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Brigitte Biesinger - One of the best experts on this subject based on the ideXlab platform.
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Herpesvirus Saimiri protein StpB associates with cellular Src.
The Journal of general virology, 2001Co-Authors: Simon Hör, Armin Ensser, Christine Reiss, Kurt Ballmer-hofer, Brigitte BiesingerAbstract:Subgroup B isolates of Herpesvirus Saimiri are less efficient in T lymphocyte transformation when compared with subgroups A or C. Here it is shown that subgroup B strain SMHI encodes a protein, StpB, at a position equivalent to those of the ORFs for the Saimiri transforming proteins (Stp) of subgroups A and C. StpB shares little similarity with StpA or StpC, but interacts with the SH2 domain of cellular Src, as does StpA. Thus, factors other than c-Src binding determine the efficiency of primary T cell transformation by Herpesvirus Saimiri.
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Herpesvirus Saimiri Tip gene causes T-cell lymphomas in transgenic mice.
DNA and cell biology, 2001Co-Authors: Lars-erik Wehner, Brigitte Biesinger, Natalia Schröder, Kenji Kamino, Ute Friedrich, Ulrich RütherAbstract:New World primates develop T-cell lymphomas on infection with Herpesvirus Saimiri. To investigate the oncogenic potential of the Tip gene of Herpesvirus Saimiri strain C488, we tried to establish transgenic mice that should express Tip under control of a constitutive promoter. Although transgene-positive embryos were found, lines could not be established. However, using a system in which the transgene has to be activated by a Cre recombinase-mediated deletion, we were able to obtain several Tip transgenic lines. At high expression levels, the mice developed T-cell lymphomas. Thus, Tip can induce lymphomas and is therefore very likely responsible for the oncogenicity of Herpesvirus Saimiri.
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A Herpes Saimiri oncogene causing peripheral T-cell lymphoma in transgenic mice.
Oncogene, 1996Co-Authors: C. Kretschmer, Bernhard Fleckenstein, Brigitte Biesinger, Helmut Fickenscher, Carol Murphy, Johannes Beckers, Thomas Kirchner, Ulrich RütherAbstract:Herpesvirus Saimiri is an oncogenic virus causing rapid T-cell lymphomas in New World primates and rabbits. Deletion analysis of one strain of H Saimiri has indicated an open reading frame, StpA, necessary for oncongenicity in monkeys. We have investigated the function of StpA in tumor induction by the generation of transgenic mice. Expression of two different constructs caused the development of peripheral lymphomas. The infiltrating cells were of T-cell origin, expressing mainly the CD4 phenotype and restricted sets of V beta chains. Thus, StpA is not only necessary for the oncogenicity of Herpesvirus Saimiri, but is also sufficient for the induction of peripheral pleomorphic T-cell lymphomas.
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the product of the herpesvirus Saimiri open reading frame 1 tip interacts with t cell specific kinase p56lck in transformed cells
Journal of Biological Chemistry, 1995Co-Authors: Brigitte Biesinger, Alexander Y. Tsygankov, Bernhard Fleckenstein, Helmut Fickenscher, Joseph B. Bolen, F Emmrich, Barbara M. BrökerAbstract:Abstract Subgroup C strains of Herpesvirus Saimiri, a leukemogenic virus of non-human primates, transform human T cells to permanent growth in culture. These cells retain their antigen specificity, and they are becoming widely used as a model for activated human T cells. Though a variety of human cell types can be infected by H. Saimiri, transformation appears to be specific for CD4+ and CD8+ T cells. Our investigation of early signaling events in H. Saimiri-transformed T cells revealed a novel 40-kDa phosphoprotein complexed with the T cell-specific tyrosine protein kinase p56lck. This protein, termed Tip (tyrosine kinase interacting protein), is identified as a viral protein encoded by the open reading frame 1 (ORF1). In the transformed cells Tip is expressed together with the gene product of ORF2, the viral oncoprotein StpC, which acts on epithelial cells. The H. Saimiri genome has 75 ORFs, but only ORF1 and ORF2 are transcribed in transformed human cells. Tip is phosphorylated on tyrosine in cell-free systems containing Lck, indicating that the viral protein is a substrate for this T cell-specific kinase. Alteration of T cell signaling pathways by Tip may be the second event complementing the action of StpC in a new mechanism of T cell transformation.
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Primary structure of the herpesvirus Saimiri genome.
Journal of virology, 1992Co-Authors: Jens-christian Albrecht, Brigitte Biesinger, Sabine Wittmann, John Nicholas, D Biller, K R Cameron, C Newman, M A Craxton, H Coleman, Bernhard FleckensteinAbstract:This report describes the complete nucleotide sequence of the genome of herpesvirus Saimiri, the prototype of gammaherpesvirus subgroup 2 (rhadinoviruses). The unique low-G + C-content DNA region has 112,930 bp with an average base composition of 34.5% G + C and is flanked by about 35 noncoding high-G + C-content DNA repeats of 1,444 bp (70.8% G + C) in tandem orientation. We identified 76 major open reading frames and a set of seven U-RNA genes for a total of 83 potential genes. The genes are closely arranged, with only a few regions of sizable noncoding sequences. For 60 of the predicted proteins, homologous sequences are found in other herpesviruses. Genes conserved between herpesvirus Saimiri and Epstein-Barr virus (gammaherpesvirus subgroup 1) show that their genomes are generally collinear, although conserved gene blocks are separated by unique genes that appear to determine the particular phenotype of these viruses. Several deduced protein sequences of herpesvirus Saimiri without counterparts in most of the other sequenced herpesviruses exhibited significant homology with cellular proteins of known function. These include thymidylate synthase, dihydrofolate reductase, complement control proteins, the cell surface antigen CD59, cyclins, and G protein-coupled receptors. Searching for functional protein motifs revealed that the virus may encode a cytosine-specific methylase and a tyrosine-specific protein kinase. Several herpesvirus Saimiri genes are potential candidates to cooperate with the gene for Saimiri transformation-associated protein of subgroup A (STP-A) in T-lymphocyte growth stimulation.
Bernhard Fleckenstein - One of the best experts on this subject based on the ideXlab platform.
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Herpesvirus Saimiri Replaces ZAP-70 for CD3- and CD2-mediated T Cell Activation
The Journal of biological chemistry, 2001Co-Authors: Edgar Meinl, Bernhard Fleckenstein, Françoise Le Deist, Tobias Derfuss, Rainer Pirzer, Norbert Blank, Doris Lengenfelder, Antoine Blancher, Claire HivrozAbstract:Abstract The protein tyrosine kinase ZAP-70 plays a pivotal role involved in signal transduction through the T cell receptor and CD2. Defects in ZAP-70 result in severe combined immunodeficiency. We report that Herpesvirus Saimiri, which does not code for a ZAP-70 homologue, can replace this tyrosine kinase.H. Saimiri is an oncogenic virus that transforms human T cells to stable growth based on mutual CD2-mediated activation. Although CD2-mediated proliferation of ZAP-70-deficient uninfected T cells was absent, we could establish H. Saimiri-transformed T cell lines from two unrelated patients presenting with ZAP-70 deficiencies. In these cell lines, CD2 and CD3 activation were restored in terms of [Ca2+]i, MAPK activation, cytokine production, and proliferation. Activation-induced tyrosine phosphorylation of ζ remained defective. The transformed cells expressed very high levels of the ZAP-70-related kinase Syk. This increased expression was not observed in the primary T cells from the patients and was not due to the transformation by the virus because transformed cell lines established from control T cells did not present this particularity. In conclusion, wild type H. Saimiri can restore CD2- and CD3-mediated activation in signaling-deficient human T cells. It extends our understanding of interactions between the oncogenic H. Saimiri and the infected host cells.
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Activation induces apoptosis in Herpesvirus Saimiri-transformed T cells independent of CD95 (Fas, APO-1).
European journal of immunology, 1997Co-Authors: Barbara M. Bröker, Bernhard Fleckenstein, Michael S. Kraft, Ulricke Klauenberg, Françoise Le Deist, Jean-pierre De Villartay, Bernhard Fleischer, Edgar MeinlAbstract:Signaling via the T cell receptor (TCR)/CD3 complex of pre-activated T cells induces apoptosis. Such an activation-induced cell death (AICD) is thought to play an important role in the regulation of cellular immune responses. In this study we analyzed pathways of AICD by using human T cells transformed by Herpesvirus Saimiri. These growth-transformed T cells show the phenotype of activated mature T cells and continue to express a functionally intact TCR. We show that human H. Saimiri-transformed T cell clones readily undergo cell death upon signaling via the TCR/CD3 complex or via phorbol 12-myristate 13-acetate (PMA) + ionomycin. The AICD in H. Saimiri-transformed T cells was detectable a few hours after activation and it was not affected by the presence of interleukin (IL)-2 or by anti-CD4 cross-linking. However, AICD required tyrosine phosphorylation, since it could be blocked by herbimycin A. Cyclosporin A (CsA) did not block the development of AICD, but other consequences of activation in H. Saimiri-transformed T cells like the production of interferon-gamma. Surprisingly, the development of AICD was not reduced by neutralizing antibodies to tumor necrosis factor (TNF)-alpha or blocking antibodies directed to CD95 (Fas, APO-1), although H. Saimiri-transformed T cells were sensitive to CD95 ligation. To confirm that this form of AICD is really independent of CD95, we have established an H. Saimiri-transformed T cell line from a patient with a homozygous deletion in the CD95 gene. This CD95-deficient T cell line was as sensitive to AICD as other CD95-expressing H. Saimiri-transformed T cells. In conclusion, we describe here a type of AICD in H. Saimiri-transformed T cells that is independent of CD95 and TNF-alpha, not sensitive to CsA, but requires tyrosine phosphorylation. This system should be useful for the investigation of CD95-independent forms of AICD.
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A Herpes Saimiri oncogene causing peripheral T-cell lymphoma in transgenic mice.
Oncogene, 1996Co-Authors: C. Kretschmer, Bernhard Fleckenstein, Brigitte Biesinger, Helmut Fickenscher, Carol Murphy, Johannes Beckers, Thomas Kirchner, Ulrich RütherAbstract:Herpesvirus Saimiri is an oncogenic virus causing rapid T-cell lymphomas in New World primates and rabbits. Deletion analysis of one strain of H Saimiri has indicated an open reading frame, StpA, necessary for oncongenicity in monkeys. We have investigated the function of StpA in tumor induction by the generation of transgenic mice. Expression of two different constructs caused the development of peripheral lymphomas. The infiltrating cells were of T-cell origin, expressing mainly the CD4 phenotype and restricted sets of V beta chains. Thus, StpA is not only necessary for the oncogenicity of Herpesvirus Saimiri, but is also sufficient for the induction of peripheral pleomorphic T-cell lymphomas.
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the product of the herpesvirus Saimiri open reading frame 1 tip interacts with t cell specific kinase p56lck in transformed cells
Journal of Biological Chemistry, 1995Co-Authors: Brigitte Biesinger, Alexander Y. Tsygankov, Bernhard Fleckenstein, Helmut Fickenscher, Joseph B. Bolen, F Emmrich, Barbara M. BrökerAbstract:Abstract Subgroup C strains of Herpesvirus Saimiri, a leukemogenic virus of non-human primates, transform human T cells to permanent growth in culture. These cells retain their antigen specificity, and they are becoming widely used as a model for activated human T cells. Though a variety of human cell types can be infected by H. Saimiri, transformation appears to be specific for CD4+ and CD8+ T cells. Our investigation of early signaling events in H. Saimiri-transformed T cells revealed a novel 40-kDa phosphoprotein complexed with the T cell-specific tyrosine protein kinase p56lck. This protein, termed Tip (tyrosine kinase interacting protein), is identified as a viral protein encoded by the open reading frame 1 (ORF1). In the transformed cells Tip is expressed together with the gene product of ORF2, the viral oncoprotein StpC, which acts on epithelial cells. The H. Saimiri genome has 75 ORFs, but only ORF1 and ORF2 are transcribed in transformed human cells. Tip is phosphorylated on tyrosine in cell-free systems containing Lck, indicating that the viral protein is a substrate for this T cell-specific kinase. Alteration of T cell signaling pathways by Tip may be the second event complementing the action of StpC in a new mechanism of T cell transformation.
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role of human t cell leukemia virus type 1 x region proteins in immortalization of primary human lymphocytes in culture
Journal of Virology, 1992Co-Authors: Ralph Grassmann, Bernhard Fleckenstein, S Berchtold, I Radant, M Alt, Joseph Sodroski, William A Haseltine, U RamstedtAbstract:Human T-cell leukemia virus type 1 (HTLV-1) immortalizes human CD4+ T lymphocytes in culture. Previous studies show that in the context of a herpesvirus Saimiri vector, the sequence of the X region at the 3' end of the HTLV-1 genome is also capable of immortalizing CD4+ lymphocytes in the absence of HTLV-1 structural proteins. The X region of HTLV-1 encodes two trans-acting viral proteins, the 42-kDa Tax protein and the 27-kDa Rex protein. Infection of human cord blood cells with herpesvirus Saimiri recombinants which contain HTLV-1 X region sequences defective for expression of tax, rex, or both tax and rex demonstrates that tax function is necessary and sufficient for immortalization of primary human CD4+ cord blood lymphocytes in culture in the context of the herpesvirus Saimiri vector.
Barbara M. Bröker - One of the best experts on this subject based on the ideXlab platform.
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Downregulation of p56(lck) tyrosine kinase activity in T cells of squirrel monkeys (Saimiri sciureus) correlates with the nontransforming and apathogenic properties of herpesvirus Saimiri in its natural host.
Journal of virology, 2001Co-Authors: Timm Greve, Helmut Fickenscher, Bernhard Fleischer, Gültekin Tamgüney, Barbara M. BrökerAbstract:Herpesvirus Saimiri is capable of transforming T lymphocytes of various primate species to stable growth in culture. The interaction of the T-cellular tyrosine kinase p56lck with the transformation-associated viral protein Tip has been shown before to activate the kinase and provides one model for the T-cell-specific transformation by herpesvirus Saimiri subgroup C strains. In contrast to other primate species, squirrel monkeys (Saimiri sciureus) are naturally infected with the virus without signs of lymphoma or other disease. Although the endogenous virus was regularly recovered from peripheral blood cells from squirrel monkeys, we observed that the T cells lost the virus genomes in culture. Superinfection with virus strain C488 did not induce growth transformation, in contrast to parallel experiments with T cells of other primate species. Surprisingly, p56lck was enzymatically inactive in primary T-cell lines derived from different squirrel monkeys, although the T cells reacted appropriately to stimulatory signals. The cDNA sequence revealed minor point mutations only, and transfections in COS-7 cells demonstrated that the S. sciureus lck gene codes for a functional enzyme. In S. sciureus, the tyrosine kinase p56lck was not activated after T-cell stimulation and enzymatic activity could not be induced by Tip of herpesvirus Saimiri C488. However, the suppression of p56lck was partially released after administration of the phosphatase inhibitor pervanadate. This argues for unique species-specific conditions in T cells of S. sciureus which may interfere with the transforming activity and pathogenicity of herpesvirus Saimiri subgroup C strains in their natural host.
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Activation induces apoptosis in Herpesvirus Saimiri-transformed T cells independent of CD95 (Fas, APO-1).
European journal of immunology, 1997Co-Authors: Barbara M. Bröker, Bernhard Fleckenstein, Michael S. Kraft, Ulricke Klauenberg, Françoise Le Deist, Jean-pierre De Villartay, Bernhard Fleischer, Edgar MeinlAbstract:Signaling via the T cell receptor (TCR)/CD3 complex of pre-activated T cells induces apoptosis. Such an activation-induced cell death (AICD) is thought to play an important role in the regulation of cellular immune responses. In this study we analyzed pathways of AICD by using human T cells transformed by Herpesvirus Saimiri. These growth-transformed T cells show the phenotype of activated mature T cells and continue to express a functionally intact TCR. We show that human H. Saimiri-transformed T cell clones readily undergo cell death upon signaling via the TCR/CD3 complex or via phorbol 12-myristate 13-acetate (PMA) + ionomycin. The AICD in H. Saimiri-transformed T cells was detectable a few hours after activation and it was not affected by the presence of interleukin (IL)-2 or by anti-CD4 cross-linking. However, AICD required tyrosine phosphorylation, since it could be blocked by herbimycin A. Cyclosporin A (CsA) did not block the development of AICD, but other consequences of activation in H. Saimiri-transformed T cells like the production of interferon-gamma. Surprisingly, the development of AICD was not reduced by neutralizing antibodies to tumor necrosis factor (TNF)-alpha or blocking antibodies directed to CD95 (Fas, APO-1), although H. Saimiri-transformed T cells were sensitive to CD95 ligation. To confirm that this form of AICD is really independent of CD95, we have established an H. Saimiri-transformed T cell line from a patient with a homozygous deletion in the CD95 gene. This CD95-deficient T cell line was as sensitive to AICD as other CD95-expressing H. Saimiri-transformed T cells. In conclusion, we describe here a type of AICD in H. Saimiri-transformed T cells that is independent of CD95 and TNF-alpha, not sensitive to CsA, but requires tyrosine phosphorylation. This system should be useful for the investigation of CD95-independent forms of AICD.
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Selective Activation of T Cell Kinase p56lck by Herpesvirus Saimiri Protein Tip
The Journal of biological chemistry, 1996Co-Authors: Nicole Wiese, Alexander Y. Tsygankov, Ulricke Klauenberg, Bernhard Fleischer, Joseph B. Bolen, Barbara M. BrökerAbstract:Abstract Infection with Herpesvirus Saimiri, a T lymphotropic virus of non-human primates, immortalizes human T cells in vitro. The cells show a mature activated phenotype and retain their antigen specificity. We have previously shown that in H. Saimiri transformed cells a viral gene product termed tyrosine kinase interacting protein (Tip) associates with the T cell-specific tyrosine kinase p56lck and becomes phosphorylated by the enzyme on tyrosine residues. Here we show that p56lck is activated by recombinant and native Tip in cell-free systems. A dramatic increase of Lck activity was also observed in T cell lines transfected with Tip. p60fyn and p53/56lyn, the other Src-related kinases expressed in H. Saimiri transformed T cells, did not phosphorylate Tip, and they were not activated by the protein. The selective activation of p56lck by Tip could contribute to the transformed phenotype of H. Saimiri infected cells, and it might explain the T cell selectivity of the transformation event.
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the product of the herpesvirus Saimiri open reading frame 1 tip interacts with t cell specific kinase p56lck in transformed cells
Journal of Biological Chemistry, 1995Co-Authors: Brigitte Biesinger, Alexander Y. Tsygankov, Bernhard Fleckenstein, Helmut Fickenscher, Joseph B. Bolen, F Emmrich, Barbara M. BrökerAbstract:Abstract Subgroup C strains of Herpesvirus Saimiri, a leukemogenic virus of non-human primates, transform human T cells to permanent growth in culture. These cells retain their antigen specificity, and they are becoming widely used as a model for activated human T cells. Though a variety of human cell types can be infected by H. Saimiri, transformation appears to be specific for CD4+ and CD8+ T cells. Our investigation of early signaling events in H. Saimiri-transformed T cells revealed a novel 40-kDa phosphoprotein complexed with the T cell-specific tyrosine protein kinase p56lck. This protein, termed Tip (tyrosine kinase interacting protein), is identified as a viral protein encoded by the open reading frame 1 (ORF1). In the transformed cells Tip is expressed together with the gene product of ORF2, the viral oncoprotein StpC, which acts on epithelial cells. The H. Saimiri genome has 75 ORFs, but only ORF1 and ORF2 are transcribed in transformed human cells. Tip is phosphorylated on tyrosine in cell-free systems containing Lck, indicating that the viral protein is a substrate for this T cell-specific kinase. Alteration of T cell signaling pathways by Tip may be the second event complementing the action of StpC in a new mechanism of T cell transformation.
Alexander Y. Tsygankov - One of the best experts on this subject based on the ideXlab platform.
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Cell transformation by Herpesvirus Saimiri.
Journal of Cellular Physiology, 2005Co-Authors: Alexander Y. TsygankovAbstract:Herpesvirus Saimiri (Saimiriine herpesvirus-2), a γ2-herpesvirus (rhadinovirus) of non-human primates, causes T-lymphoproliferative diseases in susceptible organisms and transforms human and non-human T lymphocytes to continuous growth in vitro in the absence of stimulation. T cells transformed by H. Saimiri retain many characteristics of intact T lymphocytes, such as the sensitivity to interleukin-2 and the ability to recognize the corresponding antigens. As a result, H. Saimiri is widely used in immunobiology for immortalization of various difficult-to-obtain and/or -to-maintain T cells in order to obtain useful experimental models. In particular, H. Saimiri-transformed human T cells are highly susceptible to infection with HIV-1 and -2. This makes them a convenient tool for propagation of poorly replicating strains of HIV, including primary clinical isolates. Therefore, the mechanisms mediating transformation of T cells by H. Saimiri are of considerable interest. A single transformation-associated protein, StpA or StpB, mediates cell transformation by H. Saimiri strains of group A or B, respectively. Strains of group C, which exhibit the highest oncogenic potential, have two proteins involved in transformation—StpC and Tip. Both proteins have been shown to dramatically affect signal transduction pathways leading to the activation of crucial transcription factors. This review is focused on the biological effects and molecular mechanisms of action of proteins involved in H. Saimiri-dependent transformation. © 2004 Wiley-Liss, Inc.
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Tip, an Lck-interacting protein of Herpesvirus Saimiri, causes Fas- and Lck-dependent apoptosis of T lymphocytes
Virology, 2004Co-Authors: Muneer G. Hasham, Alexander Y. TsygankovAbstract:Saimiriine herpesvirus-2 (Herpesvirus Saimiri) transforms T lymphocytes, including human, to continuous growth in vitro. H. Saimiri-induced transformation is becoming an important tool of T-cell biology, including studies of HIV replication. Two proteins of H. Saimiri subgroup C, Tip and StpC, are essential for T-cell transformation. In spite of the important role of these proteins, their biological functions and the molecular mechanisms of their action remain insufficiently understood. To further elucidate the effects of Tip on T cells, we transduced T lymphocytes, using an efficient lentiviral gene transfer system, to express Tip in the absence of other H. Saimiri proteins. Our results indicate that Tip specifically inhibits IL-2 production by human T lymphocytes. Furthermore, Tip promotes T-cell apoptosis, which appears to be the reason for the observed decrease in IL-2 production. Finally, the apoptotic effect of Tip in T cells is mediated by Fas and requires the presence of active Lck in the cell.
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Molecular mechanisms of the effect of Herpesvirus Saimiri protein StpC on the signaling pathway leading to NF-κB activation
Journal of Biological Chemistry, 2004Co-Authors: Elena M Sorokina, Joseph J. Merlo, Alexander Y. TsygankovAbstract:Abstract Herpesvirus Saimiri (Saimiriine herpesvirus-2) causes lethal T lymphoproliferative diseases in the susceptible species and transforms T lymphocytes to continuous growth in vitro. H. Saimiri-induced transformation of T cells is becoming an important experimental tool of biomedical research. Two proteins of H. Saimiri subgroup C, Tip and StpC, are essential for T cell transformation by this virus. It has been shown previously that StpC transforms fibroblasts, activates NF-κB, and binds to tumor necrosis factor (TNF)-receptor-associated factor (TRAF) proteins, but the molecular mechanism of its action remains insufficiently understood. This study further characterized the effect of StpC on NF-κB. First, StpC activates NF-κB via the consensus pathway involving activation of I-κB kinase and subsequent phosphorylation and degradation of I-κB in both T lymphoid and epithelial cells. Second, triggering of this pathway by StpC in both T lymphoid and epithelial cells is dependent on the presence of functional NF-κB-inducing kinase (NIK). Third, StpC physically interacts with TRAF in epithelial cells, and the effect of StpC on NF-κB activity in these cells requires the presence of functional TRAF. Finally the effect of StpC is completely independent of TNF-α, a well described stimulus of NF-κB activity. Moreover it appears that StpC uncouples stimulation of NF-κB activity from TNF-α stimulation. Overall these results argue that the effect of StpC on NF-κB is similar to the effects of other viral proteins, “usurping” the TRAF/NIK/I-κB kinase pathway, and reinforce the notion that the role of StpC in cell transformation by H. Saimiri may be mediated by signaling that results in NF-κB activation.
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Selective Activation of T Cell Kinase p56lck by Herpesvirus Saimiri Protein Tip
The Journal of biological chemistry, 1996Co-Authors: Nicole Wiese, Alexander Y. Tsygankov, Ulricke Klauenberg, Bernhard Fleischer, Joseph B. Bolen, Barbara M. BrökerAbstract:Abstract Infection with Herpesvirus Saimiri, a T lymphotropic virus of non-human primates, immortalizes human T cells in vitro. The cells show a mature activated phenotype and retain their antigen specificity. We have previously shown that in H. Saimiri transformed cells a viral gene product termed tyrosine kinase interacting protein (Tip) associates with the T cell-specific tyrosine kinase p56lck and becomes phosphorylated by the enzyme on tyrosine residues. Here we show that p56lck is activated by recombinant and native Tip in cell-free systems. A dramatic increase of Lck activity was also observed in T cell lines transfected with Tip. p60fyn and p53/56lyn, the other Src-related kinases expressed in H. Saimiri transformed T cells, did not phosphorylate Tip, and they were not activated by the protein. The selective activation of p56lck by Tip could contribute to the transformed phenotype of H. Saimiri infected cells, and it might explain the T cell selectivity of the transformation event.
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the product of the herpesvirus Saimiri open reading frame 1 tip interacts with t cell specific kinase p56lck in transformed cells
Journal of Biological Chemistry, 1995Co-Authors: Brigitte Biesinger, Alexander Y. Tsygankov, Bernhard Fleckenstein, Helmut Fickenscher, Joseph B. Bolen, F Emmrich, Barbara M. BrökerAbstract:Abstract Subgroup C strains of Herpesvirus Saimiri, a leukemogenic virus of non-human primates, transform human T cells to permanent growth in culture. These cells retain their antigen specificity, and they are becoming widely used as a model for activated human T cells. Though a variety of human cell types can be infected by H. Saimiri, transformation appears to be specific for CD4+ and CD8+ T cells. Our investigation of early signaling events in H. Saimiri-transformed T cells revealed a novel 40-kDa phosphoprotein complexed with the T cell-specific tyrosine protein kinase p56lck. This protein, termed Tip (tyrosine kinase interacting protein), is identified as a viral protein encoded by the open reading frame 1 (ORF1). In the transformed cells Tip is expressed together with the gene product of ORF2, the viral oncoprotein StpC, which acts on epithelial cells. The H. Saimiri genome has 75 ORFs, but only ORF1 and ORF2 are transcribed in transformed human cells. Tip is phosphorylated on tyrosine in cell-free systems containing Lck, indicating that the viral protein is a substrate for this T cell-specific kinase. Alteration of T cell signaling pathways by Tip may be the second event complementing the action of StpC in a new mechanism of T cell transformation.
Mark A. Batzer - One of the best experts on this subject based on the ideXlab platform.
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Recently integrated Alu insertions in the squirrel monkey (Saimiri) lineage and application for population analyses
Mobile DNA, 2018Co-Authors: Jasmine N. Baker, Jerilyn A. Walker, Michael W. Denham, Charles D. Loupe, Mark A. BatzerAbstract:Background The evolution of Alu elements has been ongoing in primate lineages and Alu insertion polymorphisms are widely used in phylogenetic and population genetics studies. Alu subfamilies in the squirrel monkey ( Saimiri ), a New World Monkey (NWM), were recently reported. Squirrel monkeys are commonly used in biomedical research and often require species identification. The purpose of this study was two-fold: 1) Perform locus-specific PCR analyses on recently integrated Alu insertions in Saimiri to determine their amplification dynamics, and 2) Identify a subset of Alu insertion polymorphisms with species informative allele frequency distributions between the Saimiri sciureus and Saimiri boliviensis groups. Results PCR analyses were performed on a DNA panel of 32 squirrel monkey individuals for 382 Alu insertion events ≤2% diverged from 46 different Alu subfamily consensus sequences, 25 Saimiri specific and 21 NWM specific Alu subfamilies. Of the 382 loci, 110 were polymorphic for presence / absence among squirrel monkey individuals, 35 elements from 14 different Saimiri specific Alu subfamilies and 75 elements from 19 different NWM specific Alu subfamilies (13 of 46 subfamilies analyzed did not contain polymorphic insertions). Of the 110 Alu insertion polymorphisms, 51 had species informative allele frequency distributions between Saimiri sciureus and Saimiri boliviensis groups. Conclusions This study confirms the evolution of Alu subfamilies in Saimiri and provides evidence for an ongoing and prolific expansion of these elements in Saimiri with many active subfamilies concurrently propagating. The subset of polymorphic Alu insertions with species informative allele frequency distribution between Saimiri sciureus and Saimiri boliviensis will be instructive for specimen identification and conservation biology.
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Recently integrated Alu insertions in the squirrel monkey (Saimiri) lineage and application for population analyses
Mobile DNA, 2018Co-Authors: Jasmine N. Baker, Jerilyn A. Walker, Michael W. Denham, Charles D. Loupe, Mark A. BatzerAbstract:The evolution of Alu elements has been ongoing in primate lineages and Alu insertion polymorphisms are widely used in phylogenetic and population genetics studies. Alu subfamilies in the squirrel monkey (Saimiri), a New World Monkey (NWM), were recently reported. Squirrel monkeys are commonly used in biomedical research and often require species identification. The purpose of this study was two-fold: 1) Perform locus-specific PCR analyses on recently integrated Alu insertions in Saimiri to determine their amplification dynamics, and 2) Identify a subset of Alu insertion polymorphisms with species informative allele frequency distributions between the Saimiri sciureus and Saimiri boliviensis groups. PCR analyses were performed on a DNA panel of 32 squirrel monkey individuals for 382 Alu insertion events ≤2% diverged from 46 different Alu subfamily consensus sequences, 25 Saimiri specific and 21 NWM specific Alu subfamilies. Of the 382 loci, 110 were polymorphic for presence / absence among squirrel monkey individuals, 35 elements from 14 different Saimiri specific Alu subfamilies and 75 elements from 19 different NWM specific Alu subfamilies (13 of 46 subfamilies analyzed did not contain polymorphic insertions). Of the 110 Alu insertion polymorphisms, 51 had species informative allele frequency distributions between Saimiri sciureus and Saimiri boliviensis groups. This study confirms the evolution of Alu subfamilies in Saimiri and provides evidence for an ongoing and prolific expansion of these elements in Saimiri with many active subfamilies concurrently propagating. The subset of polymorphic Alu insertions with species informative allele frequency distribution between Saimiri sciureus and Saimiri boliviensis will be instructive for specimen identification and conservation biology.
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Evolution of Alu Subfamily Structure in the Saimiri Lineage of New World Monkeys.
Genome biology and evolution, 2017Co-Authors: Jasmine N. Baker, Jerilyn A. Walker, Michael W. Denham, John A. Vanchiere, Kacie R. Phillippe, Corey P. St Romain, Paulina Gonzalez-quiroga, Jackson R. Mierl, Miriam K. Konkel, Mark A. BatzerAbstract:Squirrel monkeys, Saimiri, are commonly found in zoological parks and used in biomedical research. S. boliviensis is the most common species for research; however, there is little information about genome evolution within this primate lineage. Here, we reconstruct the Alu element sequence amplification and evolution in the genus Saimiri at the time of divergence within the family Cebidae lineage. Alu elements are the most successful SINE (Short Interspersed Element) in primates. Here, we report 46 Saimiri lineage specific Alu subfamilies. Retrotransposition activity involved subfamilies related to AluS, AluTa10, and AluTa15. Many subfamilies are simultaneously active within the Saimiri lineage, a finding which supports the stealth model of Alu amplification. We also report a high resolution analysis of Alu subfamilies within the S. boliviensis genome [saiBol1].
