Alternative titles; symbols
HGNC Approved Gene Symbol: ID3
Cytogenetic location: 1p36.12 Genomic coordinates (GRCh38): 1:23,557,926-23,559,501 (from NCBI)
Members of the ID family of helix-loop-helix (HLH) proteins lack a basic DNA-binding domain and inhibit transcription through formation of nonfunctional dimers that are incapable of binding to DNA.
Ellmeier et al. (1992) isolated a novel human gene encoding a helix-loop-helix protein by molecular cloning of chromosome 1p36-specific CpG islands. Initially termed HEIR1, the ID3 gene was localized to the neuroblastoma consensus deletion region, 1p36.2-p36.12. Its predicted protein was 95.8% identical to the mouse HLH462 protein and had clear homology to the mouse Id and Drosophila emc proteins. The gene was expressed at high abundance in adult lung, kidney, and adrenal medulla, but not in adult brain. Despite prominent HEIR1 expression in adrenal medulla, which is a prime target for neuroblastomas, 10 of 12 neuroblastoma-derived cell lines showed very low levels of HEIR1 mRNA. Low HEIR1 expression was generally found in tumor cell lines with NMYC (164840) overexpression, whereas the 2 cell lines displaying high HEIR1 levels did not overexpress NMYC. Mutually exclusive expression of the 2 genes was also found by in situ hybridization in developing mouse tissues, particularly in the forebrain neuroectoderm. Ellmeier et al. (1992) concluded that HEIR1 expression is reduced specifically in the majority of neuroblastomas and suggested an inverse correlation between HEIR1 and NMYC expression in these tumors and in embryonic development.
ID3 is an inhibitor of E proteins, such as E2A (147141). By Northern and Western blot analysis, Kee et al. (2001) showed that transforming growth factor-beta (190180) in mouse rapidly induced transient Id3 expression in B-lymphocyte precursors. This induction involved activation of the SMAD (see 602932) transcription factor pathway.
Kaplan et al. (2005) demonstrated that bone marrow-derived hematopoietic progenitor cells that express VEGFR1 (605070) home to tumor-specific premetastatic sites and form cellular clusters before the arrival of tumor cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1-positive cells from the bone marrow of wildtype mice abrogated the formation of these premetastatic clusters and prevented tumor metastasis, whereas reconstitution with selected Id3-competent VEGFR1-positive cells established cluster formation and tumor metastasis in Id3 knockout mice. Kaplan et al. (2005) also showed that VEGFR1-positive cells express VLA4, also known as integrin alpha-4-beta-1 (see 192975), and that tumor-specific growth factors upregulate fibronectin (135600), a VLA4 ligand, in resident fibroblasts, providing a permissive niche for incoming tumor cells. Conditioned media obtained from distinct tumor types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. Kaplan et al. (2005) concluded that their findings demonstrated a requirement for VEGFR1-positive hematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1-positive-VLA4-positive clusters dictate organ-specific tumor spread.
Deed et al. (1994) reported a comparison of the ID3 gene with ID1 (600349) and ID2 (600386) that showed a highly conserved protein-coding gene organization consistent with evolution from a common ancestral gene.
Yeh and Lim (2000) determined that both the human and mouse genes contain 3 exons spanning about 1.5 kb.
By using a YAC clone of ID3 for fluorescence in situ hybridization, Deed et al. (1994) mapped the ID3 gene to 1p36.1.
White et al. (1995) excluded ID3 as a candidate for the neuroblastoma suppressor gene because it lies outside the loss of heterozygosity region revealed by neuroblastoma studies (see 256700).
Using whole-genome, whole-exome, and transcriptome sequencing of 4 prototypical Burkitt lymphomas (113970) with immunoglobulin gene (IG; see 147220)-MYC translocation (190080), Richter et al. (2012) identified 7 recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma. In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. Richter et al. (2012) concluded that their findings suggested that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis.
Love et al. (2012) described the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual, and further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma tumors. Love et al. (2012) identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13 (604406), RET (164761), PIK3R1 (171833), and the SWI/SNF genes ARID1A (603024) and SMARCA4 (603254). Love et al. (2012) stated that their data implicate a number of genes in cancer for the first time, including CCT6B (610730), SALL3 (605079), FTCD (606806), and PC (608786). ID3 mutations occurred in 34% of Burkitt lymphomas and not in diffuse large B-cell lymphomas (DLBCLs). Love et al. (2012) showed experimentally that ID3 mutations promote cell cycle progression and proliferation.
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 (600349) and Id3 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. 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 Id1 +/- Id3 -/- mice, and any tumor growth present showed poor vascularization and extensive necrosis. 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.
Pan et al. (1999) found that Id3-deficient mice had no overt abnormalities but had compromised humoral immunity. After immunization with T cell-dependent or T cell-independent antigens, the responses of Id3-deficient mice were attenuated and severely impaired, respectively. T-cell proliferative responses appeared to be intact, but IFNG expression may have been impaired. The defect in B-cell proliferation could be rescued by ectopic expression of Id1.
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.
Li et al. (2004) observed that Id3 -/- mice had difficulty maintaining fully opened eyelids beginning at 6 months and progressing with age. Histologic and electron microscopic analysis of mutant mice revealed lymphocytic infiltration in the lachrymal and salivary glands in the absence of infection, and the CD4 (186940) and CD8 (see 186910) T cells and B cells in the infiltrates expressed both Ifng (147570) and Il4 (147780). Id3 -/- mice showed reduced tear and saliva secretion, suggesting a disease similar to Sjogren syndrome (270150). ELISA analysis detected both anti-SSA (SSA1; 109092) and anti-SSB (109090) autoantibodies in Id3 -/- mice after 1 year of age. Bone marrow transplant experiments showed that the phenotype was mediated by hemopoietic cells, and adoptive transfer analysis attributed a dominant role to Id3 -/- T lymphocytes. Elimination of T cells and neonatal thymectomy demonstrated that the tear and saliva secretion defect required sustained production of thymic T cells. Li et al. (2004) concluded that ID3-mediated T-cell development is connected to autoimmune disease, and they proposed that the Id3 -/- mouse is a model for primary Sjogren syndrome.
By selective deletion of both Id2 and Id3 at the pre-T-cell receptor (TCR) and gamma/delta TCR checkpoints in mice, Li et al. (2013) observed a partial block at the pre-TCR checkpoint as well as increased production of innate gamma/delta T cells. In addition, the double deletion resulted in a dramatic increase in invariant NKT (iNKT) cells. Li et al. (2013) proposed that there are opposing roles for ID genes in regulating the alpha/beta and innate gamma/delta lineages. They concluded that there is a dosage-dependent mechanism for ID genes in repressing the fate of innate-like gamma/delta T cells versus iNKT cells during T-cell development.
Deed, R. W., Hirose, T., Mitchell, E. L. D., Santibanez-Koref, M. F., Norton, J. D. Structural organisation and chromosomal mapping of the human Id-3 gene. Gene 151: 309-314, 1994. [PubMed: 7828896] [Full Text: https://doi.org/10.1016/0378-1119(94)90676-9]
Ellmeier, W., Aguzzi, A., Kleiner, E., Kurzbauer, R., Weith, A. Mutually exclusive expression of a helix-loop-helix gene and N-myc in human neuroblastomas and in normal development. EMBO J. 11: 2563-2571, 1992. [PubMed: 1628620] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05321.x]
Fraidenraich, D., Stillwell, E., Romero, E., Wilkes, D., Manova, K., Basson, C. T., Benezra, R. Rescue of cardiac defects in Id knockout embryos by injection of embryonic stem cells. Science 306: 247-252, 2004. [PubMed: 15472070] [Full Text: https://doi.org/10.1126/science.1102612]
Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., MacDonald, D. D., Jin, D. K., Shido, K., Kerns, S. A., Zhu, Z., Hicklin, D., and 9 others. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438: 820-827, 2005. [PubMed: 16341007] [Full Text: https://doi.org/10.1038/nature04186]
Kee, B. L., Rivera, R. R., Murre, C. Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-beta. Nature Immun. 2: 242-247, 2001. [PubMed: 11224524] [Full Text: https://doi.org/10.1038/85303]
Li, H., Dai, M., Zhuang, Y. A T cell intrinsic role of Id3 in a mouse model for primary Sjogren's syndrome. Immunity 21: 551-560, 2004. [PubMed: 15485632] [Full Text: https://doi.org/10.1016/j.immuni.2004.08.013]
Li, J., Wu, D., Jiang, N., Zhuang, Y. Combined deletion of Id2 and Id3 genes reveals multiple roles for E proteins in invariant NKT cell development and expansion. J. Immun. 191: 5052-5064, 2013. [PubMed: 24123680] [Full Text: https://doi.org/10.4049/jimmunol.1301252]
Love, C., Sun, Z., Jima, D., Li, G., Zhang, J., Miles, R., Richards, K. L., Dunphy, C. H., Choi, W. W. L., Srivastava, G., Lugar, P. L., Rizzieri, D. A., and 19 others. The genetic landscape of mutations in Burkitt lymphoma. Nature Genet. 44: 1321-1325, 2012. [PubMed: 23143597] [Full Text: https://doi.org/10.1038/ng.2468]
Lyden, D., Young, A. Z., Zagzag, D., Yan, W., Gerald, W., O'Reilly, R., Bader, B. L., Hynes, R. O., Zhuang, Y., Manova, K., Benezra, R. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401: 670-677, 1999. [PubMed: 10537105] [Full Text: https://doi.org/10.1038/44334]
Pan, L., Sato, S., Frederick, J. P., Sun, X.-H., Zhuang, Y. Impaired immune responses and B-cell proliferation in mice lacking the Id3 gene. Molec. Cell. Biol. 19: 5969-5980, 1999. [PubMed: 10454544] [Full Text: https://doi.org/10.1128/MCB.19.9.5969]
Richter, J., Schlesner, M., Hoffmann, S., Kreuz, M., Leich, E., Burkhardt, B., Rosolowski, M., Ammerpohl, O., Wagener, R., Bernhart, S. H., Lenze, D., Szczepanowski, M., and 44 others. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nature Genet. 44: 1316-1320, 2012. [PubMed: 23143595] [Full Text: https://doi.org/10.1038/ng.2469]
White, P. S., Maris, J. M., Beltinger, C., Sulman, E., Marshall, H. N., Fujimori, M., Kaufman, B. A., Biegel, J. A., Allen, C., Hilliard, C., Valentine, M. B., Look, A. T., Enomoto, H., Sakiyama, S., Brodeur, G. M. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3. Proc. Nat. Acad. Sci. 92: 5520-5524, 1995. [PubMed: 7777541] [Full Text: https://doi.org/10.1073/pnas.92.12.5520]
Yeh, K., Lim, R. W. Genomic organization and promoter analysis of the murine Id3 gene. Gene 254: 163-171, 2000. [PubMed: 10974547] [Full Text: https://doi.org/10.1016/s0378-1119(00)00274-2]