Involvement of Wnt signaling pathway in murine medulloblastoma induced by human neurotropic JC virus

Gan, Dai-Di; Reiss, Krzysztof; Carrill, Timothy; Valle, Luis Del; Croul, Sidney; Giordano, Antonio; Fishman, Pnina; Khalili, Kamel

doi:10.1038/sj.onc.1204670

Cited by 53 publications

(37 citation statements)

References 28 publications

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“…As a subset of human medulloblastomas have shown deregulation of the Wnt signaling pathway, T-antigen-positive and -negative mouse medulloblastoma cell lines were evaluated for their levels of b-catenin, its cellular partner, LEF-1, and their activity on their downstream target, c-myc. Of interest, enhanced levels of b-catenin and LEF-1 and a subsequent increase in c-myc levels were observed in T-antigen-positive cells compared with T-antigen-negative cells (Gan et al, 2001). In another recent line of study, a role for the insulin-like growth factor I receptor (IGF-IR) signaling system has been observed in the T-antigen-positive medulloblastoma cell lines.…”

Section: Mechanisms Of T-antigen-mediated Transformationmentioning

confidence: 87%

Human neurotropic polyomavirus, JCV, and its role in carcinogenesis

et al. 2003

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A number of recent studies have reported the detection of the ubiquitous human polyomavirus, JC virus (JCV), in samples derived from several types of neural as well as non-neural human tumors. The human neurotropic JCV was first identified as the etiologic agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy, which usually occurs in individuals with defects in cell-mediated immunity, including AIDS. However, upon mounting evidence of the oncogenic potential of the viral regulatory protein, T-antigen, and JCV's oncogenecity in a broad range of animal models, studies were initiated to determine its potential involvement in human carcinogenesis. Initially, the most frequently observed tumors in rodent models, including medulloblastoma, astrocytoma, glioblastoma, and other neural-origin tumors were analysed. These studies were followed by analysis of non-neural tumors such as colorectal carcinomas. In a subset of each tumor type examined, JC viral genomic DNA sequences could be detected by PCR and confirmed by Southern blot hybridization or direct sequencing. In a smaller subset of the tumors, the expression of T-antigen was observed by immunohistochemical analysis. Owing to the established functions of T-antigen including its ability to interact with tumor suppressor proteins such as Rb and p53, and its ability to influence chromosomal stability, potential mechanisms of JCV T-antigen-mediated cellular dysregulation are discussed. Further, as increasing evidence suggests that T-antigen is not required for maintenance of a transformed phenotype, a hit-and-run model for T-antigen-induced transformation is proposed.

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Section: Mechanisms Of T-antigen-mediated Transformationmentioning

confidence: 87%

Human neurotropic polyomavirus, JCV, and its role in carcinogenesis

et al. 2003

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“…In light of the previous observations showing elevated levels of b-catenin in T-antigen-positive murine medulloblastomas compared to its level in the Tantigen-negative cells (Gan et al, 2001), and the current data on the binding of T-antigen to b-catenin, the stability of b-catenin in the presence of T-antigen was determined. In the first attempt, human astrocytoma cells, U-87MG, were transfected with plasmids expressing full-length b-catenin either alone or together with a plasmid that expresses JCV T-antigen.…”

Section: Resultsmentioning

confidence: 99%

“…The expression of T-antigen was detected in tumor mass, and in cell lines derived from the tumor (Krynska et al, 2000). In our earlier studies, we demonstrated an elevated level of b-catenin and its nuclear import in the cells expressing T-antigen (Gan et al, 2001). In this study, we utilized a wellcharacterized cell line, BSB8, from the JCV-T mouse medulloblastoma, and human astrocytoma cells, U-87MG, to investigate the mechanism of T-antigeninduced dysregulation of the Wnt pathway by focusing on the interplay between T-antigen and b-catenin.…”

Section: Introductionmentioning

confidence: 99%

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Interaction between JCV large T-antigen and β-catenin

Gan

Khalili

2004

Oncogene

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Expression of the JCV early protein T-antigen in transgenic mice leads to the development of cerebellar primitive neuroectodermal tumors (PNETs). In light of earlier reports on the association of JCV with PNETs in humans and the involvement of the Wnt signaling pathway in the development of cerebellar tumors, we investigated the interplay between T-antigen and bcatenin, the key protein of the Wnt pathway. Our results demonstrate the physical interaction of T-antigen with bcatenin through the central domain of T-antigen spanning residues 82-628, and the C-terminus of b-catenin located between amino acids 695 and 781. The association of Tantigen with b-catenin elevates the level of b-catenin in the cells due to increased in the stability of the protein. In the presence of T-antigen, b-catenin was found in the nuclei of cells, suggesting that the interaction of b-catenin with T-antigen facilitates its nuclear import. In cells expressing mutant T-antigen with no nuclear localization domain, b-catenin was found in the cytoplasm. Coexpression of T-antigen with b-catenin increased the transcription of the c-myc promoter, a known downstream target of b-catenin, and artificial promoter whose activity is bcatenin dependent. These observations ascribe a new oncogenic pathway for T-antigen, and offer an alternative mechanism for the deregulation of the Wnt pathway through stabilization of b-catenin upon its association with the viral oncoprotein.

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“…As stated earlier, the stability of b-catenin in cells results in its nuclear import through its partnership (Gan et al, 2001) with LEF/TCF where it stimulates expression of genes such as cyclin D1 and c-myc. This event can eventually lead to uncontrolled cell growth and proliferation (Ferkey and Kimelman, 2000).…”

Section: Introductionmentioning

confidence: 99%

Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells

et al. 2002

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The A3 adenosine receptor, A3AR, belongs to the family of Gi proteins, which upon induction, suppresses the formation of cAMP and its downstream e ectors. Recent studies have indicated that activation of A3AR by its agonist, IB-MECA, results in growth inhibition of malignant cells. Here we demonstrate the ability of IB-MECA to decrease the levels of protein kinase A, a downstream e ector of cAMP, and protein kinase B/Akt in melanoma cells. Examination of glycogen synthase kinase 3b, GSK-3b, whose phosphorylation is controlled by protein kinase A and B, showed a substantial decrease in the levels of its phosphorylated form and an increase in total GSK-3b levels in IB-MECA treated melanoma cells. This observation suggests that the treatment of cells with IB-MECA augments the activity of GSK-3b in the cells. Evaluation of b-catenin, a key component of Wnt signaling pathway which, upon phosphorylation by GSK-3b rapidly ubiquitinates, showed a substantial decrease in its level after IB-MECA treatment. Accordingly, the level of b-catenin responsive cell growth regulatory genes including c-myc and cyclin D1 was severely declined upon treatment of the cells with IB-MECA. These observations which link cAMP to the Wnt signaling pathway provide mechanistic evidence for the involvement of Wnt pathway via its key elements GSK-3b and b-catenin in the anti-tumor activity of A3AR agonists.

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Involvement of Wnt signaling pathway in murine medulloblastoma induced by human neurotropic JC virus

Cited by 53 publications

References 28 publications

Human neurotropic polyomavirus, JCV, and its role in carcinogenesis

Human neurotropic polyomavirus, JCV, and its role in carcinogenesis

Interaction between JCV large T-antigen and β-catenin

Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells

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