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INHIBITOR OF DNA BINDING 1; ID1

INHIBITOR OF DNA BINDING 1; ID1

Alternative titles; symbolsINHIBITOR OF DIFFERENTIATION 1HGNC Approved Gene Symbol: ID1Cytogenetic location: 20q11.21 Genomic coordinates (GRCh38): 20:31,605...

Alternative titles; symbols

  • INHIBITOR OF DIFFERENTIATION 1

HGNC Approved Gene Symbol: ID1

Cytogenetic location: 20q11.21 Genomic coordinates (GRCh38): 20:31,605,288-31,606,509 (from NCBI)

▼ Description

ID proteins contain a helix-loop-helix (HLH) motif and regulate tissue-specific transcription within several cell lineages. They do not bind DNA directly, but inhibit lineage commitment by binding basic helix-loop-helix (bHLH) transcription factors through their HLH motif. ID proteins contribute to cell growth, senescence, differentiation, and angiogenesis.

▼ Cloning and Expression

Hara et al. (1994) identified 2 human Id-related genes, ID1 and ID2. Nehlin et al. (1997) found that an ID1-prime isoform is generated by a failure of the gene to splice its 1 intron, resulting in the replacement of the last 13 C-terminal amino acids with 7 different amino acids. A 2.2-kb sequence from the 5-prime region of ID1 was sufficient to direct transcription of a reporter gene, but it did not confer the growth-regulated expression normally seen with ID1.

By Northern blot analysis of mouse tissues, Singh et al. (2001) found high expression of Id1 in heart, lung and kidney, and lower expression in brain and liver.

▼ Gene Function

During B-cell differentiation, Id inhibitory proteins, particularly ID1 and ID2 (600386), are expressed at high levels in pro-B cells (Sun et al., 1991; Wilson et al., 1991) and are downregulated as cells differentiate into pre-B and mature B cells, presumably for the purpose of releasing the bHLH proteins (e.g., E2A; 147141) that are important for differentiation. Sun (1994) hypothesized that blocking downregulation of the ID genes would interfere with B-cell development. To test this hypothesis, the author established lines of transgenic mice that constitutively expressed the mouse Id1 gene in lymphoid cells. A severe defect in B-cell development occurred in these mice, demonstrating that the activity of bHLH proteins and the downregulation of the Id1 gene are crucial for B-cell differentiation to proceed. The fact that the effect is observed by manipulating Id1 gene transcription indicates that the Id1 gene is controlled primarily at the transcriptional level.

All normal vertebrate diploid cells have only a limited capacity to proliferate, a phenomenon that is known as replicative senescence. Human diploid fibroblasts derived from embryonic tissue gradually lose the ability to initiate DNA synthesis in response to external stimuli and cease proliferation after 50 to 80 population doublings. Hara et al. (1994) showed that Id-related genes are expressed transiently during both early and late G1 phase and that senescent human diploid fibroblasts fail to express these Id-related genes in response to serum stimulation.

Hara et al. (1994) found that human ID1 and ID2 mRNAs were barely detectable in quiescent early passage fibroblasts; serum coordinately induced both mRNAs, with 2 peaks of expression, in early and late G1. Antisense oligomers complementary to ID1 and ID2 mRNA prevented early passage fibroblasts from entering the S phase of the cell cycle. In senescent cells, serum barely induced the ID1 and ID2 mRNAs, although the level of MYC expression induced was similar in early passage and senescent cells.

Singh et al. (2001) found that Id1 mRNA expression paralleled that of Znf289 (606908) during mouse mammary gland development. Both Id1 and Znf289 are expressed during ductal and lobuloalveolar morphogenesis when there is extensive proliferation of mammary epithelial cells. Both are downregulated in differentiated, growth-arrested lactating epithelial cells.

The protein ID1 is a negative transcriptional regulator of CDKN2A (600160), which is associated with the development of malignant melanoma (Ohtani et al., 2001). Polsky et al. (2001) examined 21 melanocytic lesions at various stages of malignant progression from common melanocytic nevi to metastatic melanomas for ID1 and CDKN2A expression. Upregulation of ID1 expression was limited to the earliest stages of melanoma, suggesting that ID1 is important in early melanoma development.

Volpert et al. (2002) identified Id1 target genes by differential display of genes expressed by wildtype and Id1 null embryonic mouse fibroblasts. They identified several genes involved in diverse biologic functions, such as matrix remodeling, intracellular signaling, and angiogenesis. They further characterized the effect of Id1 disruption on thrombospondin-1 (THBS1; 188060), an inhibitor of neovascularization, and found that Id1 is a potent repressor of Tsp1 transcription.

By in vivo selection, transcriptomic analysis, functional verification, and clinical validation, Minn et al. (2005) identified a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumor and in the lung microenvironment. Others contribute to aggressive growth selectivity in the lung. Among the lung metastasis signature genes identified, several, including ID1, were functionally validated. Those subjects expressing the lung metastasis signature had a significantly poorer lung metastasis-free survival, but not bone metastasis-free survival, compared to subjects without the signature.

Kebebew et al. (2004) characterized the expression and distribution of the ID1 protein in normal, hyperplastic, and neoplastic human thyroid tissue. They also evaluated the effect of the ID1 gene on thyroid cancer cell growth and markers of thyroid cell differentiation. Normal thyroid tissue had the lowest level of ID1 protein expression. Anaplastic thyroid cancer had the highest level compared to benign and malignant thyroid tissues. ID1 protein expression was higher in malignant thyroid tissue than in hyperplastic thyroid tissue. They found no significant association between the level of ID1 protein expression and patient age, sex, tumor-node-metastasis stage, tumor size, primary tumor versus lymph node metastasis, primary tumor versus recurrent tumors, and extent of tumor differentiation. Inhibiting ID1 mRNA expression in thyroid cancer cell lines using ID1 antisense oligonucleotides resulted in growth inhibition and decreased thyroglobulin (TG; 188450) and sodium-iodide symporter (NIS; 601843) mRNA expression. The authors concluded that ID1 is overexpressed in hyperplastic and neoplastic thyroid tissue and directly regulates the growth of thyroid cancer cells of follicular cell origin, but is not a marker of aggressive phenotype in differentiated thyroid cancer.

Using mouse models of pulmonary metastasis, Gao et al. (2008) identified bone marrow-derived endothelial progenitor cells as critical regulators of the angiogenic switch from micrometastasis to macrometastasis. Gao et al. (2008) showed that tumors induced the expression of the transcription factor Id1 in endothelial progenitor cells and that suppression of Id1 after metastatic colonization blocked endothelial progenitor cell mobilization, caused angiogenesis inhibition, impaired pulmonary macrometastases, and increased survival of tumor-bearing animals.

Gumireddy et al. (2009) showed that the transcriptional regulators KLF17 (ZNF393; 609602) and ID2 were inversely expressed in human and mouse mammary tumor cell lines and in primary human breast cancers, with KLF17 predominantly expressed in cells and tumors of low metastatic potential, and ID2 predominantly expressed in cells and tumors with high metastatic potential. Electrophoretic mobility shift, chromatin immunoprecipitation, and reporter gene assays showed that mouse Klf17 bound directly to 1 of 2 CACCC boxes in the 5-prime UTR of the mouse Id2 gene and suppressed its expression. Knockdown of KLF17 via short hairpin RNA caused epithelial-to-mesenchymal transition and increased metastasis in vivo, and dual knockdown of KLF17 and ID2 normalized these effects.

Ding et al. (2010) demonstrated that liver sinusoidal endothelial cells (LSECs) constitute a unique population of phenotypically and functionally defined Vegfr3 (136352)+/Cd34 (142230)-/Vegfr2 (191306)+/VE-cadherin (601120)+/factorVIII (300841)+/Cd45 (151460)- endothelial cells, which through the release of angiocrine trophogens initiate and sustain liver regeneration induced by 70% partial hepatectomy. After partial hepatectomy, residual liver vasculature remains intact without experiencing hypoxia or structural damage, which allows study of physiologic liver regeneration. Using this model, Ding et al. (2010) showed that inducible genetic ablation of Vegfr2 in the LSECs impairs the initial burst of hepatocyte proliferation (days 1-3 after partial hepatectomy) and subsequent reconstitution of the hepatovascular mass (days 4-8 after partial hepatectomy) by inhibiting upregulation of the endothelial cell-specific transcription factor Id1. Accordingly, Id1-deficient mice also manifested defects throughout liver regeneration, owing to diminished expression of LSEC-derived angiocrine factors, including hepatocyte growth factor (HGF; 142409) and Wnt2 (147870). Notably, in in vitro cocultures, Vegfr2-Id1 activation in LSECs stimulated hepatocyte proliferation. Indeed, intrasplenic transplantation of Id1 wildtype or Id1-null LSECs transduced with Wnt2 and Hgf reestablished an inductive vascular niche in the liver sinusoids of the Id1-null mice, initiating and restoring hepatovascular regeneration. Therefore, Ding et al. (2010) concluded that in the early phases of physiologic liver regeneration, VEGFR2-ID1-mediated inductive angiogenesis in LSECs through release of angiocrine factors WNT2 and HGF provokes hepatic proliferation. Subsequently, VEGFR2-ID1-dependent proliferative angiogenesis reconstitutes liver mass.

Ding et al. (2014) combined an inducible endothelial cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury to show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The profibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors CXCR7 (610376) and CXCR4 (162643) in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor ID1 (600349), deploying proregenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors. By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive Fgfr1 (136350) signaling in liver sinusoidal endothelial cells counterbalanced Cxcr7-dependent proregenerative response and augmented Cxcr4 expression. This predominance of Cxcr4 over Cxcr7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin (125660)-positive hepatic stellate-like cells and enforcing a profibrotic vascular niche. Endothelial cell-specific ablation of either Fgfr1 or Cxcr4 in mice restored the proregenerative pathway and prevented Fgfr1-mediated maladaptive subversion of angiocrine factors. Similarly, selective Cxcr7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. Ding et al. (2014) demonstrated that in response to liver injury, differential recruitment of proregenerative CXCR7-ID1 versus profibrotic FGFR1-CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis.

▼ Gene Structure

Nehlin et al. (1997) found that the ID1 gene contains 2 exons.

▼ Mapping

By somatic cell hybrid analysis and fluorescence in situ hybridization, Mathew et al. (1995) mapped the ID1 gene to chromosome 20q11.

▼ Animal Model

Id proteins may control cell differentiation by interfering with DNA binding of transcription factors. Lyden et al. (1999) demonstrated that the targeted disruption of Id1 and Id3 (600277) in mice results in premature withdrawal of neuroblasts in the cell cycle and expression of neural-specific differentiation markers. Lyden et al. (1999) crossed Id1 +/- and Id3 +/- mice. Offspring lacking 1 to 3 Id alleles in any combination were indistinguishable from wildtype, but no animals lacking all 4 Id alleles were born. By embryonic day 12.5, double knockout embryos exhibited cranial hemorrhage, and no double knockout embryos survived beyond embryonic day 13.5. The Id1-Id3 double knockout mice displayed vascular malformations in forebrain and absence of branching and sprouting of blood vessels in the neuroectoderm. As angiogenesis both in the brain and in tumors requires invasion of avascular tissue by endothelial cells, Lyden et al. (1999) examined Id knockout mice for their ability to support the growth of tumor xenografts. Three different tumors failed to grow and/or metastasize in mice carrying only 1 Id1 allele, and any tumor growth present showed poor vascularization and extensive necrosis. Thus, Lyden et al. (1999) concluded that Id genes are required to maintain the timing of neuronal differentiation in the embryo and invasiveness of the vasculature. Because the Id genes are expressed at very low levels in adults, they make attractive targets for antiangiogenic drug design. Lyden et al. (1999) also concluded that the premature neuronal differentiation in Id1-Id3 double knockout mice indicates that ID1 or ID3 is required to block the precisely timed expression and activation of positively acting bHLH proteins during murine development.

In the developing heart, Id1, Id2 (600386), and Id3 are detected in the endocardial cushion mesenchyme from embryonic days 10.5 through 16.5, but Id4 (600581) is absent. Fraidenraich et al. (2004) showed that Id1 to Id3 are also expressed in the epicardium and endocardium but are absent in the myocardium. Id1 to Id3 expression becomes confined in the leaflets of the cardiac valves as the atrioventricular endocardial cushion tissue myocardializes. Id1 and Id3 expression persists in the cardiac valves, endocardium, endothelium, and epicardium at postnatal day 7. Fraidenraich et al. (2004) found that double and triple Id knockout embryos displayed severe cardiac defects and died at midgestation. Embryo size was reduced by 10 to 30%. Knockout embryos displayed ventricular septal defects associated with impaired ventricular trabeculation and thinning of the compact myocardium. Trabeculae had disorganized sheets of myocytes surrounded by discontinuous endocardial cell lining. Cell proliferation in the myocardial wall was defective. Fraidenraich et al. (2004) showed that midgestation lethality of embryos was rescued by the injection of 15 wildtype embryonic stem (ES) cells into mutant blastocysts. Myocardial markers altered in Id mutant cells were restored to normal throughout the chimeric myocardium. Intraperitoneal injection of ES cells into female mice before conception also partially rescued the cardiac phenotype with no incorporation of ES cells. Insulin-like growth factor-1 (IGF1; 147440), a long-range secreted factor, in combination with Wnt5a (164975), a locally secreted factor, were thought likely to account for complete reversion of the cardiac phenotype. Fraidenraich et al. (2004) concluded that ES cells have the potential to reverse congenital defects through Id-dependent local and long-range effects in a mammalian embryo.

Tags: 20q11.21