JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors

Shollar, Danielle; Valle, Luis Del; Khalili, Kamel; Otte, Jessica; Gordon, Jennifer

doi:10.1038/sj.onc.1207728

Cited by 44 publications

(49 citation statements)

References 32 publications

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“…In general, T-Ag of JCV is found predominantly in the nucleus; however, we were able to detect a pool of T-Ag at the cell surface that colocalized with b-catenin. This is in accord with other observations where JCV T-Ag was reported to interact with a variety of membrane-associated proteins such as NF2 or IRS-1 (Shollar et al, 2004). Accordingly, a close relative of JCV T-Ag, the SV40 T-Ag was also demonstrated to associate with the membrane (Butel et al, 1989).…”

Section: Discussionsupporting

confidence: 81%

A novel role of Rac1 GTPase in JCV T-antigen-mediated β-catenin stabilization

2007

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Wnt signaling follows canonical and non-canonical pathways to regulate a variety of processes during cellular homeostasis and development. The large T-antigen (T-Ag) of the human neurotropic JC virus, has been shown to modulate the Wnt-signaling pathway via interaction with b-catenin, one of the most important components of the canonical Wnt pathway. Here, we have identified an alternative non-canonical pathway that allows T-Ag to recruit Rac1 for stabilizing b-catenin by inhibiting its ubiquitin-dependent proteasomal degradation. We demonstrate that inhibition of Rac1 by its dominant negative mutant, RacN17, abrogates T-Ag-mediated stabilization of b-catenin yet exhibits no impact on the transcriptional activity of b-catenin. Results from immunocytochemistry revealed that together with T-Ag, a pool of b-catenin appears at the cell surface, particularly at the membrane ruffles where active Rac1 is positioned. Interestingly, cooperativity between T-Ag and b-catenin leads to activation of Rac1, which in turn, stimulates its association with b-catenin. These observations unravel the interplay between b-catenin and Rac1 that is initiated by T-Ag and results in stabilization of b-catenin and its presence in cell membrane ruffles.

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Section: Discussionsupporting

confidence: 81%

A novel role of Rac1 GTPase in JCV T-antigen-mediated β-catenin stabilization

2007

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“…5,[9][10][11]30,33,49,54,59 Glioblastoma and other astrocytic, glial-derived primary brain tumors have been reproduced experimentally in laboratory rodents (Sprague Dawley rats) and nonhuman primates (new world owl and squirrel monkeys) after intracranial inoculation of JCV. In these studies, large T antigen was demonstrated in neoplastic cells, and the JCV genome was integrated into the cellular DNA, indicating a clonal origin for the tumors.…”

Section: Discussionmentioning

confidence: 99%

Temporal and Geographic Clustering of Polyomavirus-Associated Olfactory Tumors in 10 Free-Ranging Raccoons (Procyon lotor)

et al. 2013

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Reports of primary nervous system tumors in wild raccoons are extremely rare. Olfactory tumors were diagnosed postmortem in 9 free-ranging raccoons from 4 contiguous counties in California and 1 raccoon from Oregon within a 26-month period between 2010 and 2012. We describe the geographic and temporal features of these 10 cases, including the laboratory diagnostic investigations and the neuropathologic, immunohistochemical, and ultrastructural characteristics of these tumors in the affected animals. All 9 raccoons from California were found within a localized geographic region of the San Francisco Bay Area (within a 44.13-km radius). The tight temporal and geographic clustering and consistent anatomic location in the olfactory system of tumor types not previously described in raccoons (malignant peripheral nerve sheath tumors and undifferentiated sarcomas) strongly suggest either a common cause or a precipitating factor leading to induction or potentiation of neuro-oncogenesis and so prompted an extensive diagnostic investigation to explore possible oncogenic infectious and/or toxic causes. By a consensus polymerase chain reaction strategy, a novel, recently reported polyomavirus called raccoon polyomavirus was identified in all 10 tumors but not in the normal brain tissue from the affected animals, suggesting that the virus might play a role in neurooncogenesis. In addition, expression of the viral protein T antigen was detected in all tumors containing the viral sequences. We discuss the potential role of raccoon polyomavirus as an oncogenic virus.

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“…These bonds promote the impairment of the homology-directed DNA repair mechanism, 38 the enhancement of c-myc and cyclin D1 gene expression, 34,35 the lack of positive regulation of p53 36 and the significant decrement of the apoptotic process. BKV T Ag activates the DNA methyltransferase 1 gene 39 that is associated with tumorigenesis through tumor suppressor gene hypermethylation (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, other cellular proteins, such as insulin receptor substrate 1 (IRS-1), 33 β-catenin, 34,35 the neurofibromatosis type 2 gene product 36 and the anti-apoptotic protein survivin, 37 are implicated in binding to JCV T Ag. These bonds promote the impairment of the homology-directed DNA repair mechanism, 38 the enhancement of c-myc and cyclin D1 gene expression, 34,35 the lack of positive regulation of p53 36 and the significant decrement of the apoptotic process.…”

Section: Introductionmentioning

confidence: 99%

A Potential Linkage Between the JC and BK Polyomaviruses and Brain and Urinary Tract Tumors: A Review of the Literature

Carluccio¹,

Signorini²,

Elia³

et al. 2014

Advances in Tumor Virology

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JC virus (JCV) and BK virus (BKV) belong to the Polyomaviridae family and were the first human polyomaviruses (PyVs) discovered. Both JCV and BKV remain latent in the kidneys and can reactivate in immunocompromised hosts, causing progressive multifocal leukoencephalopathy (PML) and nephropathy, respectively. PyVs induce cell transformation in vitro and in animal models, where they infect non-permissive cells. The molecular mechanisms of tumor formation are based on the large tumor antigen (T Ag) protein, which is able to bind and inactivate pRb and p53, inducing uncontrolled cell cycle progression. Many studies on clinical samples also indicate a positive association between JCV and BKV and human solid tumors; however no direct involvement of PyVs in the development of human cancers has been demonstrated. In this review we focused on the potential association between JCV and BKV with brain and urinary tract tumors, respectively.

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JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors

Cited by 44 publications

References 32 publications

A novel role of Rac1 GTPase in JCV T-antigen-mediated β-catenin stabilization

A novel role of Rac1 GTPase in JCV T-antigen-mediated β-catenin stabilization

Temporal and Geographic Clustering of Polyomavirus-Associated Olfactory Tumors in 10 Free-Ranging Raccoons (Procyon lotor)

A Potential Linkage Between the JC and BK Polyomaviruses and Brain and Urinary Tract Tumors: A Review of the Literature

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