Interaction between JCV large T-antigen and β-catenin

Gan, Dai-Di; Khalili, Kamel

doi:10.1038/sj.onc.1207018

Cited by 64 publications

(70 citation statements)

References 25 publications

(29 reference statements)

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“…We have shown previously that the HCV NS5A protein stabilized b-catenin in a PI3K-dependent fashion (Street et al, 2005), in common with other viruses associated with human tumours (Cha et al, 2004;Fujimuro et al, 2003;Gan & Khalili, 2004;Morrison et al, 2003;Tomita et al, 2006). PI3K is known to activate b-catenin via the Akt/ GSK-3b pathway; consistent with this, our previous data showed both b-catenin activation and GSK-3b inhibition upon expression of the complete HCV polyprotein.…”

Section: Discussionsupporting

confidence: 75%

“…Dysregulation of b-catenin, by mutation of either bcatenin itself or one of the myriad of regulatory proteins that control its activity, is associated with a range of tumours, including both colorectal carcinoma (Gavert & Ben-Ze'ev, 2007) and HCC (de La Coste et al, 1998). Of note, b-catenin is also upregulated by other oncogenic viruses, including Epstein-Barr virus (EBV) (Morrison et al, 2003), Kaposi's sarcoma herpes virus (Fujimuro et al, 2003), the papovavirus JC (Gan & Khalili, 2004), hepatitis B virus (Cha et al, 2004) and human Tlymphotropic virus 1 (Tomita et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis C virus NS5A protein interacts with -catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion

Milward

Mankouri

Harris

2009

Journal of General Virology

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Hepatitis C virus (HCV) infection is increasingly associated with the development of hepatocellular carcinoma (HCC). HCV is not thought to be directly oncogenic but, by modulating a range of cellular functions, may predispose patients to the development of liver tumours. However, the molecular mechanisms by which HCV infection might contribute to HCC remain to be characterized. In this regard, we showed previously that the HCV NS5A protein bound to the p85 regulatory subunit of phosphoinositide-3 kinase (PI3K), thereby stimulating the activity of the p110 catalytic subunit of the enzyme. One of the downstream consequences of this was the stabilization of the proto-oncogene, b-catenin, with a concomitant stimulation of its transcriptional activity. Here, we further analyse the mechanism by which NS5A mediates activation of b-catenin. Although our previous data were consistent with a role for the PI3K downstream effector kinases, Akt and glycogen synthase kinase-3b, in NS5A-mediated activation of b-catenin, we demonstrate here that it is in fact independent of both of these kinases. Truncation analysis revealed that both the N and C termini of NS5A are required for full activation of b-catenin. Furthermore, we demonstrate that NS5A, either alone or in complex with p85, is able to bind directly to b-catenin; again both N and C termini contribute to this interaction. We propose that NS5A activates bcatenin via a novel mechanism that involves a direct interaction between the two proteins and is augmented by PI3K activity. This may contribute to the association between chronic HCV infection and the development of HCC.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus NS5A protein interacts with -catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion

Milward

Mankouri

Harris

2009

Journal of General Virology

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“…In accord with our earlier report (Gan and Khalili, 2004), the level of b-catenin increased in cells expressing T-Ag ( Figure 1a, lanes 1 and 2). In the absence of T-Ag, treatment of cells with the proteasomal inhibitor, acetyle-L-leucyl-L-norleucinal (ALLN), increased the level of b-catenin (Figure 1a, compare lanes 1 and 3), whereas in the presence of T-Ag, this treatment had no effect on the level of b-catenin (Figure 1a, compare lanes 2 and 4) suggesting that T-Ag may stabilize b-catenin by inhibiting its proteasomal degradation.…”

Section: T-ag Enhances B-catenin Expression Level By Inhibiting Its Usupporting

confidence: 81%

“…In the absence of T-Ag, ALLN treatment, which elevated the level of full-length b-catenin (Figure 1b, lanes 1 and 3), showed no increase on the level of DNb-catenin (Figure 1b, lanes 5 and 7). In light of earlier results on the ability of both full-length b-catenin and DNbcatenin mutant in binding to T-Ag (Gan and Khalili, 2004), these observations suggest that T-Ag may stabilize b-catenin by an alternative pathway, that is, inhibition of proteasomal degradation, which appear to be independent from T-Ag interaction.…”

Section: T-ag Enhances B-catenin Expression Level By Inhibiting Its Umentioning

confidence: 84%

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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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Viruses in colorectal cancer

Marongiu

Allgayer

2021

Molecular Oncology

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Increasing evidence suggests that microorganisms might represent at least highly interesting cofactors in colorectal cancer (CRC) oncogenesis and progression. Still, associated mechanisms, specifically in colonocytes and their microenvironmental interactions, are still poorly understood. Although, currently, at least seven viruses are being recognized as human carcinogens, only three of these – Epstein–Barr virus (EBV), human papillomavirus (HPV) and John Cunningham virus (JCV) – have been described, with varying levels of evidence, in CRC. In addition, cytomegalovirus (CMV) has been associated with CRC in some publications, albeit not being a fully acknowledged oncovirus. Moreover, recent microbiome studies set increasing grounds for new hypotheses on bacteriophages as interesting additional modulators in CRC carcinogenesis and progression. The present Review summarizes how particular groups of viruses, including bacteriophages, affect cells and the cellular and microbial microenvironment, thereby putatively contributing to foster CRC. This could be achieved, for example, by promoting several processes – such as DNA damage, chromosomal instability, or molecular aspects of cell proliferation, CRC progression and metastasis – not necessarily by direct infection of epithelial cells only, but also by interaction with the microenvironment of infected cells. In this context, there are striking common features of EBV, CMV, HPV and JCV that are able to promote oncogenesis, in terms of establishing latent infections and affecting p53‐/pRb‐driven, epithelial–mesenchymal transition (EMT)‐/EGFR‐associated and especially Wnt/β‐catenin‐driven pathways. We speculate that, at least in part, such viral impacts on particular pathways might be reflected in lasting (e.g. mutational or further genomic) fingerprints of viruses in cells. Also, the complex interplay between several species within the intestinal microbiome, involving a direct or indirect impact on colorectal and microenvironmental cells but also between, for example, phages and bacterial and viral pathogens, and further novel species certainly might, in part, explain ongoing difficulties to establish unequivocal monocausal links between specific viral infections and CRC.

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Interaction between JCV large T-antigen and β-catenin

Cited by 64 publications

References 25 publications

Hepatitis C virus NS5A protein interacts with -catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion

Hepatitis C virus NS5A protein interacts with -catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion

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

Viruses in colorectal cancer

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