inhibitor of differentiation proteins


Summary: Inhibitor of differentiation proteins are negative regulators of BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS. They inhibit CELL DIFFERENTIATION and induce CELL PROLIFERATION by modulating different CELL CYCLE regulators.

Top Publications

  1. 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. ..
  2. 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. ..
  3. ALONZO E, Gottschalk R, Das J, Egawa T, Hobbs R, Pandolfi P, et al. Development of promyelocytic zinc finger and ThPOK-expressing innate gamma delta T cells is controlled by strength of TCR signaling and Id3. J Immunol. 2010;184:1268-79 pubmed publisher
    ..This study defines the factors that control the propensity of the immune system to produce potentially disease-causing T cell subsets. ..
  4. Ueda Hayakawa I, Mahlios J, Zhuang Y. Id3 restricts the developmental potential of gamma delta lineage during thymopoiesis. J Immunol. 2009;182:5306-16 pubmed publisher
    ..Our data indicates that Id3 suppresses Vgamma1.1 rearrangement and gammadelta lineage potential among T cell progenitors that have completed TCRbeta gene rearrangement without producing a functional TCRbeta protein. ..
  5. Kee B. E and ID proteins branch out. Nat Rev Immunol. 2009;9:175-84 pubmed publisher
  6. Noetzel E, Veeck J, Horn F, Hartmann A, Knuchel R, Dahl E. [Promoter methylation of ID4. A marker for recurrence-free survival in human breast cancer]. Pathologe. 2008;29 Suppl 2:319-27 pubmed publisher
    ..Thus, ID4 methylation status could serve as a prognostic biomarker in human breast cancer. ..
  7. Verykokakis M, Boos M, Bendelac A, Kee B. SAP protein-dependent natural killer T-like cells regulate the development of CD8(+) T cells with innate lymphocyte characteristics. Immunity. 2010;33:203-15 pubmed publisher
    ..Our findings reveal that accumulation of NKT-like cells promotes conventional CD8(+) thymocytes to acquire innate lymphocyte characteristics. ..
  8. de Candia P, Akram M, Benezra R, Brogi E. Id4 messenger RNA and estrogen receptor expression: inverse correlation in human normal breast epithelium and carcinoma. Hum Pathol. 2006;37:1032-41 pubmed
    ..Further investigations are required to define the functions of Id4 in the human normal breast and in mammary neoplasia. ..
  9. 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. ..

More Information


  1. Carey J, Asirvatham A, Galm O, Ghogomu T, Chaudhary J. Inhibitor of differentiation 4 (Id4) is a potential tumor suppressor in prostate cancer. BMC Cancer. 2009;9:173 pubmed publisher
  2. Maruyama T, Li J, Vaque J, Konkel J, Wang W, Zhang B, et al. Control of the differentiation of regulatory T cells and T(H)17 cells by the DNA-binding inhibitor Id3. Nat Immunol. 2011;12:86-95 pubmed publisher
    ..Therefore, a network of factors acts in a TGF-β-dependent manner to control Foxp3 expression and inhibit the development of T(H)17 cells. ..
  3. Chaudhary J, Johnson J, Kim G, Skinner M. Hormonal regulation and differential actions of the helix-loop-helix transcriptional inhibitors of differentiation (Id1, Id2, Id3, and Id4) in Sertoli cells. Endocrinology. 2001;142:1727-36 pubmed
    ..Id1 may act to maintain Sertoli cell growth potential, whereas Id2 and Id4 may be involved in the differentiation and hormone regulation of Sertoli cells. ..
  4. Kiewitz S, Cabrele C. Synthesis and conformational properties of protein fragments based on the Id family of DNA-binding and cell-differentiation inhibitors. Biopolymers. 2005;80:762-74 pubmed
    ..In contrast, it is suggested that the regions beyond this domain could rather play a destabilizing role, for example, by increasing the flexibility of the folded protein. ..
  5. Sakurai D, Tsuchiya N, Yamaguchi A, Okaji Y, Tsuno N, Kobata T, et al. Crucial role of inhibitor of DNA binding/differentiation in the vascular endothelial growth factor-induced activation and angiogenic processes of human endothelial cells. J Immunol. 2004;173:5801-9 pubmed
    ..Based on these findings, it was proposed that inhibition of expression and/or function of Id1 and Id3 may potentially be of therapeutic value for conditions associated with pathological angiogenesis. ..
  6. Shan L, Yu M, Qiu C, Snyderwine E. Id4 regulates mammary epithelial cell growth and differentiation and is overexpressed in rat mammary gland carcinomas. Am J Pathol. 2003;163:2495-502 pubmed
    ..The results implicate Id4 in rat mammary gland carcinogenesis and suggest that Id4 may contribute to carcinogenesis by inhibiting mammary epithelial cell differentiation and stimulating mammary epithelial cell growth. ..
  7. Kee B, Rivera R, Murre C. Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-beta. Nat Immunol. 2001;2:242-7 pubmed
    ..Our data show a key role for E proteins in lymphocyte survival and link the activity of E proteins, and their antagonists, to members of the TGF-beta family of cytokines. ..
  8. Kuzontkoski P, Mulligan Kehoe M, Harris B, Israel M. Inhibitor of DNA binding-4 promotes angiogenesis and growth of glioblastoma multiforme by elevating matrix GLA levels. Oncogene. 2010;29:3793-802 pubmed publisher
    ..Inhibition of MGP resulted in smaller and less vascularized xenografts. Our finding shows a novel function for ID4 in tumor angiogenesis, and identifies ID4 and MGP as possible therapeutic targets for GBM. ..
  9. Murad J, Place C, Ran C, Hekmatyar S, Watson N, Kauppinen R, et al. Inhibitor of DNA binding 4 (ID4) regulation of adipocyte differentiation and adipose tissue formation in mice. J Biol Chem. 2010;285:24164-73 pubmed publisher
    ..Our results demonstrate the importance of ID4 in adipocyte differentiation and the implications of this regulation for adipose tissue formation. ..
  10. Garrett Engele C, Tasch M, Hwang H, Fero M, Perlmutter R, Clurman B, et al. A mechanism misregulating p27 in tumors discovered in a functional genomic screen. PLoS Genet. 2007;3:e219 pubmed
    ..Thus, we have identified and characterized transcriptional repression of p27 by Id3 as a new mechanism decreasing p27 protein in tumors...
  11. Lauritsen J, Wong G, Lee S, Lefebvre J, Ciofani M, Rhodes M, et al. Marked induction of the helix-loop-helix protein Id3 promotes the gammadelta T cell fate and renders their functional maturation Notch independent. Immunity. 2009;31:565-75 pubmed publisher
    ..Taken together, these findings identify Id3 as a central player that controls both adoption of the gammadelta fate and its maturation in the thymus. ..
  12. 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. ..
  13. Li J, Maruyama T, Zhang P, Konkel J, Hoffman V, Zamarron B, et al. Mutation of inhibitory helix-loop-helix protein Id3 causes ?? T-cell lymphoma in mice. Blood. 2010;116:5615-21 pubmed publisher
    ..Our model will provide a tool for studying the molecular mechanisms and development of human ?? T-cell lymphoma. ..
  14. Riechmann V, Sablitzky F. 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 t. Cell Growth Differ. 1995;6:837-43 pubmed
    ..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. ..
  15. Yu L, Liu C, Vandeusen J, Becknell B, Dai Z, Wu Y, et al. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat Genet. 2005;37:265-74 pubmed
    ..We also identified Idb4 as a putative tumor-suppressor gene that is methylated in most mouse and human leukemias but in only a minority of other human cancers. ..
  16. Bounpheng M, Dimas J, Dodds S, Christy B. Degradation of Id proteins by the ubiquitin-proteasome pathway. FASEB J. 1999;13:2257-64 pubmed
    ..Bounpheng, M. A., Dimas, J. J., Dodds, S. G., Christy, B. A. Degradation of Id proteins by the ubiquitin-proteasome pathway. ..
  17. Reynaud Deonauth S, Zhang H, Afouda A, Taillefert S, Beatus P, Kloc M, et al. Notch signaling is involved in the regulation of Id3 gene transcription during Xenopus embryogenesis. Differentiation. 2002;69:198-208 pubmed
    ..The data presented here suggest that Notch control of differentiation may involve activation of transcription of Id, a negative regulator of bHLH transcription factors. ..
  18. Bellido M, Aventin A, Lasa A, Estivill C, Carnicer M, Pons C, et al. Id4 is deregulated by a t(6;14)(p22;q32) chromosomal translocation in a B-cell lineage acute lymphoblastic leukemia. Haematologica. 2003;88:994-1001 pubmed
    ..A genetic recombination between Alu-repeated sequences may not be the exclusive mechanism of generating pathogenic chromosomal translocations. ..
  19. Pagliuca A, Bartoli P, Saccone S, Della Valle G, Lania L. Molecular cloning of ID4, a novel dominant negative helix-loop-helix human gene on chromosome 6p21.3-p22. Genomics. 1995;27:200-3 pubmed
    ..Transfection experiments indicated that enforced expression of Id-4H protein inhibits the trans-activation of the muscle creatine kinase E-box enhancer by MyoD. Finally, we localized the ID4 gene to the chromosome 6p21-p22 region. ..
  20. Norton J, Atherton G. Coupling of cell growth control and apoptosis functions of Id proteins. Mol Cell Biol. 1998;18:2371-81 pubmed
    ..These findings highlight the close coupling between the G1 progression and apoptosis functions of Id proteins and hint at a common mechanism for this family of transcriptional regulators in cell determination. ..
  21. Rivera R, Johns C, Quan J, Johnson R, Murre C. Thymocyte selection is regulated by the helix-loop-helix inhibitor protein, Id3. Immunity. 2000;12:17-26 pubmed
    ..Finally, we show that E2A and Id3 interact genetically to regulate thymocyte development. These observations identify the HLH inhibitory protein Id3 as an essential component required for proper thymocyte maturation. ..
  22. Fontemaggi G, Dell Orso S, Trisciuoglio D, Shay T, Melucci E, Fazi F, et al. The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis. Nat Struct Mol Biol. 2009;16:1086-93 pubmed publisher
    ..These findings highlight the transcriptional axis mutant p53, E2F1 and ID4 as a still undefined molecular mechanism contributing to tumor neo-angiogenesis. ..
  23. Yokota Y. Id and development. Oncogene. 2001;20:8290-8 pubmed
    ..The topics discussed include neurogenesis, natural killer cell development, lymphoid organogenesis, mammary gland development and spermatogenesis. ..
  24. Gupta G, Perk J, Acharyya S, de Candia P, Mittal V, Todorova Manova K, et al. ID genes mediate tumor reinitiation during breast cancer lung metastasis. Proc Natl Acad Sci U S A. 2007;104:19506-11 pubmed
    ..These results shed light on the proliferative mechanisms that initiate metastatic colonization, and they implicate Id1 and Id3 as mediators of this malignant function in the TN subgroup of breast cancers. ..
  25. Maeda Y, Tsuji K, Nifuji A, Noda M. Inhibitory helix-loop-helix transcription factors Id1/Id3 promote bone formation in vivo. J Cell Biochem. 2004;93:337-44 pubmed
    ..Furthermore, Id1/Id3 heterozygous knock out mice suppressed BMP-induced bone formation in vivo. These results indicated that Id1 and Id3 are positive factors to promote bone formation in vivo. ..
  26. Russell L, Akasaka T, Majid A, Sugimoto K, Loraine Karran E, Nagel I, et al. t(6;14)(p22;q32): a new recurrent IGH@ translocation involving ID4 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood. 2008;111:387-91 pubmed
    ..This study defines a new subgroup of BCP-ALL characterized by ID4 over-expression and CDKN2A and PAX5 deletions. Preliminary survival data suggest that this subgroup may be associated with a good response to therapy. ..
  27. Haks M, Lefebvre J, Lauritsen J, Carleton M, Rhodes M, Miyazaki T, et al. Attenuation of gammadeltaTCR signaling efficiently diverts thymocytes to the alphabeta lineage. Immunity. 2005;22:595-606 pubmed
    ..Our data support a model whereby gammadelta versus alphabeta lineage commitment is controlled by TCR signal strength, which depends critically on the ERK MAPK-Egr pathway. ..
  28. Asirvatham A, Schmidt M, Chaudhary J. Non-redundant inhibitor of differentiation (Id) gene expression and function in human prostate epithelial cells. Prostate. 2006;66:921-35 pubmed
    ..A complex equilibrium between Id isoforms determines the cell fate. Id1 and Id3 target cellular proliferation, Id2 targets apoptosis, and Id4 may act as a potential tumor suppressor in prostate epithelial cells. ..
  29. Kulterer B, Friedl G, Jandrositz A, Sanchez Cabo F, Prokesch A, Paar C, et al. Gene expression profiling of human mesenchymal stem cells derived from bone marrow during expansion and osteoblast differentiation. BMC Genomics. 2007;8:70 pubmed
    ..With a variety of assays we could show that MSC represent a cell population which can be expanded for therapeutic applications. ..
  30. Perry S, Zhao Y, Nie L, Cochrane S, Huang Z, Sun X. Id1, but not Id3, directs long-term repopulating hematopoietic stem-cell maintenance. Blood. 2007;110:2351-60 pubmed
    ..These findings suggest a unique role for Id1 in LT-HSC maintenance and hematopoietic development. ..
  31. Lasorella A, Iavarone A, Israel M. Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins. Mol Cell Biol. 1996;16:2570-8 pubmed
  32. Yang H, Liu H, Liu G, Zhu H, Meng Q, Qu L, et al. Expression and prognostic values of Id-1 and Id-3 in gastric adenocarcinoma. J Surg Res. 2011;167:258-66 pubmed publisher
    ..Consequently, Id-3 might be used to independently predict survival of patients with gastric cancer. ..
  33. Roldan G, Delgado L, Musé I. Tumoral expression of BRCA1, estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer. Cancer Biol Ther. 2006;5:505-10 pubmed
    ..These results suggest that ID4 participates in the molecular events that regulate BRCA1 and ER expression, suggesting its role as a tumor marker or potential therapeutic target. ..
  34. Jeon H, Sohn Y, Oh S, Oh S, Kim S, Beck S, et al. ID4 imparts chemoresistance and cancer stemness to glioma cells by derepressing miR-9*-mediated suppression of SOX2. Cancer Res. 2011;71:3410-21 pubmed publisher
    ..Together, our results reveal a novel regulatory mechanism by which ID4-driven suppression of miR-9* induces SOX2, which imparts stemness potential and chemoresistance to glioma cells and GSCs. ..
  35. Iavarone A, Lasorella A. ID proteins as targets in cancer and tools in neurobiology. Trends Mol Med. 2006;12:588-94 pubmed
    ..Here, we discuss how unique properties of ID proteins in cancer cells and neurons pave the way to unexpected therapeutic opportunities. ..
  36. Yashiro Ohtani Y, He Y, Ohtani T, Jones M, Shestova O, Xu L, et al. Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A. Genes Dev. 2009;23:1665-76 pubmed publisher
    ..Our findings also suggest new strategies for inhibiting Notch1 signaling in pathologic conditions. ..
  37. Beger C, Pierce L, Kruger M, Marcusson E, Robbins J, Welcsh P, et al. Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach. Proc Natl Acad Sci U S A. 2001;98:130-5 pubmed
    ..Our data suggest that Id4 is a crucial gene regulating BRCA1 expression and might therefore be important for the BRCA1 regulatory pathway involved in the pathogenesis of sporadic breast and ovarian cancer. ..
  38. Oatley M, Kaucher A, Racicot K, Oatley J. Inhibitor of DNA binding 4 is expressed selectively by single spermatogonia in the male germline and regulates the self-renewal of spermatogonial stem cells in mice. Biol Reprod. 2011;85:347-56 pubmed publisher
    ..Collectively, these results indicate that ID4 is a distinguishing marker of SSCs in the mammalian germline and plays an important role in the regulation of self-renewal...
  39. Wu Q, Hoffmann M, Hartmann F, Schulz W. Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer. Mol Cancer. 2005;4:16 pubmed
    ..3 in bladder cancer is expected to be non-uniform, thereby contributing to the highly variable biological and clinical behavior of advanced stage tumors. ID4 is a potential oncogene in a small subset of bladder cancers. ..
  40. Noetzel E, Veeck J, Niederacher D, Galm O, Horn F, Hartmann A, et al. Promoter methylation-associated loss of ID4 expression is a marker of tumour recurrence in human breast cancer. BMC Cancer. 2008;8:154 pubmed publisher
    ..Thus, ID4 methylation status could serve as a prognostic biomarker in human breast cancer. ..
  41. Chan A, Tsui W, Chen X, Chu K, Chan T, Chan A, et al. Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma. Oncogene. 2003;22:6946-53 pubmed
    ..The significant association of ID4 and hMLH1 promoter hypermethylation suggested that ID4 may also be among the genes being targeted in the CpG island methylator phenotype tumorigenic pathway. ..
  42. Sharma P, Patel D, Chaudhary J. Id1 and Id3 expression is associated with increasing grade of prostate cancer: Id3 preferentially regulates CDKN1B. Cancer Med. 2012;1:187-97 pubmed publisher
    ..We propose that increased Id1 and Id3 expression attenuates all three cyclin-dependent kinase inhibitors (CDKN2B, -1A, and -1B) resulting in a more aggressive PCa phenotype. ..
  43. Hong S, Lee J, Lee J, Ji J, Bhatia M. ID1 and ID3 represent conserved negative regulators of human embryonic and induced pluripotent stem cell hematopoiesis. J Cell Sci. 2011;124:1445-52 pubmed publisher
    ..Our study uniquely identifies ID1 and ID3 as negative regulators of the hPSC-hematopoietic transition from a hemogenic to a committed hematopoietic fate, and demonstrates that this is conserved between hESCs and hiPSCs. ..
  44. Chen S, Claus R, Lucas D, Yu L, Qian J, Ruppert A, et al. Silencing of the inhibitor of DNA binding protein 4 (ID4) contributes to the pathogenesis of mouse and human CLL. Blood. 2011;117:862-71 pubmed publisher
    ..Collectively, this study confirms the importance of the silencing of ID4 in murine and human CLL pathogenesis. ..
  45. Chassot A, Turchi L, Virolle T, Fitsialos G, Batoz M, Deckert M, et al. Id3 is a novel regulator of p27kip1 mRNA in early G1 phase and is required for cell-cycle progression. Oncogene. 2007;26:5772-83 pubmed
    ..In conclusion, this study identifies a novel mechanism of p27 regulation which besides p27 protein degradation also implicates a transcriptional mechanism mediated by Id3. ..
  46. Tokuzawa Y, Yagi K, Yamashita Y, Nakachi Y, Nikaido I, Bono H, et al. Id4, a new candidate gene for senile osteoporosis, acts as a molecular switch promoting osteoblast differentiation. PLoS Genet. 2010;6:e1001019 pubmed publisher
    ..The new role of Id4 in promoting osteoblast differentiation renders it a target for preventing the onset of senile osteoporosis. ..
  47. Christy B, Sanders L, Lau L, Copeland N, Jenkins N, Nathans D. An Id-related helix-loop-helix protein encoded by a growth factor-inducible gene. Proc Natl Acad Sci U S A. 1991;88:1815-9 pubmed
    ..On the basis of its structural and functional similarity to Id, we suggest that HLH462 may inhibit the activities of helix-loop-helix transcription factors during the cellular growth response and during development. ..
  48. Yun K, Mantani A, Garel S, Rubenstein J, Israel M. Id4 regulates neural progenitor proliferation and differentiation in vivo. Development. 2004;131:5441-8 pubmed
    ..These observations, together with evidence for the premature differentiation of early cortical stem cells, indicate that Id4 has a unique and complex function in regulating neural stem cell proliferation and differentiation. ..
  49. Kondo T, Raff M. The Id4 HLH protein and the timing of oligodendrocyte differentiation. EMBO J. 2000;19:1998-2007 pubmed
    ..These findings suggest that a progressive fall in Id4 transcription is part of the intracellular timer that helps determine when oligodendrocyte precursor cells withdraw from the cell cycle and differentiate. ..
  50. Gómez del Pulgar T, Valdes Mora F, Bandres E, Pérez Palacios R, Espina C, Cejas P, et al. Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism. Int J Oncol. 2008;33:185-93 pubmed
    ..05). Cdc42 may have a role in the development of colon cancer. Furthermore, inhibition of Cdc42 activity may have a direct impact in the management of colorectal cancer. ..
  51. Deleu S, Savonet V, Behrends J, Dumont J, Maenhaut C. Study of gene expression in thyrotropin-stimulated thyroid cells by cDNA expression array: ID3 transcription modulating factor as an early response protein and tumor marker in thyroid carcinomas. Exp Cell Res. 2002;279:62-70 pubmed
    ..Our results suggest that ID3 expression might be more related to the differentiating process induced by TSH than to the proliferative action of this hormone. ..
  52. O Brien C, Kreso A, Ryan P, Hermans K, Gibson L, Wang Y, et al. ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21. Cancer Cell. 2012;21:777-92 pubmed publisher
    ..Additionally, silencing of ID1 and ID3 increases sensitivity of CC-ICs to the chemotherapeutic agent oxaliplatin, linking tumor initiation function with chemotherapy resistance. ..
  53. Langenfeld E, Hong C, Lanke G, Langenfeld J. Bone morphogenetic protein type I receptor antagonists decrease growth and induce cell death of lung cancer cell lines. PLoS ONE. 2013;8:e61256 pubmed publisher
    ..Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade. ..