DF/HCC Associations

Member, Center Scientific Council

Research Abstract

The highly oncogenic mouse polyomavirus is amenable to study both in cell culture and in its natural host. This system thus provides opportunities to study genetic determinants of virus and host as they effect tumor development in a variety of tissues.

Viral Determinants - The virus is armed with proto-oncogene activation functions through interaction of the middle T protein with pp60c-src and subsequent activation of Shc-ras-raf-MAPK, P13-K, and PL-Cg pathways, and also with tumor suppressor gene inactivation functions through binding of p110Rb by the large T protein. [Interestingly, polyoma has not been shown to interact with p53.] Effects of mutations of discrete viral functions on tumor induction are not always predictable based on results in cell culture system. For example, pRb binding mutants are unable to replicate in or to promote immortalization of primary cells in vitro but replicate and induce tumors well in the mouse; middle T mutants that are defective in transforming established fibroblasts can still induce a broad array of tumors, but with changes in the tissue spectrum and histological properties of the tumors. Differences in growth control networks operating in different target cell types must affect the response to the virus and the likelihood of undergoing neoplastic transformation.

Host Determinants - Responses to polyoma vary greatly among inbred mouse strains. The ability to mount an effective anti-tumor immune response is a major determinant of resistance. This ability is linked to MHC type and can be overcome by irradiation or other immunosuppressive treatments. Susceptible mice have mechanisms that actively override or prevent anti-tumor immune responses. Highly susceptible standard inbred strains are all of the H2k haplotype. These strains also express an endogenous mouse mammary tumor virus superantigen that effectively deletes essential precursors of polyoma specific cytotoxic T lymphocytes (CTLs). Some recently derived 'wild' mouse inbred strains show a different form of susceptibility that is based not on endogenous superantigen but rather on an inability to generate virus-specific CTLs from available precursors.
A non-immunological form of resistance has also been documented. This is based on the observation that mice of certain strains fail to develop tumors even if irradiated prior to virus inoculation. The radiation-resistant form of host resistance targets the virus directly and blocks its dissemination by an unknown mechanism. The host genetic background can also affect tumor development or behavior in a tissue-specific manner. Mus. spretus, for example, shows strong resistance to development of mammary tumors but develops all the other major tumor types. Polyoma tumors are generally not highly metastatic; however, in one of the 'wild' inbred strains primary bone tumors metastasize regularly to both lung and liver.

Publications

• Velupillai P, Yoshizawa I, Dey DC, Nahill SR, Carroll JP, Bronson RT, Benjamin TL.Wild-derived inbred mice have a novel basis of susceptibility to polyomavirus-induced tumors.J Virol 1999 Dec;73(12):10079-85.
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• Tsai B, Gilbert JM, Stehle T, Lencer W, Benjamin TL, Rapoport TA.Gangliosides are receptors for murine polyoma virus and SV40.EMBO J 2003 Sep 1;22(17):4346-55.
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• Gilbert JM, Goldberg IG, Benjamin TL.Cell penetration and trafficking of polyomavirus.J Virol 2003 Feb;77(4):2615-22.
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• Velupillai P, Carroll JP, Benjamin TL.Susceptibility to polyomavirus-induced tumors in inbred mice: role of innate immune responses.J Virol 2002 Oct;76(19):9657-63.
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• Dey D, Dahl J, Cho S, Benjamin TL.Induction and bypass of p53 during productive infection by polyomavirus.J Virol 2002 Sep;76(18):9526-32.
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• Li D, Dower K, Ma Y, Tian Y, Benjamin TL.A tumor host range selection procedure identifies p150(sal2) as a target of polyoma virus large T antigen.Proc Natl Acad Sci U S A 2001 Dec 4;98(25):14619-24.
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• Benjamin TL.Polyoma virus: old findings and new challenges.Virology 2001 Oct 25;289(2):167-73.
  11689038
• Cho S, Tian Y, Benjamin TL.Binding of p300/CBP co-activators by polyoma large T antigen.J Biol Chem 2001 Sep 7;276(36):33533-9.
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• Gilbert JM, Benjamin TL.Early steps of polyomavirus entry into cells.J Virol 2000 Sep;74(18):8582-8.
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• Dey DC, Bronson RP, Dahl J, Carroll JP, Benjamin TL.Accelerated development of polyoma tumors and embryonic lethality: different effects of p53 loss on related mouse backgrounds.Cell Growth Differ 2000 May;11(5):231-7.
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• Bauer PH, Cui C, Liu R, Stehle T, Harrison SC, DeCaprio JA, Benjamin TL.Discrimination between sialic acid-containing receptors and pseudoreceptors regulates polyomavirus spread in the mouse.J Virol 1999 Jul;73(7):5826-32.
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• Carroll JP, Fung JS, Bronson RT, Razvi E, Benjamin TL.Radiation-resistant and radiation-sensitive forms of host resistance to polyomavirus.J Virol 1999 Feb;73(2):1213-8.
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• Dahl J, Jurczak A, Cheng LA, Baker DC, Benjamin TL.Evidence of a role for phosphatidylinositol 3-kinase activation in the blocking of apoptosis by polyomavirus middle T antigen.J Virol 1998 Apr;72(4):3221-6.
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• Culleré X, Rose P, Thathamangalam U, Chatterjee A, Mullane KP, Pallas DC, Benjamin TL, Roberts TM, Schaffhausen BS.Serine 257 phosphorylation regulates association of polyomavirus middle T antigen with 14-3-3 proteins.J Virol 1998 Jan;72(1):558-63.
  9420259
• Bauer PH, Benjamin TL.A novel 39-kilodalton membrane protein binds GTP in polyomavirus-transformed cells.J Virol 1997 May;71(5):4128-32.
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• Dahl J, Freund R, Blenis J, Benjamin TL.Studies of partially transforming polyomavirus mutants establish a role for phosphatidylinositol 3-kinase in activation of pp70 S6 kinase.Mol Cell Biol 1996 Jun;16(6):2728-35.
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• Young AT, Dahl J, Hausdorff SF, Bauer PH, Birnbaum MJ, Benjamin TL.Phosphatidylinositol 3-kinase binding to polyoma virus middle tumor antigen mediates elevation of glucose transport by increasing translocation of the GLUT1 transporter.Proc Natl Acad Sci
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• Bauer PH, Bronson RT, Fung SC, Freund R, Stehle T, Harrison SC, Benjamin TL.Genetic and structural analysis of a virulence determinant in polyomavirus VP1.J Virol 1995 Dec;69(12):7925-31.
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• Lukacher AE, Ma Y, Carroll JP, Abromson-Leeman SR, Laning JC, Dorf ME, Benjamin TL.Susceptibility to tumors induced by polyoma virus is conferred by an endogenous mouse mammary tumor virus superantigen.J Exp Med 1995 May 1;181(5):1683-92.
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• Freund R, Bauer PH, Crissman HA, Bradbury EM, Benjamin TL.Host range and cell cycle activation properties of polyomavirus large T-antigen mutants defective in pRB binding.J Virol 1994 Nov;68(11):7227-34.
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• Stehle T, Yan Y, Benjamin TL, Harrison SC.Structure of murine polyomavirus complexed with an oligosaccharide receptor fragment.Nature 1994 May 12;369(6476):160-3.
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• Johnson SC, Dahl J, Shih TL, Schedler DJ, Anderson L, Benjamin TL, Baker DC.Synthesis and evaluation of 3-modified 1D-myo-inositols as inhibitors and substrates of phosphatidylinositol synthase and inhibitors of myo-inositol uptake by cells.J Med Chem 199
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• Lukacher AE, Freund R, Carroll JP, Bronson RT, Benjamin TL.Pyvs: a dominantly acting gene in C3H/BiDa mice conferring susceptibility to tumor induction by polyoma virus.Virology 1993 Sep;196(1):241-8.
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