Tumor induction by a transformation-defective polyoma virus mutant blocked in signaling through Shc

Bronson, Roderick T.; Dawe, Clyde J.; Carroll, John P.; Benjamin, Thomas L.

doi:10.1073/pnas.94.15.7954

Cited by 31 publications

(37 citation statements)

References 32 publications

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“…Third, of the two CD8 ϩ T cell populations recognizing each of the overlapping epitopes contained within the MT245 sequence, only the K b -restricted MT246 epitope was selectively maintained in persistent infection; this population alone showed maturation in functional avidity. It is of interest to note that tyrosine 250 within the MT246 epitope is not only a dominant anchor for antigenic peptide binding to K b , but also constitutes a phosphotyrosine-based binding site for the Src homology 2 domains of ShcA and the p85 subunit of PI3K (38); MT binding to ShcA and PI3K is essential for MT-induced cellular transformation and affects tumor induction by PyV (39,40). From a teleological perspective, it is advantageous to the host to maintain a high avidity CD8 ϩ T cell population directed toward a viral domain essential for cellular transformation.…”

Section: Discussionmentioning

confidence: 99%

Late Priming and Variability of Epitope-Specific CD8+ T Cell Responses during a Persistent Virus Infection

Kemball

Lee

Vezys

et al. 2005

The Journal of Immunology

126

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Control of persistently infecting viruses requires that antiviral CD8+ T cells sustain their numbers and effector function. In this study, we monitored epitope-specific CD8+ T cells during acute and persistent phases of infection by polyoma virus, a mouse pathogen that is capable of potent oncogenicity. We identified several novel polyoma-specific CD8+ T cell epitopes in C57BL/6 mice, a mouse strain highly resistant to polyoma virus-induced tumors. Each of these epitopes is derived from the viral T proteins, nonstructural proteins produced by both productively and nonproductively (and potentially transformed) infected cells. In contrast to CD8+ T cell responses described in other microbial infection mouse models, we found substantial variability between epitope-specific CD8+ T cell responses in their kinetics of expansion and contraction during acute infection, maintenance during persistent infection, as well as their expression of cytokine receptors and cytokine profiles. This epitope-dependent variability also extended to differences in maturation of functional avidity from acute to persistent infection, despite a narrowing in TCR repertoire across all three specificities. Using a novel minimal myeloablation-bone marrow chimera approach, we visualized priming of epitope-specific CD8+ T cells during persistent virus infection. Interestingly, epitope-specific CD8+ T cells differed in CD62L-selectin expression profiles when primed in acute or persistent phases of infection, indicating that the context of priming affects CD8+ T cell heterogeneity. In summary, persistent polyoma virus infection both quantitatively and qualitatively shapes the antiviral CD8+ T cell response.

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Section: Discussionmentioning

confidence: 99%

Late Priming and Variability of Epitope-Specific CD8+ T Cell Responses during a Persistent Virus Infection

Kemball

Lee

Vezys

et al. 2005

The Journal of Immunology

126

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“…However, the¯k-17/7 in vitro dierentiation system established in this study in combination with either well-characterized mutants of the polyoma middle T oncogene which are no longer able to bind and activate certain signal mediating molecules (Bronson et al, 1997;Glenn and Eckhart, 1995;Young et al, 1995) or with downstream eector molecules (Chang et al, 1997) represents a unique tool to genetically dissect the signal transduction pathways downstream of an activated Flk-1 receptor.…”

Section: Discussionmentioning

confidence: 99%

Formation of transformed endothelial cells in the absence of VEGFR-2/Flk-1 by Polyoma middle T oncogene

et al. 1999

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The middle T antigen of murine Polyomavirus (PymT) rapidly transforms endothelial cells leading to vascular malformations reminiscent of endothelial tumors or hemangiomas. Flk-1, a receptor tyrosine kinase which is activated upon binding of its ligand VEGF, is predominantly expressed in endothelial cells and essential for the formation of blood vessels since absence of Flk-1 prevents the development of mature endothelial cells in mice and in ES-cell dierentiation experiments. To investigate the role of Flk-1 in PymT-induced vascular tumor formation, we studied the expression of Flk-1 and VEGF in PymT-transformed endothelial cells (Endothelioma cells, END. cells). The receptor and its ligand were both expressed in END. cells suggesting that a VEGF/ Flk-1 autocrine loop might be causally involved in the formation of vascular tumors. To test this hypothesis, ES cells lacking Flk-1 were generated and the transforming potential of PymT was analysed after in vitro dierentiation. Flk-17/7 END. cell lines were established which are morphologically identical to¯k-1+/+ END. cells and which express several markers characteristic for endothelial cells. This result suggests that PymT functionally replaces the requirement of Flk-1 in expansion and/or survival of endothelial progenitor cells. Therefore,¯k-17/7 END. cells provide a powerful tool to dissect the downstream signaling pathways of Flk-1.

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“…Complete autopsies were performed, and both gross and microscopic examinations were done. Five mice from each time point (4,8,12, and 16 weeks) from transgenic strains MMTV/ MT, MMTV/MT-Y250F, and MMTV/MT-Y315/22F and nontransgenic strain FVB/N were analyzed. Upper left mammary fat pad tissues were fixed in 4% paraformaldehyde, blocked in paraffin, sectioned at 5 m, stained with hematoxylin and eosin, and examined.…”

Section: Dna Constructionsmentioning

confidence: 99%

Requirement for Both Shc and Phosphatidylinositol 3′ Kinase Signaling Pathways in Polyomavirus Middle T-Mediated Mammary Tumorigenesis

Webster¹,

Hutchinson²,

Rauh

et al. 1998

Molecular and Cellular Biology

187

227

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Transgenic mice expressing the polyomavirus (PyV) middle T antigen (MT) develop multifocal mammary tumors which frequently metastasize to the lung. The potent transforming activity of PyV MT is correlated with its capacity to activate and associate with a number of signaling molecules, including the Src family tyrosine kinases, the 85-kDa Src homology 2 subunit of the phosphatidylinositol 3 (PI-3) kinase, and the Shc adapter protein. To uncover the role of these signaling proteins in MT-mediated mammary tumorigenesis, we have generated transgenic mice that express mutant PyV MT antigens decoupled from either the Shc or the PI-3 kinase signaling pathway. In contrast to the rapid induction of metastatic mammary tumors observed in the strains expressing wild-type PyV MT, mammary epithelial cell-specific expression of either mutant PyV MT resulted in the induction of extensive mammary epithelial hyperplasias. The mammary epithelial hyperplasias expressing the mutant PyV MT defective in recruiting the PI-3 kinase were highly apoptotic, suggesting that recruitment of PI-3 kinase by MT affects cell survival. Whereas the initial phenotypes observed in both strains were global mammary epithelial hyperplasias, focal mammary tumors eventually arose in all female transgenic mice. Genetic and biochemical analyses of tumorigenesis in the transgenic strains expressing the PyV MT mutant lacking the Shc binding site revealed that a proportion of the metastatic tumors arising in these mice displayed evidence of reversion of the mutant Shc binding site. In contrast, no evidence of reversion of the PI-3 kinase binding site was noted in tumors derived from the strains expressing the PI-3 kinase binding site MT mutant. Tumor progression in both mutant strains was further correlated with upregulation of the epidermal growth factor receptor family members which are known to couple to the PI-3 kinase and Shc signaling pathways. Taken together, these observations suggest that PyV MT-mediated tumorigenesis requires activation of both Shc and PI-3 kinase, which appear to be required for stimulation of cell proliferation and survival signaling pathways, respectively.Mammary epithelial cell-specific expression of the polyomavirus (PyV) middle T (MT) oncogene in transgenic mice results in the induction of multifocal metastatic mammary tumors involving 100% of the transgene carriers (19). The potent oncogenic properties of the PyV MT are due to its ability to associate with and activate a number of cellular signaling proteins. One class of cellular enzymes activated by PyV MT consists of members of the Src family tyrosine kinases (c-Src and c-Yes) (8,12,27,30). Expression of PyV MT in mammary glands of Src-deficient mice rarely results in the induction of mammary tumors (20), suggesting that activation of Src by PyV MT is required for mammary tumorigenesis. Whereas activation of c-Src is required for the rapid induction of mammary tumors, this event is not sufficient, because expression of a constitutively active version of Src in the mammary ...

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Tumor induction by a transformation-defective polyoma virus mutant blocked in signaling through Shc

Abstract: ABSTRACT

Cited by 31 publications

References 32 publications

Late Priming and Variability of Epitope-Specific CD8+ T Cell Responses during a Persistent Virus Infection

Late Priming and Variability of Epitope-Specific CD8+ T Cell Responses during a Persistent Virus Infection

Formation of transformed endothelial cells in the absence of VEGFR-2/Flk-1 by Polyoma middle T oncogene

Requirement for Both Shc and Phosphatidylinositol 3′ Kinase Signaling Pathways in Polyomavirus Middle T-Mediated Mammary Tumorigenesis

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