inhibitor of differentiation protein 1


Summary: A HELIX-LOOP-HELIX MOTIF-containing negative regulator of BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS that blocks activation of CYCLIN-DEPENDENT KINASE INHIBITOR P16 and is de-regulated in a variety of NEOPLASMS.

Top Publications

  1. Zhang X, Ling M, Wang Q, Lau C, Leung S, Lee T, et al. Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells. J Biol Chem. 2007;282:33284-94 pubmed
  2. Qi Z, Sun X. Hyperresponse to T-cell receptor signaling and apoptosis of Id1 transgenic thymocytes. Mol Cell Biol. 2004;24:7313-23 pubmed
    ..Collectively, these results suggest that E2A and HEB proteins are crucial for controlling the threshold for TCR signaling, and Id1 expression lowers the threshold, resulting in apoptosis of developing thymocytes. ..
  3. Kim H, Chung H, Yoo Y, Kim H, Lee J, Lee M, et al. Inhibitor of DNA binding 1 activates vascular endothelial growth factor through enhancing the stability and activity of hypoxia-inducible factor-1alpha. Mol Cancer Res. 2007;5:321-9 pubmed
    ..In conclusion, we provide the molecular mechanism of the cross talk between HIF-1alpha and Id-1, which may play a critical role in tumor angiogenesis. ..
  4. Li H, Zhuang Z, Wang Q, Pang J, Wang X, Wong H, et al. Epstein-Barr virus latent membrane protein 1 (LMP1) upregulates Id1 expression in nasopharyngeal epithelial cells. Oncogene. 2004;23:4488-94 pubmed
    ..Induction of Id1 by LMP1 may facilitate clonal expansion of premalignant nasopharyngeal epithelial cells infected with EBV and may promote their malignant transformation. ..
  5. 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. ..
  6. Mellick A, Plummer P, Nolan D, Gao D, Bambino K, Hahn M, et al. Using the transcription factor inhibitor of DNA binding 1 to selectively target endothelial progenitor cells offers novel strategies to inhibit tumor angiogenesis and growth. Cancer Res. 2010;70:7273-82 pubmed publisher
    ..By exploiting the selectivity of Id1 gene expression in EPCs, our results establish a strategy to track and target EPCs in vivo, clarifying the significant role that EPCs play in BM-mediated tumor angiogenesis. ..
  7. Cheng Y, Geng H, Cheng S, Liang P, Bai Y, Li J, et al. KRAB zinc finger protein ZNF382 is a proapoptotic tumor suppressor that represses multiple oncogenes and is commonly silenced in multiple carcinomas. Cancer Res. 2010;70:6516-26 pubmed publisher
    ..Our data show that ZNF382 is a functional tumor suppressor frequently methylated in multiple carcinomas. ..
  8. Darby S, Cross S, Brown N, Hamdy F, Robson C. BMP-6 over-expression in prostate cancer is associated with increased Id-1 protein and a more invasive phenotype. J Pathol. 2008;214:394-404 pubmed
    ..001) across all samples for both benign and cancer cases. These data demonstrate that BMP-6 promotes migration and invasion of prostate cancer cells, potentially through activation of Id-1 and MMP activation. ..
  9. Jang T, Jung K, Choi E. Id-1 gene downregulation by sulindac sulfide and its upregulation during tumor development in gastric cancer. Int J Cancer. 2006;118:1356-63 pubmed
    ..Id-1, one of the repressed genes, is upregulated in gastric cancers and has positive role in tumor progression and histogenesis of intestinal-type cancers. ..

More Information


  1. Ling M, Lau T, Zhou C, Chua C, Kwok W, Wang Q, et al. Overexpression of Id-1 in prostate cancer cells promotes angiogenesis through the activation of vascular endothelial growth factor (VEGF). Carcinogenesis. 2005;26:1668-76 pubmed
    ..Since increased Id-1 has been reported in many types of advanced human cancers, our results indicate that downregulation of Id-1 may be a novel target to inhibit the growth of metastatic cancers through the suppression of angiogenesis. ..
  2. Kebebew E. Id1 gene expression and regulation in human thyroid tissue. Thyroid. 2005;15:522-30 pubmed
  3. Gao D, Nolan D, McDonnell K, Vahdat L, Benezra R, Altorki N, et al. Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression. Biochim Biophys Acta. 2009;1796:33-40 pubmed publisher
    ..Thromb. Vasc. Biol. 28 (2008) 1584-1595. [5]; F. Timmermans, J. Plum, M.C. Yoder, D.A. Ingram, B. Vandekerckhove and J. Case, J. Cell. Mol. Med. 13 (2009) 87-102. [6]] and reviews by Bertolini, Voest and Yoder in this issue. ..
  4. 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. ..
  5. Maw M, Fujimoto J, Tamaya T. Expression of the inhibitor of DNA-binding (ID)-1 protein as an angiogenic mediator in tumour advancement of uterine cervical cancers. Br J Cancer. 2008;99:1557-63 pubmed publisher
    ..Therefore, ID-1 might work on tumour advancement through angiogenic activity and is considered to be a candidate for a prognostic indicator in uterine cervical cancers. ..
  6. Lee J, Kang M, Jang S, Qian T, Kim H, Kim C, et al. Id-1 activates Akt-mediated Wnt signaling and p27(Kip1) phosphorylation through PTEN inhibition. Oncogene. 2009;28:824-31 pubmed publisher
  7. Perk J, Iavarone A, Benezra R. Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer. 2005;5:603-14 pubmed publisher
  8. Cheung H, Ling M, Tsao S, Wong Y, Wang X. Id-1-induced Raf/MEK pathway activation is essential for its protective role against taxol-induced apoptosis in nasopharyngeal carcinoma cells. Carcinogenesis. 2004;25:881-7 pubmed
    ..Our evidence also indicates a novel treatment strategy to increase anticancer drug-induced apoptosis through inactivation of the Id-1 protein. ..
  9. Ling Y, Tao J, Fang S, Hui Z, Fang Q. Downregulation of Id1 by small interfering RNA in prostate cancer PC3 cells in vivo and in vitro. Eur J Cancer Prev. 2011;20:9-17 pubmed publisher
    ..Our results show that inactivation of Id1 can suppress cell proliferation, induce apoptosis and senescence in PC3. Silencing of the Id1 gene has an in-vivo preventive effect against the development of prostate cancer in a mouse model. ..
  10. Kim A, Puram S, Bilimoria P, Ikeuchi Y, Keough S, Wong M, et al. A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in postmitotic neurons. Cell. 2009;136:322-36 pubmed publisher
    ..The identification of a centrosomal Cdc20-APC ubiquitin signaling pathway holds important implications for diverse biological processes, including neuronal connectivity and plasticity. ..
  11. Suh H, Ji M, Gooya J, Lee M, Klarmann K, Keller J. Cell-nonautonomous function of Id1 in the hematopoietic progenitor cell niche. Blood. 2009;114:1186-95 pubmed publisher
    ..Thus, Id1 is required for regulating the hematopoietic progenitor cell niche but is dispensable for maintaining HSCs. ..
  12. Zhang X, Ling M, Wang X, Wong Y. Inactivation of Id-1 in prostate cancer cells: A potential therapeutic target in inducing chemosensitization to taxol through activation of JNK pathway. Int J Cancer. 2006;118:2072-81 pubmed
  13. Wang X, Di K, Zhang X, Han H, Wong Y, Leung S, et al. Id-1 promotes chromosomal instability through modification of APC/C activity during mitosis in response to microtubule disruption. Oncogene. 2008;27:4456-66 pubmed publisher
    ..These results demonstrate a novel function of Id-1 in promoting chromosomal instability through modification of APC/C activity during mitosis and provide a novel molecular mechanism accounted for the function of Id-1 as an oncogene. ..
  14. Schmidt M, Asirvatham A, Chaudhary J. Inhibitor of differentiation 1 (ID1) promotes cell survival and proliferation of prostate epithelial cells. Cell Mol Biol Lett. 2010;15:272-95 pubmed publisher
    ..The associated molecular/gene expression profile of Id1-RPE cells provides an opportunity to understand the molecular pathways associated with prostate epithelial cell survival and proliferation. ..
  15. Löfstedt T, Jögi A, Sigvardsson M, Gradin K, Poellinger L, Påhlman S, et al. Induction of ID2 expression by hypoxia-inducible factor-1: a role in dedifferentiation of hypoxic neuroblastoma cells. J Biol Chem. 2004;279:39223-31 pubmed
    ..Hypoxia-induced ID2 expression could play a significant role in the previously observed dedifferentiation of hypoxic neuroblastoma cells, which in a clinical setting could lead to less mature and more aggressive tumors. ..
  16. Jankovic V, Ciarrocchi A, Boccuni P, DeBlasio T, Benezra R, Nimer S. Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells. Proc Natl Acad Sci U S A. 2007;104:1260-5 pubmed
    ..Thus, Id1 appears to regulate the fate of HSCs by acting as a true inhibitor of differentiation. ..
  17. Ying Q, Nichols J, Chambers I, Smith A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell. 2003;115:281-92 pubmed
    ..Upon LIF withdrawal, Id-expressing ES cells differentiate but do not give rise to neural lineages. We conclude that blockade of lineage-specific transcription factors by Id proteins enables the self-renewal response to LIF/STAT3. ..
  18. Wang H, Perry S, Sun X. Id1 attenuates Notch signaling and impairs T-cell commitment by elevating Deltex1 expression. Mol Cell Biol. 2009;29:4640-52 pubmed publisher
    ..Thus, T-cell commitment may be controlled by the interplay among E proteins, Gfi1b, and GATA3 transcription regulators, which influence Notch function through the expression of Deltex1. ..
  19. 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. ..
  20. 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. ..
  21. Hui C, Cheung P, Ling M, Tsao S, Wang X, Wong Y, et al. Id-1 promotes proliferation of p53-deficient esophageal cancer cells. Int J Cancer. 2006;119:508-14 pubmed
  22. de Candia P, Benera R, Solit D. A role for Id proteins in mammary gland physiology and tumorigenesis. Adv Cancer Res. 2004;92:81-94 pubmed
    ..Thus, all four members of the Id protein family play pivotal roles in distinct aspects of normal and malignant breast biology, the subject of this review. ..
  23. Damdinsuren B, Nagano H, Kondo M, Yamamoto H, Hiraoka N, Yamamoto T, et al. Expression of Id proteins in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Int J Oncol. 2005;26:319-27 pubmed
    ..These findings suggested that Id1, 2 and 3 might play a role in the early stages of hepatocarcinogenesis, but not in the development of advanced carcinoma, and might consequently be related to HCC dedifferentiation. ..
  24. Straume O, Akslen L. Strong expression of ID1 protein is associated with decreased survival, increased expression of ephrin-A1/EPHA2, and reduced thrombospondin-1 in malignant melanoma. Br J Cancer. 2005;93:933-8 pubmed
    ..An inverse relation between ID1 and TSP-1 expression support an important role of ID1 in the regulation of this complex multitarget protein. ..
  25. Matsuda Y, Yamagiwa S, Takamura M, Honda Y, Ishimoto Y, Ichida T, et al. Overexpressed Id-1 is associated with a high risk of hepatocellular carcinoma development in patients with cirrhosis without transcriptional repression of p16. Cancer. 2005;104:1037-44 pubmed
  26. Leeanansaksiri W, Wang H, Gooya J, Renn K, Abshari M, Tsai S, et al. IL-3 induces inhibitor of DNA-binding protein-1 in hemopoietic progenitor cells and promotes myeloid cell development. J Immunol. 2005;174:7014-21 pubmed
    ..Therefore, Id1 may be part of the mechanism regulating myeloid vs lymphoid/erythroid cell fates, and macrophage vs neutrophil maturation. ..
  27. Zhang X, Ling M, Wong Y, Wang X. Evidence of a novel antiapoptotic factor: role of inhibitor of differentiation or DNA binding (Id-1) in anticancer drug-induced apoptosis. Cancer Sci. 2007;98:308-14 pubmed
    ..Our evidence also provides a possible underlying mechanism responsible for the positive role of Id-1 in the progression of human cancer. ..
  28. Qiu H, Yang B, Pei Z, Zhang Z, Ding K. WSS25 inhibits growth of xenografted hepatocellular cancer cells in nude mice by disrupting angiogenesis via blocking bone morphogenetic protein (BMP)/Smad/Id1 signaling. J Biol Chem. 2010;285:32638-46 pubmed publisher
    ..Therefore, WSS25 is a potential drug candidate for HCC therapy as a tumor angiogenesis inhibitor...
  29. Jang K, Han H, Paik S, Brown P, Kong G. Id-1 overexpression in invasive ductal carcinoma cells is significantly associated with intratumoral microvessel density in ER-negative/node-positive breast cancer. Cancer Lett. 2006;244:203-10 pubmed
    ..Thus, Id-1 presents a possible therapeutic antitumor target molecule in ER-negative and node-positive breast cancer. ..
  30. Sumida T, Itahana Y, Hamakawa H, Desprez P. Reduction of human metastatic breast cancer cell aggressiveness on introduction of either form a or B of the progesterone receptor and then treatment with progestins. Cancer Res. 2004;64:7886-92 pubmed
  31. Lee J, Kim K, Kim J, Jin H, Choi H, Lee S, et al. Id helix-loop-helix proteins negatively regulate TRANCE-mediated osteoclast differentiation. Blood. 2006;107:2686-93 pubmed
    ..Taken together, our results reveal both a new facet of negative regulation, mediated by Id proteins, as well as the mechanism whereby TRANCE signaling overcomes it, allowing osteoclastogenesis to proceed. ..
  32. Ponz Sarvisé M, Nguewa P, Pajares M, Agorreta J, Lozano M, Redrado M, et al. Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance. Clin Cancer Res. 2011;17:4155-66 pubmed publisher
    ..In our series, Id1 levels showed an independent prognostic value in patients with adenocarcinoma, regardless of the stage. Id1 silencing may sensitize adenocarcinoma cells to radiotherapy and chemotherapy. ..
  33. Forootan S, Wong Y, Dodson A, Wang X, Lin K, Smith P, et al. Increased Id-1 expression is significantly associated with poor survival of patients with prostate cancer. Hum Pathol. 2007;38:1321-9 pubmed
    ..01). These results suggest that Id-1 is a useful prognostic marker to predict the outcomes of patients with prostate cancer. ..
  34. Yu Y, Gao Y, Qin J, Kuang C, Song M, Yu S, et al. CCN1 promotes the differentiation of endothelial progenitor cells and reendothelialization in the early phase after vascular injury. Basic Res Cardiol. 2010;105:713-24 pubmed publisher
    ..Our data suggest that CCN1, from the microenvironment of injured vessels, enhances reendothelialization via a direct action on EPC differentiation, revealing a possible new mechanism underlying the process of vascular repair. ..
  35. Zhang X, Ling M, Feng H, Wong Y, Tsao S, Wang X. Id-I stimulates cell proliferation through activation of EGFR in ovarian cancer cells. Br J Cancer. 2004;91:2042-7 pubmed
    ..Our findings also implicate that Id-1 may be a potential target for the development of novel strategies in the treatment of ovarian cancer. ..
  36. Poomthavorn P, Wong S, Higgins S, Werther G, Russo V. Activation of a prometastatic gene expression program in hypoxic neuroblastoma cells. Endocr Relat Cancer. 2009;16:991-1004 pubmed publisher
    ..These processes are probably responsible for the NB cell transition from an adherent phenotype to a highly migratory, invasive and aggressive NB cell type. ..
  37. Gautschi O, Tepper C, Purnell P, Izumiya Y, Evans C, Green T, et al. Regulation of Id1 expression by SRC: implications for targeting of the bone morphogenetic protein pathway in cancer. Cancer Res. 2008;68:2250-8 pubmed publisher
    ..Taken together, these results reveal that Src positively interacts with the BMP-Smad-Id pathway and provide new ways for targeted inhibition of Id1. ..
  38. Li Y, Yang J, Luo J, Dedhar S, Liu Y. Tubular epithelial cell dedifferentiation is driven by the helix-loop-helix transcriptional inhibitor Id1. J Am Soc Nephrol. 2007;18:449-60 pubmed
  39. Cheng Y, Tsai J, Hsieh K, Yang Y, Chen Y, Huang M, et al. Id1 promotes lung cancer cell proliferation and tumor growth through Akt-related pathway. Cancer Lett. 2011;307:191-9 pubmed publisher
    ..In conclusion, inactivation of Id1 may provide a novel strategy for treatment of lung cancer patients. ..
  40. Lee T, Poon R, Yuen A, Ling M, Wang X, Wong Y, et al. Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma. Clin Cancer Res. 2006;12:6910-9 pubmed
    ..Id-1 is a novel angiogenic factor for HCC metastasis and down-regulation of Id-1 may be a novel target to inhibit HCC metastasis through suppression of angiogenesis. ..
  41. Swarbrick A, Akerfeldt M, Lee C, Sergio C, Caldon C, Hunter L, et al. Regulation of cyclin expression and cell cycle progression in breast epithelial cells by the helix-loop-helix protein Id1. Oncogene. 2005;24:381-9 pubmed
    ..These data indicate that in mammary epithelial cells, Id1 has cell cycle regulatory functions that are similar to those of c-Myc, and suggest that cyclin D1 may be involved in Id1 regulation of cell cycle progression. ..
  42. Zhao Z, Zhang Z, Zhang H, Jiang L, Wang M, Sun X. Overexpression of Id-1 protein is a marker in colorectal cancer progression. Oncol Rep. 2008;19:419-24 pubmed
    ..The cases with lymph node metastasis had a higher rate of a stronger Id-1 expression than those without lymph node metastasis. In conclusion, Id-1 overexpression plays an important role in colorectal cancer progression. ..
  43. Diaz R, Nguewa P, Diaz Gonzalez J, Hamel E, Gonzalez Moreno O, Catena R, et al. The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer. Br J Cancer. 2009;100:932-40 pubmed publisher
    ..Our results show the antitumour efficacy of P529 alone, and as a radiosensitiser, and suggest that this compound could be used in the future to treat human prostate cancer. ..
  44. Lin J, Guan Z, Wang C, Feng L, Zheng Y, Caicedo E, et al. Inhibitor of differentiation 1 contributes to head and neck squamous cell carcinoma survival via the NF-kappaB/survivin and phosphoinositide 3-kinase/Akt signaling pathways. Clin Cancer Res. 2010;16:77-87 pubmed publisher
    ..The above data, taken together, suggest that Id1 and its downstream effectors are potential targets for treatment of HNSCC because of their contribution to apoptosis resistance. ..
  45. Caldon C, Swarbrick A, Lee C, Sutherland R, Musgrove E. The helix-loop-helix protein Id1 requires cyclin D1 to promote the proliferation of mammary epithelial cell acini. Cancer Res. 2008;68:3026-36 pubmed publisher
    ..In summary, Id1 may contribute to early breast cancer by promoting excessive proliferation through cyclin D1. ..
  46. Aranha M, Sola S, Low W, Steer C, Rodrigues C. Caspases and p53 modulate FOXO3A/Id1 signaling during mouse neural stem cell differentiation. J Cell Biochem. 2009;107:748-58 pubmed publisher
    ..In conclusion, apoptosis-associated factors such as caspases and p53 temporally modulate FOXO3A/Id1 signaling and differentiation of mouse NSCs. ..
  47. Yuen H, Chiu Y, Chan K, Chan Y, Chua C, McCrudden C, et al. Prostate cancer cells modulate osteoblast mineralisation and osteoclast differentiation through Id-1. Br J Cancer. 2010;102:332-41 pubmed publisher
  48. 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. ..
  49. Fraidenraich D, Stillwell E, Romero E, Wilkes D, Manova K, Basson C, et al. Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells. Science. 2004;306:247-52 pubmed
    ..Thus, ES cells have the potential to reverse congenital defects through Id-dependent local and long-range effects in a mammalian embryo. ..
  50. Kamalian L, Gosney J, Forootan S, Foster C, Bao Z, Beesley C, et al. Increased expression of Id family proteins in small cell lung cancer and its prognostic significance. Clin Cancer Res. 2008;14:2318-25 pubmed publisher
    ..Changed expression profiles of Id proteins may play important roles in malignant progression of SCLC, and the increased Id2 in cytoplasm is a novel prognostic factor to predict the patient outcomes. ..
  51. Ling M, Wang X, Lee D, Tam P, Tsao S, Wong Y. Id-1 expression induces androgen-independent prostate cancer cell growth through activation of epidermal growth factor receptor (EGF-R). Carcinogenesis. 2004;25:517-25 pubmed
    ..Inactivation of Id-1 may provide a potential therapeutic strategy leading to inhibition of androgen-independent prostate cancer cell growth. ..
  52. 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. ..
  53. Everly D, Mainou B, Raab Traub N. The ID proteins contribute to the growth of rodent fibroblasts during LMP1-mediated transformation. Virology. 2008;376:258-69 pubmed publisher
    ..These data indicate that overexpression of the Id proteins is not sufficient for the effects of LMP1 on the cell cycle but that inhibition of Id expression does affect the growth of LMP1-transformed and parental Rat1 cells...