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At least 217 records · Page 12Linked to original sources
PubMed1995

Zinc-binding and protein-protein interactions mediated by the polyomavirus large T antigen zinc finger.

Polyomavirus large tumor antigen (LT) contains a potential C2H2 zinc binding element between residues 452 and 472. LT also contains a third histidine in this region, conserved among the polyomavirus LTs. Synthetic peptides of this region bound a single atom of zinc, as determined by spectroscopic analysis. Blotting experiments also showed that fusion proteins containing the element, as well as full-length LT, bound 65Zn. Polyomavirus middle T and small T antigens also bound zinc in the blotting assay. Site-directed mutagenesis showed the importance of this element in LT. Point mutations in four of the conserved residues (C-452, C-455, H-465, and H-469) blocked the ability of LT to function in viral DNA replication, while mutation of H-472-->L decreased replication to 1/30th that of the wild type. Point mutations in intervening residues tested had little effect on replication. Mutants resulting from mutations in the conserved cysteine or histidine residues retained the ability to bind origin DNA. However, they did show a defect in self-association. Because double-hexamer formation is involved in DNA replication, this deficiency is sufficient to explain the defect in replication. Mutants created by point mutations of the coordinating residues were also deficient in replication-associated phosphorylations.

3T3 Cells↗
PubMed1999

Binding of polyomavirus small T antigen to protein phosphatase 2A is required for elimination of p27 and support of S-phase induction in concert with large T antigen.

Although polyomavirus large T antigen readily transactivates S-phase-specific enzymes in serum-starved Swiss 3T3 mouse fibroblasts, it is incapable by itself to efficiently drive such cells into S phase. We describe here that this inability correlates with a weak proficiency of the viral protein to induce the synthesis of cyclin A and cyclin E and to stimulate the respective cyclin/cdk activities. Polyomavirus small T antigen, which together with the large T protein supports S-phase induction, strongly contributes to the synthesis of cyclin A. In addition, small T antigen causes a dramatic induction of cyclin A- and, together with large T antigen, of cyclin E-specific protein kinase activity. This latter function of polyomavirus small T antigen correlates with its competence to provoke the elimination of the kinase inhibitor p27(Kip1). An interaction of the small T antigen with the protein phosphatase 2A is essential for this activity. Hence, the ability to drive quiescent Swiss 3T3 cells into S phase results from the capacity of large T antigen to transactivate DNA synthesis enzymes by its interaction with retinoblastoma-type proteins and from the potential of the large and the small T antigens together to stimulate cyclin A synthesis and cyclin A- and cyclin E-dependent protein kinase activity.

3T3 Cells↗
PubMed2005

Induction and utilization of an ATM signaling pathway by polyomavirus.

Progression from G(1) to S is essential for polyomavirus DNA replication and depends on the interaction of large T with the retinoblastoma gene product pRb. This virus-induced replication pathway is accompanied by p53 activation resembling a DNA damage response (12). We sought to determine whether this pathway depends in part on activation of the ATM (ataxia telangiectasia mutated) kinase and whether the virus gains advantages from this pathway beyond that of entry into S. We show that polyomavirus infection activates the S- and G(2)-phase checkpoints in primary as well as established mouse cells. Infected cells undergo a prolonged S phase compared to uninfected serum-stimulated cells and show no evidence of a G(2)-->M transition before lytic death ensues. Infection is accompanied by increases in ATM activity in vitro and in the level of ATM-S1981-P in vivo. The incubation of infected cells with caffeine, a known ATM inhibitor, did not block entry into S but reduced the rate of viral compared to cellular DNA synthesis. Importantly, caffeine lowered the yields of viral DNA an average of 3- to 6-fold and those of infectious virus by as much as 10-fold. Virus yields were 10-fold lower in ATM (-/-) p53(-/-) than in ATM(+/+) p53(-/-) mouse embryo fibroblasts, indicating a p53-independent role of ATM in productive infection. Replacement of the normal SMC1 (structural maintenance of chromosomes, or cohesin) protein, a critical ATM substrate in the DNA repair pathway, with its phosphorylation mutant SMC1(S957AS966A) also lowered virus yields by roughly 90%. We suggest that polyomavirus activates and utilizes a component(s) of an ATM pathway of DNA repair to prolong S phase and aid its own replication.

Animals↗
PubMed2006

Interplay of cellular and humoral immune responses against BK virus in kidney transplant recipients with polyomavirus nephropathy.

Reactivation of the polyomavirus BK (BKV) causes polyomavirus nephropathy (PVN) in kidney transplant (KTx) recipients and may lead to loss of the renal allograft. We have identified two HLA-A*0201-restricted nine-amino-acid cytotoxic T lymphocyte (CTL) epitopes of the BKV major capsid protein VP1, VP1(p44), and VP1(p108). Using tetramer staining assays, we showed that these epitopes were recognized by CTLs in 8 of 10 (VP1(p44)) and 5 of 10 (VP1(p108)) HLA-A*0201+ healthy individuals, while both epitopes elicited a CTL response in 10 of 10 KTx recipients with biopsy-proven PVN, although at variable levels. After in vitro stimulation with the respective peptides, CTLs directed against VP1(p44) were more abundant than against VP1(p108) in most healthy individuals, while the converse was true in KTx recipients with PVN, suggesting a shift in epitope immunodominance in the setting of active BKV infection. A strong CTL response in KTx recipients with PVN appeared to be associated with decreased BK viral load in blood and urine and low anti-BKV antibody titers, while a low or undetectable CTL response correlated with viral persistence and high anti-BKV antibody titers. These results suggest that this cellular immune response is present in most BKV-seropositive healthy individuals and plays an important role in the containment of BKV in KTx recipients with PVN. Interestingly, the BKV CTL epitopes bear striking homology with the recently described CTL epitopes of the other human polyomavirus JC (JCV), JCV VP1(p36) and VP1(p100). A high degree of epitope cross-recognition was present between BKV and corresponding JCV-specific CTLs, which indicates that the same population of cells is functionally effective against these two closely related viruses.

Adult↗
PubMed1992

Identification of binding sites on the regulatory A subunit of protein phosphatase 2A for the catalytic C subunit and for tumor antigens of simian virus 40 and polyomavirus.

Protein phosphatase 2A is composed of three subunits: the catalytic subunit C and two regulatory subunits, A and B. The A subunit consists of 15 nonidentical repeats and has a rodlike shape. It is associated with the B and C subunits as well as with the simian virus 40 small T, polyomavirus small T, and polyomavirus medium T tumor antigens. We determined the binding sites on subunit A for subunit C and tumor antigens by site-directed mutagenesis of A. Twenty-four N- and C-terminal truncations and internal deletions of A were assayed by coimmunoprecipitation for their ability to bind C and tumor antigens. It was found that C binds to repeats 11 to 15 at the C terminus of A, whereas T antigens bind to overlapping but distinct regions of the N terminus. Simian virus 40 small T binds to repeats 3 to 6, and polyomavirus small T and medium T bind to repeats 2 to 8. The data suggest cooperativity between C and T antigens in binding to A. This is most apparent for medium T antigen, which can only bind to those A subunit molecules that provide the entire binding region for the C subunit. We infer from our results that B also binds to N-terminal repeats. A model of the small T/medium T/B-A-C complexes is presented.

Amino Acid Sequence↗
PubMed1996

Studies of partially transforming polyomavirus mutants establish a role for phosphatidylinositol 3-kinase in activation of pp70 S6 kinase.

Infection of mouse fibroblasts by wild-type polyomavirus results in increased phosphorylation of ribosomal protein S6 (D.A. Talmage, J. Blenis, and T.L. Benjamin, Mol. Cell. Biol. 8:2309-2315, 1988). Here we identify pp70 S6 kinase (pp70S6K) as a target for signal transduction events leading from polyomavirus middle tumor antigen (mT). Two partially transforming virus mutants altered in different mT signalling pathways have been studied to elucidate the pathway leading to S6 phosphorylation. An upstream role for mT-phosphatidylinositol 3-kinase (PI3K) complexes in pp70S6K activation is implicated by the failure of 315YF, a mutant unable to promote PI3K binding, to elicit a response. This conclusion is supported by studies using wortmannin, a known inhibitor of PI3K. In contrast, stable interaction of mT with Shc, a protein thought to be involved upstream of Ras, is dispensable for pp70S6K activation. 250YS, a mutant mT which retains a binding site for PI3K but lacks one for Shc, stimulates pp70S6K to wild-type levels. Mutants 315YF and 250YS induce partial transformation of rats fibroblasts with distinct phenotypes, as judged from morphological and growth criteria. Neither mutant induces growth in soft agar, indicating that an increase in S6 phosphorylation, while necessary for cell cycle progression in normal mitogenesis, is not sufficient for anchorage-independent cell growth. In the polyomavirus systems, the latter requires integration of signals from mT involving both Shc and PI3K.

3T3 Cells↗
PubMed2002

Stimulation of DNA replication from the polyomavirus origin by PCAF and GCN5 acetyltransferases: acetylation of large T antigen.

The PCAF and GCN5 acetyltransferases, but not p300 or CBP, stimulate DNA replication when tethered near the polyomavirus origin. Replication stimulation by PCAF and GCN5 is blocked by mutational inactivation of their acetyltransferase domains but not by deletion of sequences that bind p300 or CBP. Acetylation of histones near the polyomavirus origin assembled into chromatin in vivo is not detectably altered by expression of these acetyltransferases. PCAF and GCN5 interact with polyomavirus large T antigen in vivo, PCAF acetylates large T antigen in vitro, and large T-antigen acetylation in vivo is dependent upon the integrity of the PCAF acetyltransferase domain. These data suggest replication stimulation occurs through recruitment of large T antigen to the origin and acetylation by PCAF or GCN5.

3T3 Cells↗
PubMed1986

Transformation of chicken embryo fibroblasts and tumor induction by the middle T antigen of polyomavirus carried in an avian retroviral vector.

The middle T antigen of polyomavirus transformed primary chicken embryo fibroblasts when expressed from a replication-competent avian retrovirus. This in vitro-constructed retrovirus, SRMT1, is a variant of Rous sarcoma virus that encodes the middle T antigen in place of v-src. Inoculation of SRMT1 into 1-week-old chickens rapidly induced hemangiomas and hemangiosarcomas. As shown with mammalian cells infected with polyomavirus, polyomavirus middle T antigen appears to be associated with p60c-src in chicken cells infected with SRMT1. When lysates of SRMT1-infected cells immunoprecipitated with either a monoclonal antibody against p60src or anti-T serum were assayed in an in vitro kinase reaction, the middle T antigen was heavily phosphorylated. To see whether an excess of p60c-src could alter the extent of phosphorylation of the middle T protein or the process of cell transformation by middle T, cells were doubly infected with SRMT1 and NY501, a virus which overexpresses p60c-src. Doubly infected chicken embryo fibroblasts transformed with the same kinetics and were morphologically indistinguishable from chicken embryo fibroblasts infected with SRMT1 alone. Phosphorylation of the middle T antigen was elevated two- to fivefold relative to cells infected only with SRMT1.

Animals↗
PubMedDate not supplied

Urothelial bladder carcinoma and viral infections: different association with human polyomaviruses and papillomaviruses.

Bladder cancer is the second most commonly occurring genitourinary cancer in adults. The interaction of different carcinogenic and cocarcinogenic agents are responsible for bladder urothelial carcinoma: alcohol and smoking habits, Schistosoma haematobium infection, exposition to chemicals, analgesic and antineoplastic drugs prolonged use. Recently also viral infections have been associated to this pathology. In this study the correlation between viral infections and bladder carcinoma has been evaluated. A group of 32 patients affected by primary bladder neoplasia has been analysed. A control group of 20 autoptic samples of healthy bladder was analysed. The DNA of the following viruses has been searched by polymerase chain reaction (PCR): Adenovirus, Herpes simplex virus type 1 (HSV-1), Herpes simplex virus type 2 (HSV-2), Human Papillomaviruses (HPV), Polyomaviruses (BKV and JCV). In the examined population the association bladder carcinoma-HPV, found by others, has not been confirmed. The high percentage of human polyomaviruses present in the samples is a statistically significant data (p=0.0087) and allows to presume that BKV and JCV may play a role in the aetiology of bladder tumor. In particular the polyomavirus BK, which is found in significative percentage both in single infection (p=0.0036) and in co-infections with other viral species (p=0.035), may be an important co-factor in the pathogenesis of bladder carcinoma.

Adult↗
PubMed1999

[Polyomavirus infections in exotic birds in Switzerland].

Polyomavirus infections in budgerigars, in other parrots as well as in passeriformes have been described in many countries, but not in Switzerland so far. This paper reports on cases of polyomavirus infections in three different bird collections in Switzerland. The first outbreak occurred in a mixed collection of passeriformes, the second in a collection of parrotlets (Genus Forpus), and the third in a large groups of parrots (Psittaciformes), of which only one recently acquired Kea (Nestor notabilis) was affected. The clinical symptoms, gross necropsy changes and histopathologic findings are described. The presence of avian polyomavirus was confirmed by the polymerase chain reaction (PCR).

Animals↗
PubMed2003

Interference of mouse polyomavirus with the c-myc gene and its product in mouse mammary adenocarcinomas.

In two tumour sublines (T.wt/BL and T.wt/Bc), established from mammary adenocarcinomas caused by mouse polyoma (Py) infection of nu/nu mice, integration of polyomavirus DNA sequences into the c-myc gene locus was mapped. A complete Py genome was found to be integrated just upstream from the c-myc gene in T.wt/BL cell line, while only a part of the early Py region coding for the early proteins was inserted in the chromosomal DNA of T.wt/Bc cells. An interference of Py sequences with the regulation of c-myc gene expression gives further significance to a Py-derived tumour system that appears to be similar to some human mammary cancers in the modifications of c-myc expression. Both cell lines were found to produce truncated large T antigen and entire middle and small T antigens. In addition, production of VP1 protein was observed in the T.wt/BL cell line. The integration of polyomavirus sequences and/or expression of viral proteins caused an elevation of c-myc expression. The level of the c-myc expression was higher in both tumour cell lines in comparison with control normal murine mammary gland (NMuMG) lines, but substantially lower than in NMuMG cells infected with polyomavirus. Possible co-operation of Py proteins with c-Myc was examined. Through GST fusion protein pull-down experiments, we evidenced, that c-Myc forms a complex with the common part of the Py early antigens in the two tumour cell lines. Co-localisation of the c-myc and LT was observed in cells overexpressing c-Myc and LT.

Adenocarcinoma↗
PubMed2004

Detection of polyomavirus DNA in human brain tumors.

AIM: To investigate surgically resected human brain tumors for the presence of polyomavirus DNA. MATERIALS AND METHODS: 65 samples of surgically resected human brain tumors (57 tumors were of neuroectodermal genesis, 4--mesenchimal, 4--metastatic tumors) were examined for the presence of viral DNA by PCR analysis. RESULTS: DNA of polyomaviruses was found in oligodendroligomas (66.7% of cases), oligodendroastrocytomas (66.7% of cases) and glioblastomas (40% of cases). In metastatic tumors viral infection had not been detected. No correlation between the grade of brain tumors and infection with polyomavirus DNA has been revealed. CONCLUSION: Our data point to importance of investigation of the brain tumors and cerebrospinal fluid for determination of viral infection.

Brain Neoplasms↗
PubMedDate not supplied

[Molecular bases of papillomavirus and polyomavirus carcinogenesis].

Polyomavirus is able to induce tumors in its natural host as well as to transform cells in cultures. On the other hand, human papillomavirus has been involved in several types of neoplasias such as anogenital lesions. Little is known about the mechanisms through which these viruses induce both transformation and tumorigenesis. The present, work shows some characteristics of the mechanisms that papillomavirus and polyomavirus use to participate in tumorigenesis. It has also been noticed that the infection caused by polyomavirus resembles that performed by papillomaviruses (which belong to the same Papovaviridae family). Some similarities and differences between these viruses are considered.

Animals↗
PubMedDate not supplied

Development of a chicken model for studying avian polyomavirus infection.

The purpose of this study was to develop a chicken model for studying the pathogenesis of avian polyomaviral infection. Ninety-two 1-day-old specific-pathogen-free (SPF) chicks were divided into the following three treatment groups: nontreated controls, treated with cyclosporine and treated with cyclophosphamide (CY). All birds were inoculated with polyomavirus; half were orally inoculated and half were inoculated by intraperitoneal (IP) injection. Spontaneous mortality and lesion development consistent with polyomaviral infection in psittacine birds occurred only in the CY-treated, IP-inoculated chicks. Immunohistochemistry confirmed that the intranuclear inclusions found microscopically were associated with polyomaviral antigen. Serology demonstrated postinoculation titers against polyomavirus in several experimental groups. One-day-old SPF chickens appear to be convenient models for investigating the pathogenesis of avian polyomavirus infection.

Animals↗
PubMedDate not supplied

Fatal avian polyomavirus infection during quarantine in adult wild-caught red-faced lovebirds (Agapornis pullaria).

An outbreak of avian polyomavirus infection is reported in a group of six wild-caught red-faced lovebirds (Agapornis pullaria), all of which died during quarantine. The birds had not shown any previous symptoms. Histologic examination of the lungs, kidneys, livers, and spleens revealed the presence of basophilic intranuclear inclusions. Avian polyomavirus was isolated from the liver and the spleen. Neutralizing antibodies were detected in the sera from other lovebirds (Agapornis personata, Agapornis taranta) that had contact with the A. pullaria. A serologic comparison showed a close relationship with budgerigar polyomavirus.

Animals↗
PubMed1999

Linked production of antibodies to mammalian DNA and to human polyomavirus large T antigen: footprints of a common molecular and cellular process?

OBJECTIVE: To test whether the presence of antibodies to human polyomavirus large T antigen, a viral DNA-binding protein essential for productive polyomavirus replication, correlates with the presence of antibodies to single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), or the autologous TATA-binding protein (TBP). METHODS: Sera from patients with various diagnosed or suspected autoimmune syndromes were analyzed for the presence of antibodies to T antigen, DNA, or TATA-binding protein, and correlations were determined. Rheumatoid factor (RF) was studied as a control antibody. RESULTS: A highly significant correlation between antibodies to T antigen and antibodies to ssDNA or TATA-binding protein, but not between anti-T antigen antibodies and RF, was found in all patient groups. Of all sera that were positive for antibodies to dsDNA, 62% were positive for antibodies to T antigen (P<0.03). CONCLUSION: A non-self DNA-binding protein such as human polyomavirus large T antigen may render DNA immunogenic upon binding to nucleosomes when expressed in vivo. This is indicated by the strong correlation between antibodies to T antigen and antibodies to DNA or TBP and is consistent with a hapten-carrier model. This model implies cognate antigen-selective interaction of T antigen-specific T helper cells and DNA-specific B cells or B cells specific for other components of nucleosomes, consistent with the results of previous experiments.

Antibodies, Antinuclear↗
PubMed2005

The human polyomavirus BK: Potential role in cancer.

In human cancer, a role has been suggested for the human polyomavirus BK, primarily associated with tubulointerstitial nephritis and ureteric stenosis in renal transplant recipients, and with hemorrhagic cystitis in bone marrow transplant (BMT) recipients. After the initial infection, primarily unapparent and without clinical signs, the virus disseminates and establishes a persistent infection in the urinary tract and lymphocytes. There is correlative evidence regarding potential role of polyomavirus BK in cancer. In fact, the BK virus (BKV) DNA (complete genome and/or subgenomic fragments containing the early region) is able to transform embryonic fibroblasts and cells cultured from kidney and brain of hamster, mouse, rat, rabbit, and monkey. Nevertheless, transformation of human cells by BKV is inefficient and often abortive. Evidence supporting a possible role for BKV in human cancer has accumulated slowly in recent years, after the advent of polymerase chain reaction (PCR). BKV is known to commonly establish persistent infections in people and to be excreted in the urine by individuals who are asymptomatic, complicating the evaluation of its potential role in development of human cancer. Therefore, there is no certain proof that human polyomavirus BK directly causes the cancer in humans or acts as a cofactor in the pathogenesis of some types of human cancer.

Animals↗
PubMed2001

Identification of a DNA encapsidation sequence for human polyomavirus pseudovirion formation.

Human polyomavirus is a naked capsid virus containing a closed circular double-stranded DNA genome. The mechanism of DNA encapsidation for the viral progeny formation is not fully understood. In this study, DNA encapsidation domain of the major capsid protein, VP1, of the human polyomavirus JCV was investigated. When the first 12 amino acids were deleted, the E. coli expressed VP1 (Delta N12VP1) failed to encapsidate the host DNA although the integrity of the capsid-like structure was maintained. In addition, capsid-like particles of Delta N12VP1 did not package exogenous DNA in vitro, which is in contrast to that of the full-length VP1 protein. These findings suggest that the N-terminal of the first 12 amino acids of VP1 were responsible for DNA encapsidation. The importance of amino acids in the DNA encapsidation domain was determined further using site-directed mutagenesis. All of the positively charged amino acids at the N-terminal region of VP1 were essential for DNA encapsidation. The results indicate that the N-terminal region of the human polyomavirus major capsid protein VP1 may be involved in viral genome encapsidation during progeny maturation.

Amino Acid Sequence↗