T-antigen of the human polyomavirus JC attenuates faithful DNA repair by forcing nuclear interaction between IRS-1 and Rad51

2005 ◽  
Vol 206 (1) ◽  
pp. 35-46 ◽  
Author(s):  
Joanna Trojanek ◽  
Sidney Croul ◽  
Thu Ho ◽  
Jin Ying Wang ◽  
Armine Darbinyan ◽  
...  
Keyword(s):  
Dna Repair ◽  
Nuclear Interaction ◽  
T Antigen ◽  
Human Polyomavirus ◽  
Polyomavirus Jc

scholarly journals Physical and Functional Interaction between the Y-Box Binding Protein YB-1 and Human Polyomavirus JC Virus Large T Antigen

1999 ◽  
Vol 73 (12) ◽  
pp. 10146-10157 ◽  
Author(s):  
Mahmut Safak ◽  
Gary L. Gallia ◽  
Sameer A. Ansari ◽  
Kamel Khalili
Keyword(s):  
Rna Binding ◽  
Jc Virus ◽  
Binding Protein ◽  
Regulatory Protein ◽  
T Antigen ◽  
Human Polyomavirus ◽  
Gene Promoters ◽  
Large T Antigen ◽  
Functional Interaction ◽  
Polyomavirus Jc

ABSTRACT Y-box binding protein YB-1 is a member of a family of DNA and RNA binding proteins which have been shown to affect gene expression at both the transcriptional and translational levels. We have previously shown that YB-1 modulates transcription from the promoters of the ubiquitous human polyomavirus JC virus (JCV). Here we investigate the physical and functional interplay between YB-1 and the viral regulatory protein large T antigen (T-antigen), using JCV as a model system. Results of mobility band shift assays demonstrated that the efficiency of binding of YB-1 to a 23-bp single-stranded viral target sequence was significantly increased when T-antigen was included in the binding reaction mixture. Affinity chromatography and coimmunoprecipitation assays demonstrated that YB-1 and T-antigen physically interact with each other. Additionally, results of transcription studies demonstrated that these two proteins interact functionally on the JCV early and late gene promoters. Whereas ectopic expression of YB-1 and T-antigen results in synergistic transactivation of the viral late promoter, YB-1 alleviates T-antigen-mediated transcriptional suppression of the viral early promoter activity. Furthermore, we have localized, through the use of a series of deletion mutants, the sequences of these proteins which are important for their interaction. The T-antigen-interacting region of YB-1 is located in the cold shock domain of YB-1 and its immediate flanking sequences, and the YB-1-interacting domain of T-antigen maps to the carboxy-terminal half of T-antigen. Results of transient transfection assays with various YB-1 mutants and T-antigen expression constructs confirm the specificity of the functional interaction between YB-1 and T-antigen. Taken together, these data demonstrate that the cellular factor YB-1 and the viral regulatory protein T-antigen interact both physically and functionally and that this interaction modulates transcription from the JCV promoters.

Human polyomavirus JC variants in Papua New Guinea and Guam reflect ancient population settlement and viral evolution

2000 ◽  
Vol 2 (9) ◽  
pp. 987-996 ◽  
Author(s):  
Caroline F Ryschkewitsch ◽  
Jonathan S Friedlaender ◽  
Charles S Mgone ◽  
David V Jobes ◽  
Hansjürgen T Agostini ◽  
...  
Keyword(s):  
Papua New Guinea ◽  
Viral Evolution ◽  
New Guinea ◽  
Human Polyomavirus ◽  
Ancient Population ◽  
Polyomavirus Jc

scholarly journals Characterization of T Antigens, Including Middle T and Alternative T, Expressed by the Human Polyomavirus Associated with Trichodysplasia Spinulosa

2015 ◽  
Vol 89 (18) ◽  
pp. 9427-9439 ◽  
Author(s):  
Els van der Meijden ◽  
Siamaque Kazem ◽  
Christina A. Dargel ◽  
Nick van Vuren ◽  
Paul J. Hensbergen ◽  
...  
Keyword(s):  
Expression Pattern ◽  
T Antigen ◽  
Productive Infection ◽  
Human Polyomavirus ◽  
T Antigens ◽  
Viral Oncoprotein ◽  
Early Region ◽  
Alternative Mrna Splicing ◽  
Donor And Acceptor ◽  
Human Polyomaviruses

ABSTRACTThe polyomavirus tumor (T) antigens play crucial roles in viral replication, transcription, and cellular transformation. They are encoded by partially overlapping open reading frames (ORFs) located in the early region through alternative mRNA splicing. The T expression pattern of the trichodysplasia spinulosa-associated polyomavirus (TSPyV) has not been established yet, hampering further study of its pathogenic mechanisms and taxonomic relationship. Here, we characterized TSPyV T antigen expression in human cell lines transfected with the TSPyV early region. Sequencing of T antigen-encoded reverse transcription-PCR (RT-PCR) products revealed three splice donor and acceptor sites creating six mRNA splice products that potentially encode the antigens small T (ST), middle T (MT), large T (LT), tiny T, 21kT, and alternative T (ALTO). Except for 21kT, these splice products were also detected in skin of TSPyV-infected patients. At least three splice products were confirmed by Northern blotting, likely encoding LT, MT, ST, 21kT, and ALTO. Protein expression was demonstrated for LT, ALTO, and possibly MT, with LT detected in the nucleus and ALTO in the cytoplasm of transfected cells. Splice site and start codon mutations indicated that ALTO is encoded by the same splice product that encodes LT and uses internal start codons for initiation. The genuineness of ALTO was indicated by the identification of acetylated N-terminal ALTO peptides by mass spectrometry. Summarizing, TSPyV exhibits an expression pattern characterized by both MT and ALTO expression, combining features of rodent and human polyomaviruses. This unique expression pattern provides important leads for further study of polyomavirus-related disease and for an understanding of polyomavirus evolution.IMPORTANCEThe human trichodysplasia spinulosa-associated polyomavirus (TSPyV) is distinguished among polyomaviruses for combining productive infection with cell-transforming properties. In the research presented here, we further substantiate this unique position by indicating expression of both middle T antigen (MT) and alternative T antigen (ALTO) in TSPyV. So far, none of the human polyomaviruses was shown to express MT, which is considered the most important viral oncoprotein of rodent polyomaviruses. Coexpression of ALTO and MT, which involves a conserved, recently recognized overlapping ORF subject to positive selection, has not been observed before for any polyomavirus. As a result of our findings, this study provides valuable new insights into polyomavirus T gene use and expression. Obviously, these insights will be instrumental in further study and gaining an understanding of TSPyV pathogenicity. More importantly, however, they provide important leads with regard to the interrelationship, functionality, and evolution of polyomaviruses as a whole, indicating that TSPyV is a suitable model virus to study these entities further.

scholarly journals Merkel Cell Carcinoma: Recent Progress and Current Priorities on Etiology, Pathogenesis, and Clinical Management

2009 ◽  
Vol 27 (24) ◽  
pp. 4021-4026 ◽  
Author(s):  
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Clinical Management ◽  
Expression Profiles ◽  
T Antigen ◽  
Neuroendocrine Cells ◽  
Human Polyomavirus ◽  
Adjuvant Radiation ◽  
Cytokeratin 20 ◽  
Merkel Cell

Purpose To expedite improved understanding, diagnosis, treatment, and prevention of Merkel cell carcinoma (MCC), a rare malignancy of cutaneous neuroendocrine cells that has a 28% 2-year mortality rate. Methods This article summarizes a workshop that discussed the state-of-the-art research and priorities for research on MCC and on a new human polyomavirus (ie, MCPyV) recently discovered in 80% of MCC tumors. Results Normal Merkel cells are widely distributed in the epidermis near the end of nerve axons and may function as mechanoreceptors or chemoreceptors. Malignant MCC cells typically stain for cytokeratin 20 as well as for other epithelial and neuroendocrine markers. MCC subtypes, which are based on histology, on cell line growth properties, and on gene expression profiles, have been reported but have not been linked to prognosis. Clinical management has been empiric. MCPyV is clonally integrated at various sites in the human genome of MCC tumors, with truncating mutations in the viral, large T antigen gene that interrupt viral replication. MCPyV seroprevalence may be high, as with previously known human polyomaviruses. MCC risk is increased 11-fold with AIDS and with other cell-mediated immune deficiencies, B-cell neoplasms, and ultraviolet radiation exposure. Conclusion Development and validation of a range quantitative polymerase chain reaction and serologic assays for detection of MCPyV, as well as an infectious clone of the virus, would clarify the fundamental biology, natural history, and epidemiology of the virus, of MCC, and of other diseases. Contingent on standardized histologic diagnosis and staging of MCC, consortia are needed to clarify the risks and benefits of sentinel lymph node biopsy, adjuvant radiation therapy, and salvage therapies; consortia are needed also for epidemiologic studies of MCC etiology.

scholarly journals Novel Polyomavirus Detected in the Feces of a Chimpanzee by Nested Broad-Spectrum PCR

2005 ◽  
Vol 79 (6) ◽  
pp. 3883-3887 ◽  
Author(s):  
Reimar Johne ◽  
Dirk Enderlein ◽  
Hermann Nieper ◽  
Hermann Müller
Keyword(s):  
Pan Troglodytes ◽  
Broad Spectrum ◽  
Animal Species ◽  
Major Capsid Protein ◽  
Human Polyomavirus ◽  
Jc Polyomavirus ◽  
Distinct Virus ◽  
Field Samples ◽  
Polyomavirus Jc ◽  
Capsid Protein Vp1

ABSTRACT In order to screen for new polyomaviruses in samples derived from various animal species, degenerated PCR primer pairs were constructed. By using a nested PCR protocol, the sensitive detection of nine different polyomavirus genomes was demonstrated. The screening of field samples revealed the presence of a new polyomavirus, tentatively designated chimpanzee polyomavirus (ChPyV), in the feces of a juvenile chimpanzee (Pan troglodytes). Analysis of the region encoding the major capsid protein VP1 revealed a unique insertion in the EF loop of the protein and showed that ChPyV is a distinct virus related to the monkey polyomavirus B-lymphotropic polyomavirus and the human polyomavirus JC polyomavirus.

scholarly journals Primary Central Nervous System Lymphoma Expressing the Human Neurotropic Polyomavirus, JC Virus, Genome

2004 ◽  
Vol 78 (7) ◽  
pp. 3462-3469 ◽  
Author(s):  
Luis Del Valle ◽  
Sahnila Enam ◽  
Cesar Lara ◽  
Judith Miklossy ◽  
Kamel Khalili ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Lymphocytes ◽  
Dna Sequences ◽  
Jc Virus ◽  
T Antigen ◽  
Viral Capsid ◽  
Polyomavirus Jc ◽  
Positive Immunoreactivity ◽  
Viral Capsid Proteins

ABSTRACT B lymphocytes are known as a potential site for latency and reactivation of the human neurotropic polyomavirus, JC virus (JCV). In light of recent studies on the oncogenicity of JCV and the transforming ability of the JCV early protein, T antigen, we investigated the association of JCV with B-cell lymphomas of the central nervous system. Examination of 27 well-characterized clinical specimens by gene amplification and immunohistochemistry revealed the presence of DNA sequences corresponding to the JCV early genome and the late Agnoprotein in 22 samples and the JCV late genome encoding the viral capsid proteins in 8 samples. Expression of T antigen and that of Agnoprotein by immunohistochemistry were each detected in six specimens. No evidence of the production of viral capsid proteins was observed, ruling out productive infection of JCV in the tumor cells. The results from laser capture microdissection verified the presence of JCV T-antigen sequences in tumor cells with positive immunoreactivity to antibodies against the viral proteins T antigen and Agnoprotein. Due to previous reports demonstrating an association of the Epstein-Barr virus (EBV) with transformation of B lymphocytes, EBV DNA sequences and the EBV transforming protein, latent membrane protein 1 (LMP1), were analyzed in parallel. EBV LMP1 DNA sequences were detected in 16 of 23 samples, and LMP1 expression was detected in 16 samples, 5 of which exhibited positive immunoreactivity to JCV proteins. Double labeling demonstrated coexpression of JCV T antigen and EBV LMP1 in the same cells. The detection of the JCV genome in large numbers of B-cell lymphomas and its coexistence with EBV suggest a potential role for JCV in the pathogenesis of primary CNS lymphoma.

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