu Y, Hu W, Xie X, Ela Bella A, Fu J.

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PMID 21896993

Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts.

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PMID 10537105

Chromosomal assignment of human ID1 and ID2 genes.

Mathew S, Chen W, Murty VV, Benezra R, Chaganti RS.

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PMID 8586447

Using the transcription factor inhibitor of DNA binding 1 to selectively target endothelial progenitor cells offers novel strategies to inhibit tumor angiogenesis and growth.

Mellick AS, Plummer PN, Nolan DJ, Gao D, Bambino K, Hahn M, Catena R, Turner V, McDonnell K, Benezra R, Brink R, Swarbrick A, Mittal V.

Cancer Res. 2010 Sep 15;70(18):7273-82. Epub 2010 Aug 31.

PMID 20807818

Targeting Id1 and Id3 by a specific peptide aptamer induces E-box promoter activity, cell cycle arrest, and apoptosis in breast cancer cells.

Mern DS, Hoppe-Seyler K, Hoppe-Seyler F, Hasskarl J, Burwinkel B.

Breast Cancer Res Treat. 2010 Dec;124(3):623-33. Epub 2010 Feb 27.

PMID 20191379

High levels of Id1 expression define B1 type adult neural stem cells.

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PMID 19896442

Id proteins synchronize stemness and anchorage to the niche of neural stem cells.

Niola F, Zhao X, Singh D, Castano A, Sullivan R, Lauria M, Nam HS, Zhuang Y, Benezra R, Di Bernardo D, Iavarone A, Lasorella A.

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PMID 22522171

Id1 gene transfer confers angiogenic property on fully differentiated endothelial cells and contributes to therapeutic angiogenesis.

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Circulation. 2005 Nov 1;112(18):2840-50.

PMID 16267257

Bone morphogenetic protein 2 transiently enhances expression of a gene, Id (inhibitor of differentiation), encoding a helix-loop-helix molecule in osteoblast-like cells.

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Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9219-22.

PMID 8415680

Slow-dividing satellite cells retain long-term self-renewal ability in adult muscle.

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J Cell Sci. 2012 Mar 1;125(Pt 5):1309-17. Epub 2012 Feb 20.

PMID 22349695

Id-1 stimulates serum independent prostate cancer cell proliferation through inactivation of p16(INK4a)/pRB pathway.

Ouyang XS, Wang X, Ling MT, Wong HL, Tsao SW, Wong YC.

Carcinogenesis. 2002 May;23(5):721-5.

PMID 12016143

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PMID 17108123

The loop region of the helix-loop-helix protein Id1 is critical for its dominant negative activity.

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PMID 8247002

ID1 facilitates the growth and metastasis of non-small cell lung cancer in response to nicotinic acetylcholine receptor and epidermal growth factor receptor signaling.

Pillai S, Rizwani W, Li X, Rawal B, Nair S, Schell MJ, Bepler G, Haura E, Coppola D, Chellappan S.

Mol Cell Biol. 2011 Jul;31(14):3052-67. Epub 2011 May 23.

PMID 21606196

The transcriptional repressor of p16/Ink4a, Id1, is up-regulated in early melanomas.

Polsky D, Young AZ, Busam KJ, Alani RM.

Cancer Res. 2001 Aug 15;61(16):6008-11.

PMID 11507043

Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance.

Ponz-Sarvise M, Nguewa PA, Pajares MJ, Agorreta J, Lozano MD, Redrado M, Pio R, Behrens C, Wistuba II, Garcia-Franco CE, Garcia-Foncillas J, Montuenga LM, Calvo A, Gil-Bazo I.

Clin Cancer Res. 2011 Jun 15;17(12):4155-66. Epub 2011 May 3.

PMID 21540238

Id1 maintains embryonic stem cell self-renewal by up-regulation of Nanog and repression of Brachyury expression.

Romero-Lanman EE, Pavlovic S, Amlani B, Chin Y, Benezra R.

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PMID 22013995

The stem cell gene "inhibitor of differentiation 1" (ID1) is frequently expressed in non-small cell lung cancer.

Rothschild SI, Kappeler A, Ratschiller D, Betticher DC, Tschan MP, Gugger M, Gautschi O.

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PMID 20709421

Id proteins in development, cell cycle and cancer.

Ruzinova MB, Benezra R.

Trends Cell Biol. 2003 Aug;13(8):410-8.

PMID 12888293

Crucial role of inhibitor of DNA binding/differentiation in the vascular endothelial growth factor-induced activation and angiogenic processes of human endothelial cells.

Sakurai D, Tsuchiya N, Yamaguchi A, Okaji Y, Tsuno NH, Kobata T, Takahashi K, Tokunaga K.

J Immunol. 2004 Nov 1;173(9):5801-9.

PMID 15494533

ID1 inhibits USF2 and blocks TGF-b-induced apoptosis in mesangial cells.

Sato AY, Antonioli E, Tambellini R, Campos AH.

Am J Physiol Renal Physiol. 2011 Dec;301(6):F1260-9. Epub 2011 Sep 14.

PMID 21921026

Overexpression of Id-1 is associated with poor clinical outcome in node negative breast cancer.

Schoppmann SF, Schindl M, Bayer G, Aumayr K, Dienes J, Horvat R, Rudas M, Gnant M, Jakesz R, Birner P.

Int J Cancer. 2003 May 10;104(6):677-82.

PMID 12640673

Strong expression of ID1 protein is associated with decreased survival, increased expression of ephrin-A1/EPHA2, and reduced thrombospondin-1 in malignant melanoma.

Straume O, Akslen LA.

Br J Cancer. 2005 Oct 17;93(8):933-8.

PMID 16189525

Cyclooxygenase-2-derived prostaglandin E2 stimulates Id-1 transcription.

Subbaramaiah K, Benezra R, Hudis C, Dannenberg AJ.

J Biol Chem. 2008 Dec 5;283(49):33955-68. Epub 2008 Oct 8.

PMID 18842581

Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity in Notch3-induced T-cell lymphoma.

Talora C, Campese AF, Bellavia D, Pascucci M, Checquolo S, Groppioni M, Frati L, von Boehmer H, Gulino A, Screpanti I.

EMBO Rep. 2003 Nov;4(11):1067-72. Epub 2003 Oct 17.

PMID 14566327

Cyclin D1, Id1 and EMT in breast cancer.

Tobin NP, Sims AH, Lundgren KL, Lehn S, Landberg G.

BMC Cancer. 2011 Sep 28;11:417.

PMID 21955753

Transcription of the dominant-negative helix-loop-helix protein Id1 is regulated by a protein complex containing the immediate-early response gene Egr-1.

Tournay O, Benezra R.

Mol Cell Biol. 1996 May;16(5):2418-30.

PMID 8628310

Targeting Id1 and Id3 inhibits peritoneal metastasis of gastric cancer.

Tsuchiya T, Okaji Y, Tsuno NH, Sakurai D, Tsuchiya N, Kawai K, Yazawa K, Asakage M, Yamada J, Yoneyama S, Kitayama J, Osada T, Watanabe T, Tokunaga K, Takahashi K, Nagawa H.

Cancer Sci. 2005 Nov;96(11):784-90.

PMID 16271072

Expression and prognostic values of Id-1 and Id-3 in gastric adenocarcinoma.

Yang HY, Liu HL, Liu GY, Zhu H, Meng QW, Qu LD, Liu LX, Jiang HC.

J Surg Res. 2011 May 15;167(2):258-66. Epub 2009 Sep 9.

PMID 20080245

Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo.

Yang J, Li X, Al-Lamki RS, Southwood M, Zhao J, Lever AM, Grimminger F, Schermuly RT, Morrell NW.

Circ Res. 2010 Jul 23;107(2):252-62. Epub 2010 Jun 3.

PMID 20522807

Inhibitor of DNA binding-1 overexpression in prostate cancer: relevance to tumor differentiation.

Yu X, Xu X, Han B, Zhou R.

Pathol Oncol Res. 2009 Mar;15(1):91-6. Epub 2008 Aug 28.

PMID 18752043

Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors.

de Candia P, Solit DB, Giri D, Brogi E, Siegel PM, Olshen AB, Muller WJ, Rosen N, Benezra R.

Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12337-42. Epub 2003 Oct 2.

PMID 14526102

Citation

This paper should be referenced as such :

Castaòn, E ; Gil-Bazo, I

ID1 (inhibitor of DNA binding 1, dominant negative helix-loop-helix protein)

Atlas Genet Cytogenet Oncol Haematol. 2013;17(2):121-125.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Genes/ID1ID40914ch20q11.html

External links

	Nomenclature
	Cards
Atlas	ID1ID40914ch20q11.txt
Aliases
	Genomic and cartography
	Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)	Expression in : [Datasets] [Normal Tissue Atlas] [carcinoma Classsification] [NCI60]
BioGPS (Tissue expression)	3397
	Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
	Protein Interaction databases
	Ontologies - Pathways
	Clinical trials, drugs, therapy
	Miscellaneous
canSAR (ICR)	(select the gene name)
	Probes
	Litterature

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

indexed on : Thu Oct 18 17:39:21 CEST 2018

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