Activation of Stat3 Transcription Factor by
            <i>Herpesvirus Saimiri</i>
            STP-A Oncoprotein

Chung, Young Hwa; Cho, Nam Hyuk; García, María I. Rodríguez; Lee, Sun Hwa; Feng, Pinghui; Jung, Jae U.

doi:10.1128/jvi.78.12.6489-6497.2004

Cited by 26 publications

(25 citation statements)

References 38 publications

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“…In summary, this work provides strong evidence that STAT3 (and STAT1) activation, though consistently found in T-cell lines transformed by HVS strains in vitro or in vivo (14,59,61), is not a prerequisite for human primary T-cell transformation to antigen-independent growth by HVS subgroup C strains. Therefore, the essential role of Tip in viral T-cell transformation has to be mediated by effectors other than STAT3.…”

Section: Discussionmentioning

confidence: 65%

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

Heck

Lengenfelder

Schmidt

et al. 2005

J Virol

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Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that were originally discovered as key mediators of cytokine signaling. They are involved in signaling by the interleukin-6 (IL-6) family cytokines, the IL-2 family cytokines, and numerous growth factors, including epidermal growth factor, platelet-derived growth factor, and colony-stimulating factor 1. Latent inactive STATs reside in the cytoplasm; in response to receptor activation, they are recruited to a receptor where they are tyrosine phosphorylated by receptor tyrosine kinases (RTK) or receptor-associated tyrosine kinases, such as JAK or Trk kinases (reviewed in references 36, 42, 46, and 48). Active STAT dimers are then formed via the reciprocal interaction between the SH2 domain of one monomer and the phosphorylated tyrosine of the other. Activated dimers translocate to the nucleus, where they bind to specific DNA response elements in the promoters of target genes and activate transcription. Furthermore, various oncoproteins can activate specific STAT molecules (especially STAT3 and STAT5) (8,15), and inappropriate STAT activation directly contributes to oncogenesis by stimulating cell proliferation and preventing apoptosis. Constitutive activation of several STATs was frequently detected in a wide range of human cell lines and primary tumors, including lymphoid malignancies (lymphomas, leukemias, and multiple myelomas) (30,63,67). Constitutively activated mutant STAT3 and STAT5 proteins have been shown to possess transforming properties and to be strongly associated with tumor development and progression (7, 9).

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Section: Discussionmentioning

confidence: 65%

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

Heck

Lengenfelder

Schmidt

et al. 2005

J Virol

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“…STAT3 activation leads to overexpression of genes involved in tumorigenesis and is constitutive in most primary human tumors (11)(12)(13). STAT3 plays a significant role in the pathogenesis of the γ-herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV), and herpesvirus saimiri (14)(15)(16), all of which exploit the oncogenic effects of phosphorylated STAT3 (pSTAT3).…”

mentioning

confidence: 99%

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Sen¹,

Che²,

Rajamani³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Varicella-zoster virus (VZV) is a human α-herpesvirus that causes varicella (chickenpox) during primary infection and zoster (shingles) upon reactivation. Like other viruses, VZV must subvert the intrinsic antiviral defenses of differentiated human cells to produce progeny virions. Accordingly, VZV inhibits the activation of the cellular transcription factors IFN regulatory factor 3 (IRF3) and signal transducers and activators of transcription 1 (STAT1), thereby downregulating antiviral factors, including IFNs. Conversely, in this study, we found that VZV triggers STAT3 phosphorylation in cells infected in vitro and in human skin xenografts in SCID mice in vivo and that STAT3 activation induces the anti-apoptotic protein survivin. Small-molecule inhibitors of STAT3 phosphorylation and survivin restrict VZV replication in vitro, and VZV infection of skin xenografts in vivo is markedly impaired by the administration of the phospho-STAT3 inhibitor S3I-201. STAT3 and survivin are required for malignant transformation caused by γ-herpesviruses, such as Kaposi's sarcoma virus. We show that STAT3 activation is also critical for VZV, a nononcogenic herpesvirus, via a survivin-dependent mechanism. Furthermore, STAT3 activation is critical for the life cycle of the virus because VZV skin infection is necessary for viral transmission and persistence in the human population. Therefore, we conclude that takeover of this major cell-signaling pathway is necessary, independent of cell transformation, for herpesvirus pathogenesis and that STAT3 activation and up-regulation of survivin is a common mechanism important for the pathogenesis of lytic as well as tumorigenic herpesviruses.T he life cycle of varicella-zoster virus (VZV) in the human host depends on its tropism for T cells, skin, and neurons within sensory ganglia (1). As shown in the SCID mouse model of VZV pathogenesis, infected human T cells transport the virus to epidermal cells in human skin xenografts and to neural cells in dorsal root ganglia xenografts (2, 3). VZV establishes latency in sensory ganglia; upon reactivation, the virus migrates to the skin via axonal transport to cause zoster.VZV modulates several signaling pathways to replicate efficiently in vitro, and these regulatory effects are especially important in differentiated skin cells infected in vivo. VZV interferes with IFN induction and signaling via inhibition of IFN regulatory factor 3 (IRF3), NFκB, and STAT1 in vitro and in skin (4, 5). However, the pathogenesis of VZV skin infection requires a mechanism to overcome the constitutive IFNα expression by epidermal cells that accounts for the 10-to 21-d interval between VZV transfer into skin and the appearance of lesions at skin surfaces (6). How VZV overcomes this cutaneous IFN barrier and produces skin vesicles is not known.The STATs are ubiquitous transcription factors with many cellular functions and are at the junction of several cytokinesignaling pathways (7,8). Of the seven STAT family proteins, STAT3 exerts widespread effects through transcri...

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“…One of these sites in Tip (C484-Y72/C488-Y114) has been shown to be required for binding and activation of STAT1 and STAT3 (22). Similar sequences (PYLP) as well as STAT3 binding were described for StpA and StpB, the proteins encoded by the hypervariable region of herpesvirus saimiri subgroups A and B, respectively (10,43). These proteins had previously been reported to interact with the SH2 domain of cellular Src upon phosphorylation of a YAEI/V motif (25,33).…”

Section: Discussionmentioning

confidence: 81%

Tyrosine Phosphorylation of the Tio Oncoprotein Is Essential for Transformation of Primary Human T Cells

Albrecht

Müller-Fleckenstein

Schmidt

et al. 2005

J Virol

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Human T cells are transformed to antigen-independent permanent growth in vitro upon infection with herpesvirus saimiri subgroup C strains. The viral oncoproteins required for this process, StpC and Tip, could be replaced by Tio, the oncoprotein of herpesvirus ateles. Here we demonstrate that proliferation of lymphocytes transformed with Tio-recombinant herpesvirus saimiri required the activity of Src family kinases. Src kinases had previously been identified as interaction partners of Tio. This interaction was now shown to be independent of any of the four tyrosine residues of Tio but to be dependent on an SH3-binding motif. Mutations within this motif abrogated the transforming capabilities of Tio-recombinant herpesvirus saimiri. Furthermore, kinase interaction resulted in the phosphorylation of Tio on a single tyrosine residue at position 136. Mutation of this residue in the viral context revealed that this phosphorylation site, but none of the other tyrosine residues, was required for T-cell transformation. These data indicate that the interaction of Tio with a Src kinase is essential for both the initiation and the maintenance of T-cell transformation by recombinant herpesvirus saimiri. The requirement for the tyrosine phosphorylation site at position 136 suggests a role for Tio beyond simple deregulation of the kinase.

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Activation of Stat3 Transcription Factor by Herpesvirus Saimiri STP-A Oncoprotein

Cited by 26 publications

References 38 publications

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Tyrosine Phosphorylation of the Tio Oncoprotein Is Essential for Transformation of Primary Human T Cells

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