inhibitor of differentiation protein 2


Summary: A negative regulator of BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS. It plays a role in regulating IMMUNOGLOBULIN E expression.

Top Publications

  1. Sugai M, Gonda H, Kusunoki T, Katakai T, Yokota Y, Shimizu A. Essential role of Id2 in negative regulation of IgE class switching. Nat Immunol. 2003;4:25-30 pubmed
    ..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. ..
  2. Buitenhuis M, van Deutekom H, Verhagen L, Castor A, Jacobsen S, Lammers J, et al. Differential regulation of granulopoiesis by the basic helix-loop-helix transcriptional inhibitors Id1 and Id2. Blood. 2005;105:4272-81 pubmed
    ..These data demonstrate that both Id1 and Id2 play a critical, although differential role in granulopoiesis. ..
  3. Nishimori H, Sasaki Y, Yoshida K, Irifune H, Zembutsu H, Tanaka T, et al. The Id2 gene is a novel target of transcriptional activation by EWS-ETS fusion proteins in Ewing family tumors. Oncogene. 2002;21:8302-9 pubmed
    ..Considering these previous studies, our data suggest that the oncogenic effect of EWS-ETS may be mediated in part by up-regulating Id2 expression. doi:10.1038/sj.onc.1206025 ..
  4. Yates P, Atherton G, Deed R, Norton J, Sharrocks A. Id helix-loop-helix proteins inhibit nucleoprotein complex formation by the TCF ETS-domain transcription factors. EMBO J. 1999;18:968-76 pubmed
    ..Therefore, our results demonstrate a novel facet of Id function in the coordination of mitogenic signalling and cell cycle entry. ..
  5. Hou T, Ward S, Murad J, Watson N, Israel M, Duffield G. ID2 (inhibitor of DNA binding 2) is a rhythmically expressed transcriptional repressor required for circadian clock output in mouse liver. J Biol Chem. 2009;284:31735-45 pubmed publisher
    ..These data reveal a role for the transcriptional repressor ID2 as a circadian output regulator in the periphery. ..
  6. Onken M, Ehlers J, Worley L, Makita J, Yokota Y, Harbour J. Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. Cancer Res. 2006;66:4602-9 pubmed
    ..These findings reveal new roles for Id2 and E-cadherin in uveal melanoma progression, and they identify potential targets for therapeutic intervention. ..
  7. Kurland J, Tansey W. Myc-mediated transcriptional repression by recruitment of histone deacetylase. Cancer Res. 2008;68:3624-9 pubmed publisher
    ..These results describe a mechanistic role for MbIII in transcription, and reveal that recruitment of HDAC3 is a process by which Myc represses gene activity. ..
  8. Fukuma M, Okita H, Hata J, Umezawa A. Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma. Oncogene. 2003;22:1-9 pubmed
    ..In the present study, we suggest that Id2 is a target of the chimeric proteins and that the c-myc/Id2 pathway plays a pivotal role in the tumorigenic processes provoked by EWS/ets proteins. ..
  9. Roberts E, Deed R, Inoue T, Norton J, Sharrocks A. Id helix-loop-helix proteins antagonize pax transcription factor activity by inhibiting DNA binding. Mol Cell Biol. 2001;21:524-33 pubmed
    ..Our results therefore demonstrate a novel facet of Id function in regulating cellular differentiation by functionally antagonizing the action of members of the Pax transcription factor family. ..

More Information


  1. Ji M, Li H, Suh H, Klarmann K, Yokota Y, Keller J. Id2 intrinsically regulates lymphoid and erythroid development via interaction with different target proteins. Blood. 2008;112:1068-77 pubmed publisher
    ..1 and modulating PU.1 and GATA-1 activities. We conclude that Id2 regulates lymphoid and erythroid development via interaction with different target proteins. ..
  2. Heinz L, Platzer B, Reisner P, Jörgl A, Taschner S, Göbel F, et al. Differential involvement of PU.1 and Id2 downstream of TGF-beta1 during Langerhans-cell commitment. Blood. 2006;107:1445-53 pubmed
    ..Since TGF-beta1 represses a default monocyte pathway of common progenitor cells, PU.1 and Id2 seem to modulate lineage options of M/LC precursors, downstream of TGF-beta1. ..
  3. Benezra R, Rafii S, Lyden D. The Id proteins and angiogenesis. Oncogene. 2001;20:8334-41 pubmed
    ..This section of the review issue will focus on the key observations which have led to these conclusions, speculations about potential mechanisms and the outlook for potential therapeutic interventions. ..
  4. Park K, Waki H, Villanueva C, Monticelli L, Hong C, Kang S, et al. Inhibitor of DNA binding 2 is a small molecule-inducible modulator of peroxisome proliferator-activated receptor-gamma expression and adipocyte differentiation. Mol Endocrinol. 2008;22:2038-48 pubmed publisher
    ..These results outline a role for Id2 in the modulation of PPARgamma expression and adipogenesis and underscore the utility of adipogenic small molecules as tools to dissect adipocyte biology. ..
  5. Maw M, Fujimoto J, Tamaya T. Overexpression of inhibitor of DNA-binding (ID)-1 protein related to angiogenesis in tumor advancement of ovarian cancers. BMC Cancer. 2009;9:430 pubmed publisher
    ..Moreover, ID-1 expression levels correlated with microvessel counts. Therefore, ID-1 might work on tumor advancement via angiogenesis and is considered to be a candidate for a prognostic indicator in ovarian cancers. ..
  6. Paolella B, Havrda M, Mantani A, Wray C, Zhang Z, Israel M. p53 directly represses Id2 to inhibit the proliferation of neural progenitor cells. Stem Cells. 2011;29:1090-101 pubmed publisher
    ..These findings indicate that Id2 functions as a proproliferative gene that antagonizes p53-mediated cell cycle regulation in NPCs and may contribute to the malignant proliferation of glioma-derived tumor stem cells. ..
  7. Hacker C, Kirsch R, Ju X, Hieronymus T, Gust T, Kuhl C, et al. Transcriptional profiling identifies Id2 function in dendritic cell development. Nat Immunol. 2003;4:380-6 pubmed
    ..We also show that Id2 represses B cell genes in DCs. These findings reveal a TGF-beta-Id2 signaling pathway in DCs and suggest a mechanism by which Id2 affects the lineage choice of B cell and DC progenitors. ..
  8. Boos M, Yokota Y, Eberl G, Kee B. Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J Exp Med. 2007;204:1119-30 pubmed
    ..Our findings redefine the essential functions of Id2 in lymphoid development and provide insight into the dynamic regulation of E and Id proteins during this process. ..
  9. Wazir U, Jiang W, Sharma A, Newbold R, Mokbel K. The mRNA expression of inhibitors of DNA binding-1 and -2 is associated with advanced tumour stage and adverse clinical outcome in human breast cancer. Anticancer Res. 2013;33:2179-83 pubmed
    ..Inhibitors of DNA binding (ID) are known to have a role in embryogenesis and oncogenesis. In this study, we analyzed the role of ID1 and ID2 in breast cancer, by assessing associations of mRNA expression with clinicopathological parameters...
  10. Spits H, Di Santo J. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2011;12:21-7 pubmed publisher
    ..Analogous to helper T cell subsets, these evolutionarily conserved yet distinct ILCs seem to have important roles in protective immunity, and their dysregulation can promote immune pathology. ..
  11. Biggs J, Murphy E, Israel M. A human Id-like helix-loop-helix protein expressed during early development. Proc Natl Acad Sci U S A. 1992;89:1512-6 pubmed
    ..These findings suggest that Id-2 is an inhibitor of tissue-specific gene expression, although its distinctive pattern of expression during development suggests a role different from that of Id. ..
  12. Iavarone A, Garg P, Lasorella A, Hsu J, Israel M. The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes Dev. 1994;8:1270-84 pubmed
  13. Lian R, Kumar V. Murine natural killer cell progenitors and their requirements for development. Semin Immunol. 2002;14:453-60 pubmed
    ..1 has a somewhat selective role. In addition, recent studies have identified T/NK progenitors (T/NKPs) in the fetal liver that precede migration to the fetal thymus as well as the earliest committed NK precursors in the bone marrow. ..
  14. Yuen H, Chan Y, Chan K, Chu Y, Wong M, Law S, et al. Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma. Br J Cancer. 2007;97:1409-15 pubmed
    ..Our results suggest that Id-1 may promote distant metastasis in ESCC, and both Id-1 and Id-2 may be used for prognostication for ESCC patients. ..
  15. Iavarone A, King E, Dai X, Leone G, Stanley E, Lasorella A. Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Nature. 2004;432:1040-5 pubmed
    ..1, a master regulator of macrophage differentiation. Thus, Rb has a cell autonomous function in fetal liver macrophages, and restrains Id2 in these cells in order to implement definitive erythropoiesis. ..
  16. Kondo M, Cubillo E, Tobiume K, Shirakihara T, Fukuda N, Suzuki H, et al. A role for Id in the regulation of TGF-beta-induced epithelial-mesenchymal transdifferentiation. Cell Death Differ. 2004;11:1092-101 pubmed
  17. Lasorella A, Noseda M, Beyna M, Yokota Y, Iavarone A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature. 2000;407:592-8 pubmed
    ..Thus, a dual connection links Id2 and Rb: during normal cell-cycle, Rb prohibits the action of Id2 on its natural targets, but oncogenic activation of the Myc-Id2 transcriptional pathway overrides the tumour-suppressor function of Rb. ..
  18. Pistilli E, Siu P, Alway S. Molecular regulation of apoptosis in fast plantaris muscles of aged rats. J Gerontol A Biol Sci Med Sci. 2006;61:245-55 pubmed
    ..These data suggest that a pro-apoptotic environment may contribute to aging-associated atrophy in fast skeletal muscle, but apoptotic signaling differs by age. ..
  19. Gonda H, Sugai M, Nambu Y, Katakai T, Agata Y, Mori K, et al. The balance between Pax5 and Id2 activities is the key to AID gene expression. J Exp Med. 2003;198:1427-37 pubmed
    ..Finally, enforced expression of Pax5 induces AID transcription in pro-B cell lines. Our results provide evidence that the balance between Pax5 and Id2 activities has a key role in AID gene expression. ..
  20. Duffield G, Watson N, Mantani A, Peirson S, Robles Murguia M, Loros J, et al. A role for Id2 in regulating photic entrainment of the mammalian circadian system. Curr Biol. 2009;19:297-304 pubmed publisher
    ..These data suggest that the Id genes may be important for entrainment and operation of the mammalian circadian system, potentially acting through BMAL1 and CLOCK targets. ..
  21. Saika S, Ikeda K, Yamanaka O, Flanders K, Ohnishi Y, Nakajima Y, et al. Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice. Am J Physiol Cell Physiol. 2006;290:C282-9 pubmed
    ..Gene transfer of BMP-7, Id2, or Id3 delayed injury-induced EMT of lens epithelial cells and subsequent sealing of the capsular break with fibrous tissue in mice. ..
  22. Desprez P, Sumida T, Coppe J. Helix-loop-helix proteins in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2003;8:225-39 pubmed
    ..The purpose of this review is to summarize the evidence implicating HLH proteins in the regulation of normal and transformed mammary epithelial cell phenotypes. ..
  23. Moldes M, Boizard M, Liepvre X, Feve B, Dugail I, Pairault J. 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 adip. Biochem J. 1999;344 Pt 3:873-80 pubmed
    ..Taken together, our data show that Id products are functionally involved in modulating ADD1/SREBP-1c transcriptional activity, and thus lipogenesis in adipocytes. ..
  24. Rollin J, Blechet C, Regina S, Tenenhaus A, Guyetant S, Gidrol X. The intracellular localization of ID2 expression has a predictive value in non small cell lung cancer. PLoS ONE. 2009;4:e4158 pubmed publisher
    ..036). These results suggest that ID2 could be involved in tumor dedifferentiation processes of NSCLC, and could be used as prognostic marker for patients with poorly differentiated tumors. ..
  25. Kee B, Murre C. Induction of early B cell factor (EBF) and multiple B lineage genes by the basic helix-loop-helix transcription factor E12. J Exp Med. 1998;188:699-713 pubmed
    ..Our data demonstrate that, in the context of this macrophage line, E12 induces expression of EBF and together these transcription factors coordinately regulate numerous B lineage-associated genes. ..
  26. Kusunoki T, Sugai M, Katakai T, Omatsu Y, Iyoda T, Inaba K, et al. TH2 dominance and defective development of a CD8+ dendritic cell subset in Id2-deficient mice. J Allergy Clin Immunol. 2003;111:136-42 pubmed
    ..Id2 is an indispensable regulator of the TH1/TH2 balance, possibly through the proper development of CD8alpha+ DCs, and could be a novel target to treat allergic diseases. ..
  27. Russell R, Lasorella A, Dettin L, Iavarone A. Id2 drives differentiation and suppresses tumor formation in the intestinal epithelium. Cancer Res. 2004;64:7220-5 pubmed
    ..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. ..
  28. Ciarapica R, Annibali D, Raimondi L, Savino M, Nasi S, Rota R. Targeting Id protein interactions by an engineered HLH domain induces human neuroblastoma cell differentiation. Oncogene. 2009;28:1881-91 pubmed publisher
    ..Targeting Id dimerization may therefore be effective for triggering differentiation and restraining neuroblastoma cell tumorigenicity. ..
  29. Rawlins E, Clark C, Xue Y, Hogan B. The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development. 2009;136:3741-5 pubmed publisher
    ..Taken together, this evidence supports a model in which the distal tip of the developing lung contains a multipotent epithelial population, the fate of which changes during development. ..
  30. Coppe J, Itahana Y, Moore D, Bennington J, Desprez P. Id-1 and Id-2 proteins as molecular markers for human prostate cancer progression. Clin Cancer Res. 2004;10:2044-51 pubmed
    ..We propose that both Id-1 and Id-2 proteins control prostate cancer cell phenotypes and could serve as molecular markers of aggressive human prostate cancer. ..
  31. Yuen H, Chua C, Chan Y, Wong Y, Wang X, Chan K. Id proteins expression in prostate cancer: high-level expression of Id-4 in primary prostate cancer is associated with development of metastases. Mod Pathol. 2006;19:931-41 pubmed
    ..150-8.987, P=0.026). Our results suggest that in prostate cancer patients, differential Id proteins expressions may be a useful marker for poor prognosis, and Id-4 may be a potential prognostic marker for distant metastasis. ..
  32. Morrow M, Mayer E, Perez C, Adlam M, Siu G. Overexpression of the Helix-Loop-Helix protein Id2 blocks T cell development at multiple stages. Mol Immunol. 1999;36:491-503 pubmed
    ..Thus, overexpression of the Id2 protein has profound effects on T cell development and oncogenesis, consistent with the hypothesis that the bHLH proteins play critical roles in these processes. ..
  33. Kumar M, Hendrix J, Johnson A, Owens G. Smooth muscle alpha-actin gene requires two E-boxes for proper expression in vivo and is a target of class I basic helix-loop-helix proteins. Circ Res. 2003;92:840-7 pubmed
  34. Ikawa T, Fujimoto S, Kawamoto H, Katsura Y, Yokota Y. Commitment to natural killer cells requires the helix-loop-helix inhibitor Id2. Proc Natl Acad Sci U S A. 2001;98:5164-9 pubmed
    ..Expression of Id2 was correlated with p-NK activity. Our results suggest that Id2 is indispensable in thymic NK cell development, where it most probably restricts bipotent T/NK progenitors to the NK cell lineage. ..
  35. Mori S, Inoshima K, Shima Y, Schmidt E, Yokota Y. Forced expression of cyclin D1 does not compensate for Id2 deficiency in the mammary gland. FEBS Lett. 2003;551:123-7 pubmed
    ..These results suggest that Id2 acts downstream or independently of cyclin D1 in the control of mammary cell proliferation during pregnancy. ..
  36. Grønning L, Tingsabadh R, Hardy K, Dalen K, Jat P, Gnudi L, et al. Glucose induces increases in levels of the transcriptional repressor Id2 via the hexosamine pathway. Am J Physiol Endocrinol Metab. 2006;290:E599-606 pubmed
    ..In summary, these studies define a new mechanism by which glucose uses the hexosamine pathway to regulate gene expression by increasing levels of a transcriptional repressor. ..
  37. Miyake S, Yanagisawa Y, Yuasa Y. A novel EID-1 family member, EID-2, associates with histone deacetylases and inhibits muscle differentiation. J Biol Chem. 2003;278:17060-5 pubmed
    ..These results indicate a new family of differentiation inhibitors, although there are several differences in the biochemical mechanisms between EID-2 and EID-1. ..
  38. Riechmann V, van Crüchten I, Sablitzky F. The expression pattern of Id4, a novel dominant negative helix-loop-helix protein, is distinct from Id1, Id2 and Id3. Nucleic Acids Res. 1994;22:749-55 pubmed
    ..Comparison of the expression patterns of the four mouse dnHLH genes revealed that Id4 expression differs from the more restricted expression of Id2 as well as from the widespread expression of Id1 and Id3. ..
  39. Martinsen B, Bronner Fraser M. Neural crest specification regulated by the helix-loop-helix repressor Id2. Science. 1998;281:988-91 pubmed
    ..In addition, overexpression of Id2 resulted in overgrowth and premature neurogenesis of the dorsal neural tube. These results suggest that Id2 may allocate ectodermal precursors into neural rather than epidermal lineages. ..
  40. Ward S, Fernando S, Hou T, Duffield G. The transcriptional repressor ID2 can interact with the canonical clock components CLOCK and BMAL1 and mediate inhibitory effects on mPer1 expression. J Biol Chem. 2010;285:38987-9000 pubmed publisher
    ..These data provide the basis for a molecular mechanism through which ID2 could regulate aspects of both clock input and output through a time-of-day specific interaction with CLOCK and BMAL1. ..
  41. Chong S, Nguyen T, Chu L, Jiang Y, Korzh V. Zebrafish id2 developmental expression pattern contains evolutionary conserved and species-specific characteristics. Dev Dyn. 2005;234:1055-63 pubmed
    ..Furthermore, we show that expression of id2 is repressed in mind bomb mutants, suggesting a role of Notch upstream of Id2. ..
  42. Li X, Luo Y, Starremans P, McNamara C, Pei Y, Zhou J. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat Cell Biol. 2005;7:1202-12 pubmed
    ..Inhibition of Id2 expression by RNA interference corrects the hyperproliferative phenotype of PC1 mutant cells. We propose that Id2 has a crucial role in cell-cycle regulation that is mediated by PC1 and PC2. ..
  43. Renne C, Martin Subero J, Eickernjäger M, Hansmann M, Kuppers R, Siebert R, et al. Aberrant expression of ID2, a suppressor of B-cell-specific gene expression, in Hodgkin's lymphoma. Am J Pathol. 2006;169:655-64 pubmed
  44. Itahana Y, Singh J, Sumida T, Coppe J, Parrinello S, Bennington J, et al. Role of Id-2 in the maintenance of a differentiated and noninvasive phenotype in breast cancer cells. Cancer Res. 2003;63:7098-105 pubmed
  45. Ginhoux F, Liu K, Helft J, Bogunovic M, Greter M, Hashimoto D, et al. The origin and development of nonlymphoid tissue CD103+ DCs. J Exp Med. 2009;206:3115-30 pubmed publisher
    ..Our results reveal that nonlymphoid tissue CD103(+) DCs and lymphoid organ CD8(+) DCs derive from the same precursor and follow a related differentiation program. ..
  46. Liu J, Shi W, Warburton D. A cysteine residue in the helix-loop-helix domain of Id2 is critical for homodimerization and function. Biochem Biophys Res Commun. 2000;273:1042-7 pubmed
  47. Kurooka H, Nakahiro T, Mori K, Sano K, Yokota Y. BMP signaling is responsible for serum-induced Id2 expression. Biochem Biophys Res Commun. 2012;420:281-7 pubmed publisher
    ..Thus, we concluded that BMP signaling is primarily responsible for the serum-induced Id2 expression. Our results also suggest that some of the cellular effects caused by serum are mediated through BMP signaling. ..
  48. Liu Z, Chen J, Luo W, Yang H, Wu A, Zhen Y, et al. Overexpressed DNA-binding protein inhibitor 2 as an unfavorable prognosis factor promotes cell proliferation in nasopharyngeal carcinoma. Acta Biochim Biophys Sin (Shanghai). 2012;44:503-12 pubmed publisher
    ..Our study demonstrated that over-expression of ID2 protein is an unfavorable prognostic factor which promotes cell proliferation in NPC. ..
  49. Seillet C, Jackson J, Markey K, Brady H, Hill G, MacDonald K, et al. CD8?+ DCs can be induced in the absence of transcription factors Id2, Nfil3, and Batf3. Blood. 2013;121:1574-83 pubmed publisher
    ..Collectively, these results uncover a previously undescribed pathway by which CD8?+ DCs emerge independent of Id2, Nfil3, and Batf3, but dependent on Irf8. ..
  50. Mori S, Nishikawa S, Yokota Y. Lactation defect in mice lacking the helix-loop-helix inhibitor Id2. EMBO J. 2000;19:5772-81 pubmed
    ..A decrease in the DNA binding activity of Stat5 was also observed in Id2(-/-) mammary glands at 7 days post-coitus. Our results indicate an indispensable role of Id2 in pregnant mammary glands. ..
  51. Ji A, Dao D, Chen J, MacLellan W. EID-2, a novel member of the EID family of p300-binding proteins inhibits transactivation by MyoD. Gene. 2003;318:35-43 pubmed
    ..These data suggest that EID-1 and -2 represent a novel family of proteins that negatively regulate differentiation through a p300-dependent mechanism. ..
  52. Coma S, Amin D, Shimizu A, Lasorella A, Iavarone A, Klagsbrun M. Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F. Cancer Res. 2010;70:3823-32 pubmed publisher
  53. Lasorella A, Iavarone A. The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system. Proc Natl Acad Sci U S A. 2006;103:4976-81 pubmed
    ..These data indicate that ENH contributes to differentiation of the nervous system through cytoplasmic sequestration of Id2. They also suggest that ENH is a restraining factor of the oncogenic activity of Id proteins in neural tumors. ..