A Region of the
            <i>Herpesvirus saimiri</i>
            Genome Required for Oncogenicity

Desrosiers, Ronald C.; Bakker, Anke; Kamine, James; Falk, Lawrence A.; Hunt, Ronald D.; King, Norval W.

doi:10.1126/science.2983431

Cited by 108 publications

(97 citation statements)

References 7 publications

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“…Our RT-PCR analysis demonstrated that the ORF5 genes of both viruses are spliced near the 5Ј end of the coding sequence, which leads to the addition of 14 identical amino acids to their amino terminus, providing the amino-terminal myristoylation site for membrane attachment. Sequence comparison of 13 ORF5 alleles showed that ORF5 was relatively conserved within each subgroup but showed a dramatic sequence divergence between subgroups; for example, there was 97 to 100% identity among members of the A11 cluster of subgroup A but only 46 to 50% identity between the A11 cluster and subgroup C. Among more than 80 different open reading frames compared between HVS subgroup A11 and C488 strains, only two other open reading frames have been shown to display considerable sequence divergence (2,14,36). These are the STP oncoprotein and the Tip signaling protein.…”

Section: Discussionmentioning

confidence: 99%

“…HVS infection is endemic and nonpathogenic in its natural host, squirrel monkeys (Saimiri sciureus) (15). However, HVS infection of other species of New World primates results in rapidly progressing fatal T-cell lymphomas and leukemias (14,29). Besides its potent oncogenicity in vivo, HVS can immortalize peripheral blood mononuclear cells of human, rhesus monkey, and common marmoset to IL-2-independent growth in vitro (2,5).…”

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confidence: 99%

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Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Lee

Chung

Cho

et al. 2004

Molecular and Cellular Biology

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Because of its central regulatory role, T-cell receptor (TCR) signal transduction is a common target of viruses. We report here the identification of a small signaling protein, ORF5, of the T-lymphotropic tumor virus herpesvirus saimiri (HVS). ORF5 is predicted to contain 89 to 91 amino acids with an amino-terminal myristoylation site and six SH2 binding motifs, showing structural similarity to cellular LAT (linker for activation of T cells). Sequence analysis showed that, despite extensive sequence variation, the myristoylation site and SH2 binding motifs were completely conserved among 13 different ORF5 isolates. Upon TCR stimulation, ORF5 was efficiently tyrosine phosphorylated and subsequently interacted with cellular SH2-containing signaling proteins Lck, Fyn, SLP-76, and p85 through its tyrosine residues. ORF5 expression resulted in the marked augmentation of TCR signal transduction activity, evidenced by increased cellular tyrosine phosphorylation, intracellular calcium mobilization, CD69 surface expression, interleukin-2 production, and activation of the NF-AT, NF-B, and AP-1 transcription factors. Despite its structural similarity to cellular LAT, however, ORF5 could only partially substitute for LAT function in TCR signal transduction. These results demonstrate that HVS utilizes a novel signaling protein, ORF5, to activate TCR signal transduction. This activation probably facilitates viral gene expression and, thereby, persistent infection.Upon engagement of the T-cell antigen receptor (TCR), many cellular proteins, including TCR subunits, adaptor proteins, and other effector molecules, are phosphorylated and subsequently are involved in the formation of molecular complexes at the site of contact with the antigen-presenting cells (33, 51, 54) The earliest signaling event following TCR engagement is the sequential activation of the non-receptor protein tyrosine kinases (PTKs) of the Src and Syk families. Activated Src family PTKs, Lck and Fyn, in T cells subsequently phosphorylate tyrosine residues within a consensus sequence termed the immunoreceptor tyrosine-based activation motif in the cytosolic tails of the TCR subunits. The phosphorylated immunoreceptor tyrosine-based activation motifs of TCR in turn recruit the Syk family PTKs ZAP70 and Syk through their Src homology 2 (SH2) domains (33). Together with Lck and Fyn, the ZAP70 and Syk kinases then promote the phosphorylation of many intracellular signaling molecules, including phospholipase C-␥1 (PLC-␥1), Cbl, Vav, LAT (linker for activation of T cells) and SLP-76 (SH2-containing leukocyte protein-76) (12,25,41,45,46,53). Phosphorylation of these cellular signaling molecules ultimately induces various cellular events such as cytoskeletal alteration, intracellular Ca ϩϩ influx, transcription factor activation, and cytokine/chemokine production (4,20,38,43,59).Two adaptor proteins, LAT and SLP-76, have been shown to be critical for the optimal activation of T cells and to function in linking proximal signaling events to distal downstream signaling ac...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Lee

Chung

Cho

et al. 2004

Molecular and Cellular Biology

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“…HVS can be further sub-classified into three subgroups (A, B, and C) on the basis of the extent of DNA sequence divergence at the left end of L-DNA. Mutational analysis on the gene products in this region, designated with saimiri transforming protein (STP-A, or C) has revealed that STP is not required for viral replication but for immortalization (Desrosiers et al, 1984;1985). Previous studies have reported that STP-A11 interacts with Src at the residue of 115YAEV118 (Lee et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

STP-A11, an oncoprotein of Herpesvirus saimiri augments both NF-κB and AP-1 transcription activity through TRAF6

Jeong

Cho²,

An³

et al. 2007

Exp Mol Med

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Herpesvirus saimiri (HVS), a member of the γ-herpesvirus family, encodes an oncoprotein called Saimiri Transforming Protein (STP) which is required for lymphoma induction in non-human primates. However, a detailed mechanism of STP-A11-induced oncogenesis has not been revealed yet. We first report that STP-A11 oncoprotein interacts with TNFreceptor-associated factor (TRAF) 6 in vivo and in vitro. Mutagenesis analysis of the TRAF6-binding motif 10 PQENDE 15 in STP-A11 reveals that Glu (E) 12 residue is critical for binding to TRAF6 and NF-κB activation. Interestingly, co-expression of E12A mutant, lack of TRAF6 binding, with cellular Src (Src) results in decreased transcriptional activity of Stat3 and AP-1, a novel target of STP-A11 compared to that of wild type. Furthermore, the presence of STP-A11 enhances the association of TRAF6 with Src and induces the translocation of both TRAF6 and Src to a nonionic detergent-insoluble fraction. Taken together, these studies suggest that STP-A11 oncoprotein up-regulates both NF-κB and AP-1 transcription activity through TRAF6, which would ultimately contribute cellular transformation.

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“…Although it does not cause any disease in its natural host, infection in other New World primates such as tamarins, common marmosets, and owl monkey causes acute peripheral T cell lymphoma within less than 2 months (23,24). In addition, the virus is also capable of transforming simian and human T cells in vitro (25,26).…”

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confidence: 99%

Functional Characterization of the Complement Control Protein Homolog of Herpesvirus Saimiri

Singh

Mullick

Bernet

et al. 2006

Journal of Biological Chemistry

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Herpesvirus saimiri (HVS) is a lymphotropic virus that causes T-cell lymphomas in New World primates. It encodes a structural homolog of complement control proteins named complement control protein homolog (CCPH). Previously, CCPH has been shown to inhibit C3d deposition on target cells exposed to complement. Here we have studied the mechanism by which it inactivates complement. We have expressed the soluble form of CCPH in Escherichia coli, purified to homogeneity and compared its activity to vaccinia virus complement control protein (VCP) and human complement regulators factor H and soluble complement receptor 1. The expressed soluble form of CCPH bound to C3b (K D ‫؍‬ 19.2 M) as well as to C4b (K D ‫؍‬ 0.8 M) and accelerated the decay of the classical/lectin as well as alternative pathway C3-convertases. In addition, it also served as factor I cofactor and supported factor I-mediated inactivation of both C3b and C4b. Time course analysis indicated that although its rate of inactivation of C4b is comparable with VCP, it is 14-fold more potent than VCP in inactivating C3b. Site-directed mutagenesis revealed that Arg-118, which corresponds to Lys-120 of variola virus complement regulator SPICE (a residue critical for its enhanced C3b cofactor activity), contributes significantly in enhancing this activity. Thus, our data indicate that HVS encodes a potent complement inhibitor that allows HVS to evade the host complement attack.

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A Region of the Herpesvirus saimiri Genome Required for Oncogenicity

Cited by 108 publications

References 7 publications

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

STP-A11, an oncoprotein of Herpesvirus saimiri augments both NF-κB and AP-1 transcription activity through TRAF6

Functional Characterization of the Complement Control Protein Homolog of Herpesvirus Saimiri

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