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Gene Review

Id3  -  inhibitor of DNA binding 3

Mus musculus

Synonyms: DNA-binding protein inhibitor ID-3, HLH462, Hlh462, ID-like protein inhibitor HLH 462, Id-3, ...
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Disease relevance of Id3


Psychiatry related information on Id3

  • Id3, a member of the Id multigene family of dominant negative helix-loop-helix transcription factors, is induced sharply in murine fibroblasts by serum growth factors [4].

High impact information on Id3

  • This review summarizes the current data and examines the various functions of E proteins and their antagonists, Id2 and Id3, throughout lymphoid maturation [5].
  • The Id1-Id3 double knockout mice also display vascular malformations in the forebrain and an absence of branching and sprouting of blood vessels into the neuroectoderm [6].
  • Id3(-/-) mice were found to have autoantibodies, lymphocytic infiltrates in, and decreased secretion by exocrine glands [7].
  • Blimp-1 initiated this cascade of gene expression changes by directly repressing genes encoding several transcription factors, including Spi-B and Id3, that regulate signaling by the B cell receptor [8].
  • Finally, we show that E2A and Id3 interact genetically to regulate thymocyte development [9].

Chemical compound and disease context of Id3

  • Analyses using insulinoma cells revealed that Id-1 and Id-3 mRNA concentrations peaked 30 min after glucose was added, returned to near basal concentrations by 2 h and then progressively increased for 24 h [10].

Biological context of Id3

  • Finally, mutagenesis experiments showed that the differences between Id1 and Id3 binding map to three amino acids in the first helix and to a small cluster of upstream residues [11].
  • Inhibition of muscle-specific gene expression by Id3: requirement of the C-terminal region of the protein for stable expression and function [12].
  • Overexpression of Id3 efficiently inhibited the MyoD-mediated activation of the muscle-specific creatine kinase (MCK) reporter gene [12].
  • On the basis of these data, it is speculated that CSN-mediated phosphorylation inhibits ubiquitination of Id1 and Id3 [13].
  • Expression of the helix-loop-helix gene Id3 during murine embryonic development [14].

Anatomical context of Id3

  • Consistent with its putative role as an inhibitor of differentiation, Id3 mRNA was detected in proliferating skeletal muscle cells, was further induced by basic fibroblast growth factor (bFGF) and was down-regulated in differentiated muscle cultures [12].
  • The inhibitors of CSN associated kinases, curcumin and emodin, significantly induce ubiquitination and proteasome-dependent degradation of transiently expressed Id3 in HeLa cells [13].
  • We have investigated the potential role of Id3 in the control of muscle cell differentiation [15].
  • Id3 mRNA is expressed at a high level in proliferating myoblasts and is down-regulated following induction of differentiation [15].
  • Id3 transcripts are present throughout embryogenesis and are found in neural cells as well as in cartilage primordia and in epithelial cells lining a variety of organs [16].

Associations of Id3 with chemical compounds


Physical interactions of Id3

  • Additional far Western and pull-down studies with Id3 support our two-hybrid data and show that the transcription regulator can bind to CSN5 and CSN7 [13].
  • However, stimuli that mimic pre-T cell receptor (TCR) signaling in committed T cell precursors inhibit E47 DNA-binding activity and induce the bHLH inhibitor Id3 through a mitogen-activated protein kinase kinase-dependent pathway [21].

Regulatory relationships of Id3

  • Finally, we show by in situ hybridization that the Id3 mRNA is co-expressed with the myogenic regulatory factor myogenin in somites and developing muscle during embryogenesis, although unlike the myogenic regulatory factors, Id3 is also expressed in many other locations in the embryo [15].
  • In conclusion, these data demonstrate that BMP-7 antagonizes the TGF-beta1-dependent fibrogenic activity of mouse pulmonary myofibroblastic cells by inducing Id2 and Id3 [22].
  • Significant increases in TNF alpha-induced Id2 and Id3 mRNA were observed in the ventricular/subventricular zone, cingulum and corpus callosum [23].

Other interactions of Id3

  • Here we report that Id1, Id2, and Id3 are induced shortly after serum stimulation in arrested NIH 3T3 [24].
  • Within the detection limits of in situ hybridization, Id4 and Id3 expression is mutually exclusive in neural precursor cells of the developing brain, suggesting distinct regulatory functions for these dnHLH proteins during neurogenesis [16].
  • Chimeric protein containing the N-terminal region of Id3 and the C-terminus of Id2 was also non-functional in transfected cells [12].
  • Furthermore, previous experiments suggested a mutually exclusive expression of the proto-oncogene N-myc an Id3 [14].
  • Curcumin increased Id3-ubiquitin conjugate formation, as shown by Western blotting and His-pull-downs [13].

Analytical, diagnostic and therapeutic context of Id3

  • Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts [6].
  • Adoptive transfer experiment indicated a T cell intrinsic role for Id3 in the development of Sjogren's symptoms [3].
  • Furthermore, genetic ablation of T cells or neonatal 3 day thymectomy in Id3-deficient mice showed a rescue of disease symptoms, suggesting a thymic origin of autoimmune T cells [3].
  • Constitutive expression of Id3 completely blocks development of CD34+ cells into T cells in a fetal thymic organ culture (FTOC) [25].


  1. A role for Id proteins in mammary gland physiology and tumorigenesis. de Candia, P., Benera, R., Solit, D.B. Adv. Cancer Res. (2004) [Pubmed]
  2. Utilization of bone marrow-derived endothelial cell precursors in spontaneous prostate tumors varies with tumor grade. Li, H., Gerald, W.L., Benezra, R. Cancer Res. (2004) [Pubmed]
  3. A T cell intrinsic role of Id3 in a mouse model for primary Sjogren's syndrome. Li, H., Dai, M., Zhuang, Y. Immunity (2004) [Pubmed]
  4. E2A basic-helix-loop-helix transcription factors are negatively regulated by serum growth factors and by the Id3 protein. Loveys, D.A., Streiff, M.B., Kato, G.J. Nucleic Acids Res. (1996) [Pubmed]
  5. E protein function in lymphocyte development. Quong, M.W., Romanow, W.J., Murre, C. Annu. Rev. Immunol. (2002) [Pubmed]
  6. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. 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. Nature (1999) [Pubmed]
  7. Id3 knockout mice as a new model for sjogren's syndrome: only a T cell defect or more? Versnel, M.A. Immunity (2004) [Pubmed]
  8. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Shaffer, A.L., Lin, K.I., Kuo, T.C., Yu, X., Hurt, E.M., Rosenwald, A., Giltnane, J.M., Yang, L., Zhao, H., Calame, K., Staudt, L.M. Immunity (2002) [Pubmed]
  9. Thymocyte selection is regulated by the helix-loop-helix inhibitor protein, Id3. Rivera, R.R., Johns, C.P., Quan, J., Johnson, R.S., Murre, C. Immunity (2000) [Pubmed]
  10. Glucose and other insulin secretagogues induce, rather than inhibit, expression of Id-1 and Id-3 in pancreatic islet beta cells. Wice, B.M., Bernal-Mizrachi, E., Permutt, M.A. Diabetologia (2001) [Pubmed]
  11. Differential interactions of Id proteins with basic-helix-loop-helix transcription factors. Langlands, K., Yin, X., Anand, G., Prochownik, E.V. J. Biol. Chem. (1997) [Pubmed]
  12. Inhibition of muscle-specific gene expression by Id3: requirement of the C-terminal region of the protein for stable expression and function. Chen, B., Han, B.H., Sun, X.H., Lim, R.W. Nucleic Acids Res. (1997) [Pubmed]
  13. Ubiquitin-dependent degradation of Id1 and Id3 is mediated by the COP9 signalosome. Berse, M., Bounpheng, M., Huang, X., Christy, B., Pollmann, C., Dubiel, W. J. Mol. Biol. (2004) [Pubmed]
  14. Expression of the helix-loop-helix gene Id3 during murine embryonic development. Ellmeier, W., Weith, A. Dev. Dyn. (1995) [Pubmed]
  15. Muscle cell differentiation is inhibited by the helix-loop-helix protein Id3. Melnikova, I.N., Christy, B.A. Cell Growth Differ. (1996) [Pubmed]
  16. Mutually exclusive expression of two dominant-negative helix-loop-helix (dnHLH) genes, Id4 and Id3, in the developing brain of the mouse suggests distinct regulatory roles of these dnHLH proteins during cellular proliferation and differentiation of the nervous system. Riechmann, V., Sablitzky, F. Cell Growth Differ. (1995) [Pubmed]
  17. Inhibitory helix-loop-helix transcription factors Id1/Id3 promote bone formation in vivo. Maeda, Y., Tsuji, K., Nifuji, A., Noda, M. J. Cell. Biochem. (2004) [Pubmed]
  18. Impaired immune responses and B-cell proliferation in mice lacking the Id3 gene. Pan, L., Sato, S., Frederick, J.P., Sun, X.H., Zhuang, Y. Mol. Cell. Biol. (1999) [Pubmed]
  19. Functional antagonism between inhibitor of DNA binding (Id) and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1c (ADD1/SREBP-1c) trans-factors for the regulation of fatty acid synthase promoter in adipocytes. Moldes, M., Boizard, M., Liepvre, X.L., Fève, B., Dugail, I., Pairault, J. Biochem. J. (1999) [Pubmed]
  20. Thrombin and NAD(P)H oxidase-mediated regulation of CD44 and BMP4-Id pathway in VSMC, restenosis, and atherosclerosis. Vendrov, A.E., Madamanchi, N.R., Hakim, Z.S., Rojas, M., Runge, M.S. Circ. Res. (2006) [Pubmed]
  21. Early thymocyte development is regulated by modulation of E2A protein activity. Engel, I., Johns, C., Bain, G., Rivera, R.R., Murre, C. J. Exp. Med. (2001) [Pubmed]
  22. BMP-7 opposes TGF-beta1-mediated collagen induction in mouse pulmonary myofibroblasts through Id2. Izumi, N., Mizuguchi, S., Inagaki, Y., Saika, S., Kawada, N., Nakajima, Y., Inoue, K., Suehiro, S., Friedman, S.L., Ikeda, K. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  23. Tumor necrosis factor-alpha regulation of the Id gene family in astrocytes and microglia during CNS inflammatory injury. Tzeng, S.F., Kahn, M., Liva, S., De Vellis, J. Glia (1999) [Pubmed]
  24. Id proteins control growth induction in mammalian cells. Barone, M.V., Pepperkok, R., Peverali, F.A., Philipson, L. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  25. Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3. Heemskerk, M.H., Blom, B., Nolan, G., Stegmann, A.P., Bakker, A.Q., Weijer, K., Res, P.C., Spits, H. J. Exp. Med. (1997) [Pubmed]
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