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

2012-09-01   Eduardo Castañón , Ignacio Gil-Bazo 

New target therapies laboratory, Division of Oncology, Center for Applied Medical Research, 31621 Pamplona, Spain




Atlas Image


DNA contains 1239 bp encoding 2 coding exons.


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".



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.


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.




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.


H.sapiens: ID1; P.troglodytes: ID1; C.lupus: ID1; B.taurus: ID1; M.musculus: Id1; R.norvegicus: Id1; G.gallus: ID1; D.rerio: id1.



No germinal mutations have been reported.


No somatic mutations have been reported.

Implicated in

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Non small cell lung cancer
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.
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Gastric cancer
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.
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Breast cancer
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.
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Prostate cancer
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.
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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.
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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.
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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.
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Anaplastic thyroid tumor
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.
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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.
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Heart and vessel formation
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.
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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.
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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.
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Stemcellness and selfrenewal
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.


Pubmed IDLast YearTitleAuthors
211562872010TGF-β Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma.Anido J et al
98219641998The helix-loop-helix transcription factors Id1 and Id3 have a functional role in control of cell division in human normal and neoplastic chondrocytes.Asp J et al
21566291990The protein Id: a negative regulator of helix-loop-helix DNA binding proteins.Benezra R et al
118403262001The Id proteins and angiogenesis.Benezra R et al
116730542001Role of Id proteins in embryonic and tumor angiogenesis.Benezra R et al
204143472010Id1 promotes tumor cell migration in nonsmall cell lung cancers.Bhattacharya R et al
215363742011Id1 promotes lung cancer cell proliferation and tumor growth through Akt-related pathway.Cheng YJ et al
147423192004Id-1-induced Raf/MEK pathway activation is essential for its protective role against taxol-induced apoptosis in nasopharyngeal carcinoma cells.Cheung HW et al
180920032007Id1 restrains p21 expression to control endothelial progenitor cell formation.Ciarrocchi A et al
96714671998A novel pathway for mammary epithelial cell invasion induced by the helix-loop-helix protein Id-1.Desprez PY et al
205741542010Overexpressed Id-1 is associated with patient prognosis and HBx expression in hepatitis B virus-related hepatocellular carcinoma.Ding R et al
14266181992The gene for the helix-loop-helix protein, Id, is specifically expressed in neural precursors.Duncan M et al
183814312008Regulation of Id1 expression by SRC: implications for targeting of the bone morphogenetic protein pathway in cancer.Gautschi O et al
180483292007ID genes mediate tumor reinitiation during breast cancer lung metastasis.Gupta GP et al
82944681994Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts.Hara E et al
172278502007Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells.Jankovic V et al
206649282010Inhibition of tumourigenicity of small cell lung cancer cells by suppressing Id3 expression.Kamalian L et al
150268012004Overexpression of Id-1 is significantly associated with tumour angiogenesis in human pancreas cancers.Lee KT et al
129490532003Over-expression of Id-1 induces cell proliferation in hepatocellular carcinoma through inactivation of p16INK4a/RB pathway.Lee TK et al
171778452006The multiple roles of Id-1 in cancer progression.Ling MT et al
208815022011Downregulation of Id1 by small interfering RNA in prostate cancer PC3 cells in vivo and in vitro.Ling YX et al
218969932010Expression and prognostic relevance of Id1 in stage III esophageal squamous cell carcinoma.Liu J et al
105371051999Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts.Lyden D et al
85864471995Chromosomal assignment of human ID1 and ID2 genes.Mathew S et al
208078182010Using 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 et al
201913792010Targeting Id1 and Id3 by a specific peptide aptamer induces E-box promoter activity, cell cycle arrest, and apoptosis in breast cancer cells.Mern DS et al
198964422009High levels of Id1 expression define B1 type adult neural stem cells.Nam HS et al
225221712012Id proteins synchronize stemness and anchorage to the niche of neural stem cells.Niola F et al
162672572005Id1 gene transfer confers angiogenic property on fully differentiated endothelial cells and contributes to therapeutic angiogenesis.Nishiyama K et al
84156801993Bone morphogenetic protein 2 transiently enhances expression of a gene, Id (inhibitor of differentiation), encoding a helix-loop-helix molecule in osteoblast-like cells.Ogata T et al
223496952012Slow-dividing satellite cells retain long-term self-renewal ability in adult muscle.Ono Y et al
120161432002Id-1 stimulates serum independent prostate cancer cell proliferation through inactivation of p16(INK4a)/pRB pathway.Ouyang XS et al
171081232006Reassessment of id1 protein expression in human mammary, prostate, and bladder cancers using a monospecific rabbit monoclonal anti-id1 antibody.Perk J et al
82470021993The loop region of the helix-loop-helix protein Id1 is critical for its dominant negative activity.Pesce S et al
216061962011ID1 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 et al
115070432001The transcriptional repressor of p16/Ink4a, Id1, is up-regulated in early melanomas.Polsky D et al
215402382011Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance.Ponz-Sarvisé M et al
220139952012Id1 maintains embryonic stem cell self-renewal by up-regulation of Nanog and repression of Brachyury expression.Romero-Lanman EE et al
207094212011The stem cell gene "inhibitor of differentiation 1" (ID1) is frequently expressed in non-small cell lung cancer.Rothschild SI et al
128882932003Id proteins in development, cell cycle and cancer.Ruzinova MB et al
154945332004Crucial role of inhibitor of DNA binding/differentiation in the vascular endothelial growth factor-induced activation and angiogenic processes of human endothelial cells.Sakurai D et al
219210262011ID1 inhibits USF2 and blocks TGF-β-induced apoptosis in mesangial cells.Sato AY et al
126406732003Overexpression of Id-1 is associated with poor clinical outcome in node negative breast cancer.Schoppmann SF et al
161895252005Strong expression of ID1 protein is associated with decreased survival, increased expression of ephrin-A1/EPHA2, and reduced thrombospondin-1 in malignant melanoma.Straume O et al
188425812008Cyclooxygenase-2-derived prostaglandin E2 stimulates Id-1 transcription.Subbaramaiah K et al
145663272003Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity in Notch3-induced T-cell lymphoma.Talora C et al
219557532011Cyclin D1, Id1 and EMT in breast cancer.Tobin NP et al
86283101996Transcription 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 et al
162710722005Targeting Id1 and Id3 inhibits peritoneal metastasis of gastric cancer.Tsuchiya T et al
200802452011Expression and prognostic values of Id-1 and Id-3 in gastric adenocarcinoma.Yang HY et al
205228072010Smad-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 et al
187520432009Inhibitor of DNA binding-1 overexpression in prostate cancer: relevance to tumor differentiation.Yu X et al
145261022003Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast Candia P et al

Other Information

Locus ID:

NCBI: 3397
MIM: 600349
HGNC: 5360
Ensembl: ENSG00000125968


dbSNP: 3397
ClinVar: 3397
TCGA: ENSG00000125968


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
TGF-beta signaling pathwayKEGGko04350
TGF-beta signaling pathwayKEGGhsa04350
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oncogene Induced SenescenceREACTOMER-HSA-2559585

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
117292072002Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter.302
226984032012ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21.85
243323692013TGF-β-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition.84
122968252002Identification of a BMP-responsive element in Id1, the gene for inhibition of myogenesis.76
166824352006Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome.51
253235352014LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers.50
232430242013Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target.47
219557532011Cyclin D1, Id1 and EMT in breast cancer.41
125764502003Level of Id-1 protein expression correlates with poor differentiation, enhanced malignant potential, and more aggressive clinical behavior of epithelial ovarian tumors.40
195518632009Id-1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/AKT signaling pathway.40


Eduardo Castañón ; Ignacio Gil-Bazo

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

Atlas Genet Cytogenet Oncol Haematol. 2012-09-01

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