Abstract
By using the early genome of the human neurotropic polyomavirus, JCV, we have created transgenic animals that develop cerebellar primitive neuroectodermal tumors which model human medulloblastoma. Expression of T-antigen was found in some, but not all, tumor cells, and examination of the clonal cell lines derived from the tumor population showed enhanced tumorigenicity of cells expressing T-antigen in comparison to T-antigen negative cells. Considering the earlier notion on the potential involvement of β-catenin with human medulloblastoma, we investigated various components of the Wnt signaling pathway including β-catenin, its partner transcription factor, LEF-1, and their downstream target gene c-myc in these two cell populations. Immunohistochemical staining of the cells revealed enhanced nuclear appearance of β-catenin in T-antigen positive cells. Results from Western blot showed higher levels of β-catenin and LEF-1 in T-antigen positive cells in comparison to those in T-antigen negative cells. The enhanced level of LEF-1 expression correlated with the increase in DNA binding activity of this protein in nuclear extracts of T-antigen positive cells. Results from Northern and Western blot analyses revealed that the level of c-myc expression is augmented both at the RNA and protein levels in T-antigen positive cells. These observations corroborated results from transfection studies indicating the ability of JCV T-antigen to stimulate c-myc promoter activity. Further, co-transfection experiments revealed that the amount of c-myc and T-antigen protein in tumor cells may dictate the activity of JCV early promoter in these cells. These observations are interesting in light of recent discoveries on the association of JCV with human medulloblastoma and suggest that communication between JCV and the Wnt pathway may be an important event in the genesis of these tumors.
Similar content being viewed by others
References
Aberle H, Schwartz H, Kemler R . 1996 Cadherin-catenin complex:protein interactions and their implications for cadherin function J. Cell. Biochem. 61: 514–523
Behrens J, von Kries JP, Kühl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W . 1996 Functional interaction of b-catenin with the transcription factor LEF-1 Nature 382: 638–642
Berger JR, Concha M . 1995 Progressive multifocal leukoencephalopathy: The evolution of a disease once considered rare J. Neurovirol. 1: 5–18
Cadigan KM, Nusse R . 1997 Wnt signaling: a common theme in animal development Genes Dev. 11: 3286–3305
Cogen PH, McDonald JD . 1996 Tumor suppressor genes and medulloblastoma J. Neurooncol. 29: 103–112
Dorsky RI, Moon RT, Raible DW . 1998 Control of neural crest cell fate by the Wnt signaling pathway Nature 396: 370–372
Eberhart CG, Tihan T, Burger PC . 2000 Nuclear localization and mutation of b-catenine in medulloblastoma J. Neuropathol. Exp. Neurol. 59: 333–337
Farwell JR, Dohrmann GJ, Flannery JT . 1984 Medulloblastoma in childhood: an epidemiological study J. Neurosurg. 61: 657–664
Franks RR, Rencic A, Gordon J, Zoltick PW, Curtis M, Knobler RL, Khalili K . 1996 Formation of undifferentiated mesenteric tumors in transgenic mice expressing human neurotropic polyomavirus early protein Oncogene 12: 2573–2578
Gallia GL, Gordon J, Khalili K . 1998 Tumor pathogenesis of human neurotropic JC virus in the CNS J. Neurovirology 4: 175–181
Gordon J, Del Valle L, Otte J, Khalili K . 2000 Pituitary neoplasia induced by expression of human neurotropic polyomavirus, JCV, early genome in transgenic mice Oncogene 19: 4840–4846
Howard CM, Claudio PP, De Luca A, Stiegler P, Jori FP, Safdar NM, Caputi M, Khalili K, Giordano A . 2000 Inducible pRb2/p130 expression and growth-suppressive mechanisms: evidence of a pRb2/p130, p27kip1, and cyclin E negative feedback regulatory loop Cancer Res. 60: 2737–2744
Hülsken K, Birchmeier W, Behrens J . 1994 E-cadherin and APC complete for the interaction with beta-catenin and the cytoskeleton J. Cell Biol. 127: 2061–2069
Jou TS, Stewart DB, Stappert J, Nelson WJ, Marss JA . 1995 Genetic and biochemical dissection of protein linkages in the cadherin-catenin complex Proc. Natl. Acad. Sci. USA 92: 5067–5071
Krynska B, Gordon J, Otte J, Franks R, Knobler R, DeLuca A, Giordano A, Khalili K . 1997 Role of cell cycle regulators in tumor formation in transgenic mice expressing the human neurotropic virus, JCV, early protein J. Cell. Biochem. 67: 223–230
Krynska B, Otte J, Franks R, Khalili K, Croul S . 1999 Human ubiquitous JCVCY T-antigen gene induces brain tumors in experimental animals Oncogene 18: 39–46
Krynska B, Del Valle L, Gordon J, Otte J, Croul S, Khalili K . 2000 Identification of a novel p53 mutation in JCV-induced mouse medulloblastoma Virology 274: 65–74
Major EO, Amemiya K, Tornatore CS, Houff SA, Berger JR . 1992 Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JCV virus-induced demyelinating disease of the human brain Clin. Micro Rev. 51: 49–73
Marino S, Vooijs M, van der Gulden H, Jonkers J, Berns A . 2000 Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum Genes Dev. 14: 994–1004
May P, May E . 1999 Twenty years of p53 research: structural and functional aspects of the p53 protein Oncogene 18: 7621–7636
Miller JR, Hocking AM, Brown JD, Moon RT . 1999 Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways Oncogene 18: 7860–7872
Moon RT, Brown JD, Torres M . 1997 WNTs modulate cell fate and behavior during vertebrate development Trends Genet. 13: 157–162
Morin PJ . 1999 β-catenin signaling and cancer BioEssays 21: 1021–1030
Paggi MG, Baldi A, Bonetto F, Giordano A . 1996 Retinoblastoma protein family in cell cycle and cancer: A review J. Cell. Biochem. 62: 418–430
Peifer M . 1995 Trends Cell Biol. 5: 224
Small JA, Scangos GA, Cork L, Jay G, Koury G . 1986a The early region of human papovavirus JC induces dysmyelination in transgenic mice Cell 46: 13–18
Small JA, Khoury G, Jay G, Howley PM, Scangos GA . 1986b Early regions of JC virus and BK virus induce distinct and tissue-specific tumors in transgenic mice Proc. Natl. Acad. Sci. USA 83: 8288–8292
Taguchi F, Kajioka J, Miyamura T . 1982 Prevalence rate and age of acquisition of antibodies against JC virus and Bk virus in human sera Microbiol. Immunol. 26: 1057–1064
Walker DL, Padgett BL . 1983 The epidemiology of human papovaviruses Polyomaviruses and Human Neurological Disease. Server JL and Madden DL (eds) Alan R. Liss, New York pp. 99–106
Acknowledgements
The authors wish to thank past and present members of the Center for Neurovirology and Cancer Biology for insightful discussion, sharing of ideas and reagents. We also thank C Schriver for editorial assistance and preparation of the manuscript. This work was made possible by grants awarded by the NIH to K Khalili.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gan, DD., Reiss, K., Carrill, T. et al. Involvement of Wnt signaling pathway in murine medulloblastoma induced by human neurotropic JC virus. Oncogene 20, 4864–4870 (2001). https://doi.org/10.1038/sj.onc.1204670
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204670
- Springer Nature Limited
Keywords
This article is cited by
-
Revisiting JC virus and progressive multifocal leukoencephalopathy
Journal of NeuroVirology (2023)
-
Review on the role of the human Polyomavirus JC in the development of tumors
Infectious Agents and Cancer (2017)
-
Prevalence of JC polyomavirus large T antigen sequences among Iranian patients with central nervous system tumors
Archives of Virology (2015)
-
High JC virus load in tongue carcinomas may be a risk factor for tongue tumorigenesis
Virchows Archiv (2008)
-
DNA tumor viruses and colorectal cancer
Current Colorectal Cancer Reports (2007)