The middle t antigen, the major viral transforming protein, activates multiple signal transduction pathways essential for tumor induction. Genetic analyses have revealed that the carboxyterminal. Polyoma small and middle t antigens and sv40 small t antigen. In order to understand the regulation of hiv genome transcription induced by cell stimulation through transmembrane receptors, we have transfected cells with polyoma middle t antigen pymt expression vectors, thus mimicking activated receptordependent cell. Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly. Phosphorylation of polyoma middle t antigen and cellular proteins in purified plasma membranes of polyoma virusinfected cells. The polyoma middle t antigen is used in animal breast cancer model systems like the pymt system where it ist coupled to the mmtv promotor. Urokinase type plasminogen activator gene regulation by. Phosphatidylinositol 3kinase binding to polyoma virus. Contributions of the rhoa guanine nucleotide exchange. Virus middle t antigen an overview sciencedirect topics.
It first caught attention as being a protein associated with the polyoma middle t antigen whitman et al. Microsequencing of the 36 kd protein indicated that it was probably identical to the catalytic subunit of protein phosphatase 2a pp2a. Binding of src family kinases to membraneassociated polyoma virus middle tantigen pymt can result in the phosphorylation of pymt tyrosine 250, which serves as a docking site for the binding of shc and subsequent activation of the rafmekerk map kinase cascade. The polyomavirus middle t antigen pymt is an oncogene that activates the nonreceptor tyrosine kinase, csrc, and physically interacts with taz wwtr1. Abstract binding of src family kinases to membraneassociated polyoma virus middle t antigen pymt can result in the phosphorylation of pymt tyrosine 250, which serves as a docking site for the binding of shc and subsequent activation of the rafmekerk map kinase cascade. Middletassociated as well as uncomplexed pp60csrc is predominantly found in the plasma membrane. Phosphatidylinositol 3kinase binding to polyoma virus middle. Endothelial cell transformation by polyomavirus middle t. Middlet associates with and thereby activates p60 csrc, a cellular tyrosine kinase homologous to. Induction of interleukin2 transcription by the hamster. Wildtype polyoma virus infection led to a 3fold increase in the rate of 2deoxyglucose 2dg uptake, whereas a weakly. Middle t antigen pymt is the principal transforming component of polyomavirus, and rapidly induces hemangiomas in neonatal mice. Middle t antigen middle t, the transforming gene product of polyomavirus, associates with several cellular tyrosine kinases, such as pp60csrc.
P688351 fasta add to basket added to basket the sequence of this isoform can be found in the external entry p68835. Publications for polyoma virus, medium t antigen antibody nb10027498 we have publications tested in 1 confirmed species. Polyoma middle t antigen pmt was originally identified as the tumorigenic component of the polyomavirus genome. These results support the hypothesis that fyn is involved in signal transduction events leading to il2 transcriptional activation in t cells. The middle tumor antigen is a protein encoded in the genomes of some polyomaviruses, which. Polyoma middle t antigen activates the serthr kinase akt. Lessons in signaling and tumorigenesis from polyomavirus. Murine polyomavirus middle tantigen mt induces tumors by mimicking an activated growth factor receptor. Each of these agents is known to be able to prime hl60 cells and accelerate subsequently induced myeloid or monocytic differentiation and g0 cell cycle arrest. P0doj42 fasta add to basket added to basket the sequence of this isoform can be found in the external entry p0doj4.
Kramer, in signal transduction third edition, 2016. The middle t antigen of murine polyomavirus pymt rapidly transforms endothelial cells, leading to the formation of vascular tumors in newborn mice. The middle tumor antigen middlet of mouse polyomavirus is responsible for the transforming potential of this virus. Polyoma virus, medium t antigen antibody pymt nb100. An essential component of this action is a 22 amino. Furthermore, replication of heterologous viruses such as vesicular stomatitis virus and. Polyoma middle t antigen pi3 kinase tyrosine kinase signal transduction cancer middle tantigen mt is the principal oncogene of murine polyomavirus. Male carriers develop mammary tumors with a later onset. Polyoma virus small t antigen enhances replication of viral genomes in 3t6 mouse fibroblasts. Complex formation leads to kinase activation and is essential for cell transformation. Middlet antigen middlet, the transforming gene product of polyomavirus, associates with several cellular tyrosine kinases, such as pp60csrc.
Expression of polyomavirus middle t antigen pymt rapidly induces endothelial tumors hemangiomas in mice, with an apparent single ratelimiting step. Polyomavirus middle t antigen as a probe for t cell. Middle texpressing cells treated with the granulocytic inducer retinoic acid or the monocytic inducer 1,25dihydroxy vitamin d3 differentiated 24 h earlier than parental, mockelectroporated, or vector control cell. Natural biology of polyomavirus middle t antigen ncbi nih. To address this question, we transfected polyoma virus middle t or small t alone or middle t and small t together into j3d mouse tlymphoma cells carrying temperaturesensitive p53 ts p53. Identity was confirmed by comigration on twodimensional 2d gels and by 2d analysis of complete. Polyoma virus, medium t antigen antibody pymt nb1002749. Polyoma virus middle t antigen pymt contains 421 amino acids and is divided into at least three domains, some of which are shared with pylt and polyoma virus small t antigen pyst. Because activation of srclike kinases is thought to be an important component of pymtinduced transformation, we have analyzed the functional requirement for individual kinases in this process. Mechanism of activation of complexed pp60csrc by the middle. Protein kinase bakt is activated by polyomavirus middlet antigen.
In a screen for pymt variants that could not activate the arf tumor suppressor, we isolated a cytoplasmic nontransforming mutant. Polyoma virus middle t antigen pyvmt is a powerful viral oncogene. Furthermore, replication of heterologous viruses such as vesicular stomatitis virus and encephalomyocarditis virus was. Effective in vivo models of breast cancer are crucial for studying the development and progression of the disease in humans. Contributions of the rhoa guanine nucleotide exchange factor. Every product we sell is backed by novus 100% guarantee. These complexes have a higher tyrosine kinase activity compared with that of unassociated pp60csrc. Expression of the polyoma virus middle t antigen in hl60 cells accelerates their differentiation in response to both monocytic and granulocytic differentiationinducing agents.
Plays a role in transformation by modulating the activities of cellular proteins involved in control of cell proliferation and by acting as a functional homolog of an activated tyrosine kinaseassociated growthfactor receptor. There it functions as an oncogene, while the tissue where the tumor develops is determined by the mmtv promotor. G higgins3,5, brian s schaffhausen4, and thomas m roberts1,2 1department of cancer biology, danafarber cancer institute 2department of biological chemistry and molecular. Polyoma small t antigen triggers cell death via mitotic catastrophe arun t pores fernando1,2,6, shaida andrabi1,6,7, onur cizmecioglu1,2, cailei zhu3, david m.
Middle t antigen murine polyomavirus strain bg mpyv. The phospholipase plc and pld pathway activated by. The middle tumor antigen is used in model organisms developed to study cancer, such as the mmtvpymt system where middle t is coupled to the mmtv promoter. The polyomavirus middle tantigen oncogene activates the. Polyoma definition of polyoma by the free dictionary. This transgene expresses polyoma virus middle t antigen under the control of the mouse mammary tumor. The a205 mutant is a deletion mutant of the polyoma middle t antigen, the transforming agent of polyoma virus. Polyoma virus middle t and small t antigens cooperate to antagonize p53induced cell cycle arrest and apoptosis 1 wang qian and klas g. Pmt expression accelerated glucose transport and increased. Binding of polyoma virus large t antigen to the human hsp 70 promoter is not required fortrans activation. Inducible and coupled expression of the polyomavirus. Net1 knockout ko mice were bred to mice with mammary gland specific expression of the polyoma middle t antigen pymt oncogene.
In order to understand the regulation of hiv genome transcription induced by cell stimulation through transmembrane receptors, we have transfected cells with polyoma middle t antigen pymt expression vectors, thus mimicking activated receptordependent cell stimulation. As of the most recent 2018 taxonomy release by the international committee on taxonomy of viruses, there were 89 recognized species in this family contained within four genera, as well as 9 species that could not be assigned to a genus. Mammary gland tumorigenesis and lung metastasis were monitored. These mice express the polyoma virus middle t antigen under the direction of the mouse mammary tumor virus promoterenhancer and may be suitable for use in studies. Dec 19, 2006 binding of src family kinases to membraneassociated polyoma virus middle t antigen pymt can result in the phosphorylation of pymt tyrosine 250, which serves as a docking site for the binding of shc and subsequent activation of the rafmekerk map kinase cascade. Elevation in the rate of glucose transport in polyoma virusinfected mouse fibroblasts was dependent upon phosphatidylinositol 3kinase pi 3kinase. May 01, 1999 transformationdefective polyoma middle t antigen mutants defective in plcgamma, pi3, or src kinase activation enhance erk2 activation and promote retinoic acidinduced, cell differentiation like wildtype middle t. Unlike sv40 large t, polyoma virus large t does not bind p53, and it is still unclear how polyoma virus blocks p53 function. Microbiology and tumor biology center, karolinska institute, s171 77 stockholm, sweden abstract. Polyoma virusinduced osteosarcomas in inbred strains of. Activation of p60 csrc by middle t is accompanied both by. Association of p60 csrc with polyoma virus middlet. Polyomaviridae is a family of viruses whose natural hosts are primarily mammals and birds.
Murine polyoma virus mpyv is a small dna virus that induces tumors in multiple tissues of infected host. Consistent with the importance of erk2 activation for precommitment, ectopic expression of the a205 mutant of polyoma virus middle t antigen primes cells to differentiate in response to ra yen et al. The proximate biochemical response to tcr stimulation is the phosphorylation of several intracellular proteins on tyrosyl residues. For example, mtag binds and activates srcfamily protein tyrosine kinases in a. The rhoa activating protein net1 contributes to breast cancer cell proliferation, motility, and invasion in vitro, yet little is known about its roles in mammary gland tumorigenesis and metastasis. In recent years, the emphasis has been on cancerrelated signaling. Lessons in signaling and tumorigenesis from polyomavirus middle. Pymt is a major transforming protein responsible for inducing the phenotype of transformed cells and, without it, transformation does not occur. Pyvt, polyoma virus middle t antigen, polyoma virus.
Reduced metastasis of polyoma virus middle t antigen induced mammary cancer in plasminogendeficient mice. Source polyoma virus middle t antigen pymt is a rat. Middle t associates with and thereby activates p60 csrc, a cellular tyrosine kinase homologous to the oncogene product of rous sarcoma virus 2,3. Physical and functional interaction between polyoma virus. Polyomavirus middle tantigen is a transmembrane protein that. The insulinlike growth factor i receptor igfir and the. Lee, 1 and heiner westphap laboratory of molecular genetics, national institute of child health and development, and 2laboratory of. Abstract binding of src family kinases to membraneassociated polyoma virus middle tantigen pymt can result in the phosphorylation of pymt tyrosine 250, which serves as a docking site for the binding of shc and subsequent activation of the rafmekerk map kinase cascade. Activation of p60 csrc by middlet is accompanied both by. Lessons from polyoma middle t antigen on signaling and. Recruits upon association with host ppp2pp2a the src tyrosine kinase components src, yes and fyn, thereby activating their kinase activity. Jul 20, 2009 polyoma virus middle t antigen pyvmt is a powerful viral oncogene.
There are currently no images for polyoma virus, medium t antigen antibody nb1002749h. There it functions as an oncogene, while the tissue where the tumor develops is determined by the mmtv promoter. In a screen for pymt variants that could not activate the arf tumor suppressor, we isolated a. The potent transforming activity of middle t antigen is dependent on its association with a number of cellular proteins such as members of the src family of protein kinase and the. Previous studies have shown that the polyomavirusderived oncoprotein, middle t antigen mt, transforms rodent fibroblasts by interacting with and activating. Mmtvpymt mmtvpyvmt females develop palpable mammary tumors which metastasize to the lung.
Transformationdefective polyoma middle t antigen mutants. Polyoma virus middle t antigen antibody pymt scbt santa. Perturbed development of the mouse lens by polyomavirus. Perturbed development of the mouse lens by polyomavirus large t antigen does not lead to tumor formation anne e. The amino terminus of polyomavirus middle t antigen is. Wildtype p53 triggers two distinct biological responses, cell cycle arrest and apoptosis. Middlet associates with and thereby activates p60 csrc, a cellular tyrosine kinase homologous to the oncogene product of rous sarcoma virus 2,3. Middle t expressing cells treated with the granulocytic inducer retinoic acid or the monocytic inducer 1,25dihydroxy vitamin d3 differentiated 24 h earlier than parental, mockelectroporated, or vector control cell. Association of p60csrc with polyoma virus middlet antigen. Hiv genome transcription induced by polyoma virus middle t.
Middle t antigen murine polyomavirus strain a2 mpyv. Courtneidge sa, smith ae 1984 the complex of polyoma virus middlet antigen and pp60 csrc. The polyoma middle t antigen pymt ag allows selective proliferation of ecs in. Polyoma and sv40 proteins differentially regulate pp2a to. The polyoma virus t antigen interferes with interferon.
The potent transforming activity of middle t antigen is dependent on its association with a number of cellular proteins such as members of the src family of protein kinase and the newly identified phosphatidylinositol kinase. Polyoma virusinduced osteosarcomas in inbred strains of mice. Finally, the activation of il2 transcription by hamt and not by momt shown here parallels the ability of the. Summary the small dna tumor viruses have provided a very longlived source of insights into many aspects of the life cycle of eukaryotic cells. The middle tumor antigen also called the middle t antigen and abbreviated mtag or mt is a protein encoded in the genomes of some polyomaviruses, which are small doublestranded dna viruses. The polyomavirus middle t antigen pymt is an oncogene that activates the non receptor tyrosine kinase, csrc, and physically interacts with.
Middle t associated as well as uncomplexed pp60csrc is predominantly found in the plasma membrane. Additional lines produced include lines 121, 196, 235, 654, 668, 670. Polyoma virus middle t and small t antigens cooperate to. Identity was confirmed by comigration on twodimensional 2d gels and by 2d analysis of. Pdf urokinase type plasminogen activator gene regulation by. The polyoma middle tantigen is used in animal breast cancer model systems like the pymt system where it ist coupled to the mmtv promotor. Transformation with the polyoma middle t antigen also activates lipid signaling and the classical mitogenic pathway 44. Polyoma small t antigen triggers cell death via mitotic. We sought to engineer a novel mouse model of polyomavirus middle t antigen pyv mtmediated mammary tumourigenesis in which inducible expression of this wellcharacterized viral oncoprotein is coupled to cre recombinase teto. In polyomavirustransformed cells, pp60csrc is activated by association with polyomavirus middle t antigen. Polyomavirus middle t antigen as a probe for t cell antigen. Mutation of a cysteine residue in polyomavirus middle t antigen abolishes interactions with protein phosphatase 2a, pp60 csrc, and phosphatidylinositol3 kinase, activation of cfos expression, and cellular transformation. Engagement of the multisubunit t cell antigen receptor tcr1 complex triggers a cascade of intracellular signaling events that culminate in the activation and proliferation of t lymphocytes 1, 2.
Its study has led to the discovery of the roles of tyrosine kinase and phosphoinositide 3kinase pi3k signaling in mammalian growth control and transformation. The polyomavirus middle tantigen oncogene activates the hippo. Mt leads to the activation of cjun and cfos promoters 262, 301. Polyoma middle t antigen activates the serthr kinase akt in. We have purified the 36 and 63 kd cellular proteins known to associate with polyomavirus middle and small tumor t antigens and sv40 small t antigen. Their activation sets off a series of signaling cascades.
To investigate whether the serinethreonine kinase aktpkb, which is the protooncogene transduced by the transforming akt8 retrovirus, is activated by pmt, 3t3l1 fibroblasts were stably transfected with wild type pmt. Wildtype polyoma virus infection led to a 3fold increase in the rate of 2deoxyglucose 2dg uptake, whereas a weakly transforming polyoma virus mutant that. Transformationdefective polyoma middle t antigen mutants defective in plcgamma, pi3, or src kinase activation enhance erk2 activation and promote retinoic acidinduced, cell differentiation like wildtype middle t. Relevance of the plasminogen activation system in the pathogenesis and progression of gastric cancer. Yen a1, cherington v, schaffhausen b, marks k, varvayanis s. Association of p60 csrc with polyoma virus middlet antigen. Mtag is expressed early in the infectious cycle along with two other related proteins, the small tumor antigen and large tumor antigen. Polyoma virus, medium t antigen antibody pymt hrp nb100. In this investigation, we show that cell lines derived from wild type virusinduced breast tumors are resistant to the growth inhibitory action of interferon. Polyoma small and middle t antigens and sv40 small t. The phospholipase plc and pld pathway activated by rtk, results in the. Transgenic mice expressing middle t under control of the mouse mammary tumor virus regulatory region develop mammary tumors which metastasize to the lung 16. Myristylation of pp60csrc is not required for complex.
308 242 83 954 1148 91 117 1151 982 774 1235 1382 442 1537 1176 1172 191 947 1546 196 781 1244 725 863 371 954 725 1125 565 432 442 617 690 649 350 786 130 1158 1487 1024 1216 393 1429 411 13 493 1053