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Gene Review

Id2  -  inhibitor of DNA binding 2

Mus musculus

Synonyms: AI255428, C78922, DNA-binding protein inhibitor ID-2, Id-2, Idb2, ...
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Disease relevance of Id2

  • Role of Id-2 in the maintenance of a differentiated and noninvasive phenotype in breast cancer cells [1].
  • To assess the functional relevance of these correlations, we used an adenovirus vector to maintain Id-2 protein expression in cultured cytotrophoblasts [2].
  • Moreover, little Id-2 protein expression is detectable in human biopsies from aggressive and invasive carcinomas in comparison with in situ carcinomas [1].
  • In cases when cytotrophoblast differentiation was compromised (in placentas from women with preeclampsia, or in cells grown under hypoxic conditions in culture), Id-2 expression was maintained [2].
  • Id2 might act as molecular safeguard to suppress IgE CSR to prevent serious complications such as allergic hypersensitivity during the normal course of immune responses [3].

High impact information on Id2

  • This review summarizes the current data and examines the various functions of E proteins and their antagonists, Id2 and Id3, throughout lymphoid maturation [4].
  • In the B cell lineage, the Id1 and Id2 genes are expressed in pro-B cells and down-regulated during differentiation [5].
  • Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2 [6].
  • Id2-/- mice lack lymph nodes and Peyer's patches [6].
  • Despite the lack of cortical innervation by thalamic axons, neocortical region-specific gene expression (Cadherin-6, EphA-7, Id-2, and RZR-beta) developed normally [7].

Biological context of Id2

  • Deletion analysis indicated that the C-terminal 15 amino acids of Id3 are critical for the full inhibitory activity while deleting up to 42 residues from the C-terminus of the related protein, Id2, did not affect its ability to inhibit the MCK reporter gene [8].
  • Id2 is also a more potent inhibitor of protein/DNA complex formation at the MCK-R enhancer E-box than Identified in vitro [9].
  • The balance between Pax5 and Id2 activities is the key to AID gene expression [10].
  • Id2 plays a critical role in breast differentiation and lactation [11].
  • In vitro studies with nuclear localization sequence-tagged Id2 revealed that the nuclear localization of Id2 itself is critical for the downregulation of p21 promoter activity [12].

Anatomical context of Id2

  • Surprisingly, while overexpression of Id2 resulted in inhibition of differentiation of Sol 8 myoblast cells, overexpression of Id4 did not [9].
  • Upon B cell activation, Id2 acts as a negative regulator to prevent potentially harmful effects brought about by excessive immunological reactions; one of its special roles is to maintain low serum concentrations of immunoglobulin E (IgE) [13].
  • During gastrulation, both Id1 and Id3 are expressed in the tissues derived from the inner cell mass from 5.5 dpc onward, whereas Id2 is expressed in tissues derived from trophoblasts [14].
  • During neurogenesis, the expression of each member of the Id family is present in an unique pattern along the dorsal-ventral axis of the neural tube: In the early stages of spinal cord development, both Id1 and Id2 are expressed in the roof plate, whereas Id3 is expressed both in the roof and the floor plates [14].
  • Id2 protein, which was most abundant in Sertoli cell nuclei, was also detectable in pachytene and diplotene spermatocytes, but as with Id4, it was absent from MI/MII cells [15].

Associations of Id2 with chemical compounds


Physical interactions of Id2

  • Thus, our data are the first to establish a direct requirement of basic helix-loop-helix inhibitors in driving differentiation and define an unexpected role for the retinoblastoma-binding protein Id2 in preventing tumor formation [19].

Regulatory relationships of Id2


Other interactions of Id2

  • Chimeric protein containing the N-terminal region of Id3 and the C-terminus of Id2 was also non-functional in transfected cells [8].
  • Here we have investigated the possibility that Id2 and/or Id4 can act in a similar manner [9].
  • As development progresses, the expression of both Id1 and Id3 is detected in the dividing neuroblasts, whereas Id2 and 4 are expressed in presumptive neurons which are undergoing maturation [14].
  • The Id2 protein does this by antagonizing E2A and Pax5 activities, both of which are required for proper B cell activation [13].
  • Thus, Rb has a cell autonomous function in fetal liver macrophages, and restrains Id2 in these cells in order to implement definitive erythropoiesis [21].

Analytical, diagnostic and therapeutic context of Id2


  1. Role of Id-2 in the maintenance of a differentiated and noninvasive phenotype in breast cancer cells. Itahana, Y., Singh, J., Sumida, T., Coppe, J.P., Parrinello, S., Bennington, J.L., Desprez, P.Y. Cancer Res. (2003) [Pubmed]
  2. Id-2 regulates critical aspects of human cytotrophoblast differentiation, invasion and migration. Janatpour, M.J., McMaster, M.T., Genbacev, O., Zhou, Y., Dong, J., Cross, J.C., Israel, M.A., Fisher, S.J. Development (2000) [Pubmed]
  3. Essential role of Id2 in negative regulation of IgE class switching. Sugai, M., Gonda, H., Kusunoki, T., Katakai, T., Yokota, Y., Shimizu, A. Nat. Immunol. (2003) [Pubmed]
  4. E protein function in lymphocyte development. Quong, M.W., Romanow, W.J., Murre, C. Annu. Rev. Immunol. (2002) [Pubmed]
  5. Constitutive expression of the Id1 gene impairs mouse B cell development. Sun, X.H. Cell (1994) [Pubmed]
  6. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Yokota, Y., Mansouri, A., Mori, S., Sugawara, S., Adachi, S., Nishikawa, S., Gruss, P. Nature (1999) [Pubmed]
  7. Early neocortical regionalization in the absence of thalamic innervation. Miyashita-Lin, E.M., Hevner, R., Wassarman, K.M., Martinez, S., Rubenstein, J.L. Science (1999) [Pubmed]
  8. 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]
  9. Differential biological activities of mammalian Id proteins in muscle cells. Melnikova, I.N., Bounpheng, M., Schatteman, G.C., Gilliam, D., Christy, B.A. Exp. Cell Res. (1999) [Pubmed]
  10. The balance between Pax5 and Id2 activities is the key to AID gene expression. Gonda, H., Sugai, M., Nambu, Y., Katakai, T., Agata, Y., Mori, K.J., Yokota, Y., Shimizu, A. J. Exp. Med. (2003) [Pubmed]
  11. A role for Id proteins in mammary gland physiology and tumorigenesis. de Candia, P., Benera, R., Solit, D.B. Adv. Cancer Res. (2004) [Pubmed]
  12. Receptor activator of NF-kappaB ligand regulates the proliferation of mammary epithelial cells via Id2. Kim, N.S., Kim, H.J., Koo, B.K., Kwon, M.C., Kim, Y.W., Cho, Y., Yokota, Y., Penninger, J.M., Kong, Y.Y. Mol. Cell. Biol. (2006) [Pubmed]
  13. Role of Id proteins in B lymphocyte activation: new insights from knockout mouse studies. Sugai, M., Gonda, H., Nambu, Y., Yokota, Y., Shimizu, A. J. Mol. Med. (2004) [Pubmed]
  14. Each member of the Id gene family exhibits a unique expression pattern in mouse gastrulation and neurogenesis. Jen, Y., Manova, K., Benezra, R. Dev. Dyn. (1997) [Pubmed]
  15. Stage- and subcellular-specific expression of Id proteins in male germ and Sertoli cells implicates distinctive regulatory roles for Id proteins during meiosis, spermatogenesis, and Sertoli cell function. Sablitzky, F., Moore, A., Bromley, M., Deed, R.W., Newton, J.S., Norton, J.D. Cell Growth Differ. (1998) [Pubmed]
  16. Nucleo-cytoplasmic shuttling of Id2, a negative regulator of basic helix-loop-helix transcription factors. Kurooka, H., Yokota, Y. J. Biol. Chem. (2005) [Pubmed]
  17. Impairment of intestinal intraepithelial lymphocytes in Id2 deficient mice. Kim, J.K., Takeuchi, M., Yokota, Y. Gut (2004) [Pubmed]
  18. 1alpha,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells. Fernandez-Garcia, N.I., Palmer, H.G., Garcia, M., Gonzalez-Martin, A., del Rio, M., Barettino, D., Volpert, O., Muñoz, A., Jimenez, B. Oncogene (2005) [Pubmed]
  19. Id2 drives differentiation and suppresses tumor formation in the intestinal epithelium. Russell, R.G., Lasorella, A., Dettin, L.E., Iavarone, A. Cancer Res. (2004) [Pubmed]
  20. Id genes are direct targets of bone morphogenetic protein induction in embryonic stem cells. Hollnagel, A., Oehlmann, V., Heymer, J., Rüther, U., Nordheim, A. J. Biol. Chem. (1999) [Pubmed]
  21. Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Iavarone, A., King, E.R., Dai, X.M., Leone, G., Stanley, E.R., Lasorella, A. Nature (2004) [Pubmed]
  22. Id helix-loop-helix proteins negatively regulate TRANCE-mediated osteoclast differentiation. Lee, J., Kim, K., Kim, J.H., Jin, H.M., Choi, H.K., Lee, S.H., Kook, H., Kim, K.K., Yokota, Y., Lee, S.Y., Choi, Y., Kim, N. Blood (2006) [Pubmed]
  23. Inhibitors of differentiation and DNA binding (Ids) regulate Math1 and hair cell formation during the development of the organ of Corti. Jones, J.M., Montcouquiol, M., Dabdoub, A., Woods, C., Kelley, M.W. J. Neurosci. (2006) [Pubmed]
  24. Initiation of NALT organogenesis is independent of the IL-7R, LTbetaR, and NIK signaling pathways but requires the Id2 gene and CD3(-)CD4(+)CD45(+) cells. Fukuyama, S., Hiroi, T., Yokota, Y., Rennert, P.D., Yanagita, M., Kinoshita, N., Terawaki, S., Shikina, T., Yamamoto, M., Kurono, Y., Kiyono, H. Immunity (2002) [Pubmed]
  25. Mammary epithelial cells are not able to undergo pregnancy-dependent differentiation in the absence of the helix-loop-helix inhibitor Id2. Miyoshi, K., Meyer, B., Gruss, P., Cui, Y., Renou, J.P., Morgan, F.V., Smith, G.H., Reichenstein, M., Shani, M., Hennighausen, L., Robinson, G.W. Mol. Endocrinol. (2002) [Pubmed]
  26. Identification of inhibitor-of-differentiation 2 (Id2) as a modulator of neuronal apoptosis. Gleichmann, M., Buchheim, G., El-Bizri, H., Yokota, Y., Klockgether, T., Kügler, S., Bähr, M., Weller, M., Schulz, J.B. J. Neurochem. (2002) [Pubmed]
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