Pathology & Oncology Research

, Volume 19, Issue 3, pp 437–446 | Cite as

Expression Pattern of Id Proteins in Medulloblastoma

  • Andrew D. Snyder
  • Ashley N. Dulin-Smith
  • Ronald H. Houston
  • Ashley N. Durban
  • Bethany J. Brisbin
  • Tyler D. Oostra
  • Jordan T. Marshall
  • Basil M. Kahwash
  • Christopher R. Pierson


Inhibitor of DNA binding or inhibitor of differentiation (Id) proteins are up regulated in a variety of neoplasms, particularly in association with high-grade, poorly differentiated tumors, while differentiated tissues show little or no Id expression. The four Id genes are members of the helix-loop-helix (HLH) family of transcription factors and act as negative regulators of transcription by binding to and sequestering HLH complexes. We tested the hypothesis that Id proteins are overexpressed in medulloblastoma by performing immunohistochemistry using a medulloblastoma tissue microarray with 45 unique medulloblastoma and 11 normal control cerebella, and antibodies specific for Id1, Id2, Id3, and Id4. A semi-quantitative staining score that took staining intensity and the proportion of immunoreactive cells into account was used. Id1 was not detected in normal cerebella or in medulloblastoma cells, but 78 % of tumors showed strong Id1 expression in endothelial nuclei of tumor vessels. Id2 expression was scant in normal cerebella and increased in medulloblastoma (median staining score: 4). Id3 expression was noted in some neurons of the developing cerebellar cortex, but it was markedly up regulated in medulloblastoma (median staining score: 12) and in tumor endothelial cells. Id4 was not expressed in normal cerebella or in tumor cells. Id2 or Id3 overexpression drove proliferation in medulloblastoma cell lines by altering the expression of critical cell cycle regulatory proteins in favor of cell proliferation. This study shows that Id1 expression in endothelial cells may contribute to angiogenic processes and that increased expression of Id2 and Id3 in medulloblastoma is potentially involved in tumor cell proliferation and survival.


Medulloblastoma Id proteins Id2 Id3 Cerebellum 


  1. 1.
    Louis DN OH, Wiestler OD, Cavenee WK (eds) (2007) WHO classification of tumors of the central nervous system. LyonGoogle Scholar
  2. 2.
    Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM (2001) Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol 19(15):3470–3476PubMedGoogle Scholar
  3. 3.
    Perk J, Iavarone A, Benezra R (2005) Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer 5(8):603–614PubMedCrossRefGoogle Scholar
  4. 4.
    Jen Y, Manova K, Benezra R (1997) Each member of the Id gene family exhibits a unique expression pattern in mouse gastrulation and neurogenesis. Dev Dyn 208(1):92–106PubMedCrossRefGoogle Scholar
  5. 5.
    Lyden D, Young AZ, Zagzag D, Yan W, Gerald W, O’Reilly R et al (1999) Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401(6754):670–677PubMedCrossRefGoogle Scholar
  6. 6.
    Neuman T, Keen A, Zuber MX, Kristjansson GI, Gruss P, Nornes HO (1993) Neuronal expression of regulatory helix-loop-helix factor Id2 gene in mouse. Dev Biol 160(1):186–195PubMedCrossRefGoogle Scholar
  7. 7.
    Fong S, Debs RJ, Desprez PY (2004) Id genes and proteins as promising targets in cancer therapy. Trends Mol Med 10(8):387–392PubMedCrossRefGoogle Scholar
  8. 8.
    Ruzinova MB, Benezra R (2003) Id proteins in development, cell cycle and cancer. Trends Cell Biol 13(8):410–418PubMedCrossRefGoogle Scholar
  9. 9.
    Bain G, Cravatt CB, Loomans C, Alberola-Ila J, Hedrick SM, Murre C (2001) Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade. Nat Immunol 2(2):165–171PubMedCrossRefGoogle Scholar
  10. 10.
    Deed RW, Hara E, Atherton GT, Peters G, Norton JD (1997) Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation. Mol Cell Biol 17(12):6815–6821PubMedGoogle Scholar
  11. 11.
    Yokota Y, Mori S (2002) Role of Id family proteins in growth control. J Cell Physiol 190(1):21–28PubMedCrossRefGoogle Scholar
  12. 12.
    Zebedee Z, Hara E (2001) Id proteins in cell cycle control and cellular senescence. Oncogene 20(58):8317–8325PubMedCrossRefGoogle Scholar
  13. 13.
    Fong S, Itahana Y, Sumida T, Singh J, Coppe JP, Liu Y et al (2003) Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis. Proc Natl Acad Sci U S A 100(23):13543–13548PubMedCrossRefGoogle Scholar
  14. 14.
    Loveys DA, Streiff MB, Kato GJ (1996) E2A basic-helix-loop-helix transcription factors are negatively regulated by serum growth factors and by the Id3 protein. Nucleic Acids Res 24(14):2813–2820PubMedCrossRefGoogle Scholar
  15. 15.
    Tzeng SF (2003) Inhibitors of DNA binding in neural cell proliferation and differentiation. Neurochem Res 28(1):45–52PubMedCrossRefGoogle Scholar
  16. 16.
    Tzeng SF, de Vellis J (1998) Id1, Id2, and Id3 gene expression in neural cells during development. Glia 24(4):372–381PubMedCrossRefGoogle Scholar
  17. 17.
    Ellmeier W, Aguzzi A, Kleiner E, Kurzbauer R, Weith A (1992) Mutually exclusive expression of a helix-loop-helix gene and N-myc in human neuroblastomas and in normal development. EMBO J 11(7):2563–2571PubMedGoogle Scholar
  18. 18.
    Duncan M, DiCicco-Bloom EM, Xiang X, Benezra R, Chada K (1992) The gene for the helix-loop-helix protein, Id, is specifically expressed in neural precursors. Dev Biol 154(1):1–10PubMedCrossRefGoogle Scholar
  19. 19.
    Ellmeier W, Weith A (1995) Expression of the helix-loop-helix gene Id3 during murine embryonic development. Dev Dyn 203(2):163–173PubMedCrossRefGoogle Scholar
  20. 20.
    Vandeputte DA, Troost D, Leenstra S, Ijlst-Keizers H, Ramkema M, Bosch DA et al (2002) Expression and distribution of id helix-loop-helix proteins in human astrocytic tumors. Glia 38(4):329–338PubMedCrossRefGoogle Scholar
  21. 21.
    Kee Y, Bronner-Fraser M (2005) To proliferate or to die: role of Id3 in cell cycle progression and survival of neural crest progenitors. Genes Dev 19(6):744–755PubMedCrossRefGoogle Scholar
  22. 22.
    Prabhu S, Ignatova A, Park ST, Sun XH (1997) Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins. Mol Cell Biol 17(10):5888–5896PubMedGoogle Scholar
  23. 23.
    Ayrault O, Zindy F, Rehg J, Sherr CJ, Roussel MF (2009) Two tumor suppressors, p27Kip1 and patched-1, collaborate to prevent medulloblastoma. Mol Cancer Res 7(1):33–40PubMedCrossRefGoogle Scholar
  24. 24.
    Miyazawa K, Himi T, Garcia V, Yamagishi H, Sato S, Ishizaki Y (2000) A role for p27/Kip1 in the control of cerebellar granule cell precursor proliferation. J Neurosci 20(15):5756–5763PubMedGoogle Scholar
  25. 25.
    Phi JH, Kim JH, Eun KM, Wang KC, Park KH, Choi SA et al (2010) Upregulation of SOX2, NOTCH1, and ID1 in supratentorial primitive neuroectodermal tumors: a distinct differentiation pattern from that of medulloblastomas. J Neurosurg Pediatr 5(6):608–614PubMedCrossRefGoogle Scholar
  26. 26.
    Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC et al (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123(4):465–472PubMedCrossRefGoogle Scholar
  27. 27.
    Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, Lin SM et al (2003) Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci U S A 100(12):7331–7336PubMedCrossRefGoogle Scholar
  28. 28.
    Lasorella A, Stegmuller J, Guardavaccaro D, Liu G, Carro MS, Rothschild G et al (2006) Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 442(7101):471–474PubMedCrossRefGoogle Scholar
  29. 29.
    Iavarone A, Garg P, Lasorella A, Hsu J, Israel MA (1994) The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes Dev 8(11):1270–1284PubMedCrossRefGoogle Scholar
  30. 30.
    Lasorella A, Noseda M, Beyna M, Yokota Y, Iavarone A (2000) Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407(6804):592–598PubMedCrossRefGoogle Scholar
  31. 31.
    Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y et al (2001) Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409(6823):1067–1070PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2013

Authors and Affiliations

  • Andrew D. Snyder
    • 1
  • Ashley N. Dulin-Smith
    • 1
  • Ronald H. Houston
    • 2
  • Ashley N. Durban
    • 1
  • Bethany J. Brisbin
    • 1
    • 3
  • Tyler D. Oostra
    • 1
    • 3
  • Jordan T. Marshall
    • 1
  • Basil M. Kahwash
    • 1
  • Christopher R. Pierson
    • 1
    • 2
    • 3
    • 4
  1. 1.The Research InstituteNationwide Children’s HospitalColumbusUSA
  2. 2.Department of Pathology and Laboratory MedicineNationwide Children’s HospitalColumbusUSA
  3. 3.The Department of PathologyThe Ohio State University College of MedicineColumbusUSA
  4. 4.Department of Laboratory Medicine, Anatomic Pathology, J0359Nationwide Children’s HospitalColumbusUSA

Personalised recommendations