Interaction of retinoblastoma protein family members with large T-antigen of primate polyomaviruses

White, Martyn K.; Khalili, Kamel

doi:10.1038/sj.onc.1209618

Cited by 47 publications

(46 citation statements)

References 80 publications

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“…Necrosis, a process distinct from either apoptosis or autophagy, may also cause cell death (for a review, see reference 24). The observed cell cycle arrest upon T-antigen knockdown can be more directly explained by alterations of the Rb-E2F pathway: Rb family proteins are the master regulators of S-phase entry, and they are the prominent cellular targets for polyomavirus T antigens (13,45). Despite the fact that MCV was discovered only recently, both observational data and the experimental studies described here demonstrate that it is the likely infectious trigger for most human MCC.…”

Section: Discussionmentioning

confidence: 89%

Merkel Cell Polyomavirus-Infected Merkel Cell Carcinoma Cells Require Expression of Viral T Antigens

Houben

Shuda

Weinkam

et al. 2010

J Virol

399

439

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Merkel cell carcinoma (MCC) is the most aggressive skin cancer. Recently, it was demonstrated that human Merkel cell polyomavirus (MCV) is clonally integrated inMerkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer. Although it is rare, its reported incidence is increasing (19). MCC is associated with UV exposure and affects primarily elderly and immune-suppressed patients (5,11,17,26). The susceptibility of MCC to immune surveillance is similar to that of known virus-induced cancers and suggests that MCC has an infectious trigger (9). Recently, a new human polyomavirus, termed Merkel cell polyomavirus (MCV), was discovered to be clonally integrated into MCC tumor genomes (14). While MCV integration occurs at distinct sites in MCC tumors from different individuals, primary tumors and corresponding metastases have identical integration sites, consistent with the occurrence of MCV infection and integration prior to clonal expansion and metastasis (14,37). A number of studies have confirmed that MCV is present in 69 to 85% of MCC tumors collected from Europe and the United States (4, 15, 21, 41). Surveys of control non-MCC skin, hematolymphoid, and neuroendocrine tumors are generally negative for MCV, although incidental low-level infection can be detected (4,14,22,33,34,39,42,44).All polyomaviruses encode alternatively spliced large T (LT) and small T (sT) antigen transcripts that share exon 1 of the T-antigen (TA) locus. Additional multiply spliced TA transcripts have been described for different polyomaviruses, including the 17kT and 57kT antigens in simian virus 40 (SV40) and MCV, respectively (40,46). Research on viral proteins encoded by the TA locus has been central to uncovering cell signaling networks important in cancer biology (10, 38). The targeting of cellular proteins, such as retinoblastoma protein (Rb), p53, and protein phosphatase 2A (PP2A), by TAs contributes to polyomavirusinduced cell transformation (for reviews, see references 1 and 2). MCV TAs that are expressed in MCC tumors lack a putative p53 binding domain because of tumor-associated T-antigen deletion mutations (37,40). Other conserved tumor suppressor-targeting motifs, including the Rb binding domain (LXCXE motif), the J domain (HPDK) in LT/57kT, and a putative PP2A interaction domain in sT, remain intact (40).Current data point toward MCV as the infectious cause for most Merkel cell cancers: the virus is associated with MCC tumors and, when present, expresses T antigen in tumor cells but not in healthy surrounding tissues (7,20,39). MCV is specific to MCC and is not detected at significant levels in other cancers or in healthy skin examined to date, despite widespread circulation of MCV among human populations (8,23,29,42). Clonal analysis of MCC tumors also supports the correct temporal relationship for causality; i.e., MCV infection occurs prior to MCC tumor development (18). If MCV is a direct cause of MCC tumorigenesis, it is expected that MCC tumors will require MCV protein expression to maintain the tumor ...

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Section: Discussionmentioning

confidence: 89%

Merkel Cell Polyomavirus-Infected Merkel Cell Carcinoma Cells Require Expression of Viral T Antigens

Houben

Shuda

Weinkam

et al. 2010

J Virol

399

439

View full text Add to dashboard Cite

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“…Large T antigen has been demonstrated to exhibit numerous functions, including interaction with, and inhibition of, the retinoblastoma protein (pRb) (48,490,533) and p53 (110). Interaction with p53 also prevents apoptosis induced by checkpoint activation when cells aberrantly enter S phase (112).…”

Section: Replication Of Jcv Genomic Dnamentioning

confidence: 99%

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

et al. 2012

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SUMMARY Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.

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“…Our reasoning was that T-Ag would provide a key target because it is essential for viral DNA replication and, by binding proteins such as p53 and pRb, advancing the cell cycle into S-phase, where the cellular factors required for viral DNA synthesis become available [54,55]. This latter function means that T-Ag causes the transformation of cells in culture and can promote tumorigenesis in experimental animals [54].…”

Section: Jcvmentioning

confidence: 99%

Gene Editing for Treatment of Neurological Infections

et al. 2016

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The study of neurological infections by viruses defines the field of neurovirology, which has emerged in the last 30 years and was founded upon the discovery of a number of viruses capable of infecting the human nervous system. Studies have focused on the molecular and biological basis of viral neurological diseases with the aim of revealing new therapeutic options. The first studies of neurovirological infections can be traced back to the discovery that some viruses have an affinity for the nervous system with research into rabies by Louis Pasteur and others in the 1880s. Today, the immense public health impact of neurovirological infections is illustrated by diseases such as neuroAIDS, progressive multifocal leukoencephalopathy, and viral encephalitis. Recent research has seen the development of powerful new techniques for gene editing that promise revolutionary opportunities for the development of novel therapeutic options. In particular, clustered regulatory interspaced short palindromic repeat-associated 9 system provides an effective, highly specific and versatile tool for targeting DNA viruses that are beginning to allow the development of such new approaches. In this short review, we discuss these recent developments, how they pertain to neurological infections, and future prospects.

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Interaction of retinoblastoma protein family members with large T-antigen of primate polyomaviruses

Cited by 47 publications

References 80 publications

Merkel Cell Polyomavirus-Infected Merkel Cell Carcinoma Cells Require Expression of Viral T Antigens

Merkel Cell Polyomavirus-Infected Merkel Cell Carcinoma Cells Require Expression of Viral T Antigens

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

Gene Editing for Treatment of Neurological Infections

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