The goals of this project are to define the pathways of induction of tumors in the mouse by polyoma virus at the molecular level. To this end, mutant strains of virus that have been well characterized in cell culture systems will be inoculated into newborn mice; the latter will then be followed for development of the various tumor types which the wild-type virus is known to induce. Site- directed mutagenesis will be used to modify particular regions of the middle T viral oncogene. These mutants will then be characterized biochemically and in cell transformation assays in order to understand more fully the interactions of middle T with cellular enzymes, including the tyrosine protein kinase pp60c-src, phosphatidylinositol 3-kinase and protein phosphatase 2A. Analogues of inositol modified at the 3-position will be examined as potential inhibitors of 3-phosphoinositide metabolism in vivo. Mutants of large T, or other viral proteins potentially involved in interactions with host tumor suppressor genes, will be sought and characterized. Cellular kinases that phosphorylate the major viral capsid protein VP1 will be identified. Attempts will be made to identify additional cellular elements involved in a cascade between middle T and VP1; this cascade is viewed as overlapping with a mitogenic pathway of the host cell. Finally, an attempt will be made to identify, map, and ultimately clone, genes of the host that confer susceptibility or resistance to tumor induction by the virus.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA044343-12
Application #
2732987
Study Section
Special Emphasis Panel (SRC (88))
Program Officer
Wong, May
Project Start
1987-09-01
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Gilbert, Joanna M; Goldberg, Ilya G; Benjamin, Thomas L (2003) Cell penetration and trafficking of polyomavirus. J Virol 77:2615-22
Velupillai, Palanivel; Carroll, John P; Benjamin, Thomas L (2002) Susceptibility to polyomavirus-induced tumors in inbred mice: role of innate immune responses. J Virol 76:9657-63
Dey, Dilip; Dahl, Jean; Cho, Sayeon et al. (2002) Induction and bypass of p53 during productive infection by polyomavirus. J Virol 76:9526-32
Li, D; Dower, K; Ma, Y et al. (2001) 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 98:14619-24
Cho, S; Tian, Y; Benjamin, T L (2001) Binding of p300/CBP co-activators by polyoma large T antigen. J Biol Chem 276:33533-9
Dey, D C; Bronson, R P; Dahl, J et al. (2000) Accelerated development of polyoma tumors and embryonic lethality: different effects of p53 loss on related mouse backgrounds. Cell Growth Differ 11:231-7
Gilbert, J M; Benjamin, T L (2000) Early steps of polyomavirus entry into cells. J Virol 74:8582-8
Bauer, P H; Cui, C; Liu, W R et al. (1999) Discrimination between sialic acid-containing receptors and pseudoreceptors regulates polyomavirus spread in the mouse. J Virol 73:5826-32
Carroll, J P; Fung, J S; Bronson, R T et al. (1999) Radiation-resistant and radiation-sensitive forms of host resistance to polyomavirus. J Virol 73:1213-8
Velupillai, P; Yoshizawa, I; Dey, D C et al. (1999) Wild-derived inbred mice have a novel basis of susceptibility to polyomavirus-induced tumors. J Virol 73:10079-85

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