Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1991 Oct;65(10):5174–5183. doi: 10.1128/jvi.65.10.5174-5183.1991

The polyomavirus early region gene in transgenic mice causes vascular and bone tumors.

R Wang 1, V L Bautch 1
PMCID: PMC248994  PMID: 1654437

Abstract

Transgenic mice carrying the entire polyomavirus (Py) early region consistently develop both vascular and bone tumors. This tumor spectrum represents a subset of the tumors found in mice infected with Py and an expansion of the vascular tumor spectrum seen in Py middle T antigen (MT) transgenic mice (V. L. Bautch, S. Toda, J. A. Hassell, and D. Hanahan, Cell 51:529-538, 1987). Transgenic mice of three independent lineages develop these pathologies, and mice of individual lineages also develop lymphangiomas and fibrosarcomas. All tumors are of mesenchymal origin, and all tumor tissues express the Py transgene. Some unaffected tissues, including the testes of mice of all lineages, also express the Py transgene. The number of transgene expression sites in mice of a given lineage correlates with the severity and latency of the tumor phenotype in these animals. Analysis of transgene transcripts indicates that RNAs for Py large T antigen (LT), MT, and small T antigen (ST) are present in both tumors and testes of transgenic mice. The ratio of LT RNA to MT and ST RNAs, however, is higher in testes than in tumors and other unaffected tissues, indicating that tissue-specific differences in the relative amounts of the alternatively spliced Py RNAs exist. The finding that some sites of Py transgene expression are susceptible to tumor formation while other expressing tissues such as testes are refractory to tumorigenesis suggests that mechanisms of viral pathogenesis are influenced by a tissue specificity in the effects of the Py early region.

Full text

PDF
5174

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bautch V. L. Effects of polyoma virus oncogenes in transgenic mice. Mol Biol Med. 1989 Aug;6(4):309–317. [PubMed] [Google Scholar]
  2. Bautch V. L. Genetic background affects integration frequency of ecotropic proviral sequences into the mouse germ line. J Virol. 1986 Nov;60(2):693–701. doi: 10.1128/jvi.60.2.693-701.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bautch V. L., Toda S., Hassell J. A., Hanahan D. Endothelial cell tumors develop in transgenic mice carrying polyoma virus middle T oncogene. Cell. 1987 Nov 20;51(4):529–537. doi: 10.1016/0092-8674(87)90122-x. [DOI] [PubMed] [Google Scholar]
  4. Berebbi M., Dandolo L., Hassoun J., Bernard A. M., Blangy D. Specific tissue targeting of polyoma virus oncogenicity in athymic nude mice. Oncogene. 1988 Feb;2(2):149–156. [PubMed] [Google Scholar]
  5. Brinster R. L., Chen H. Y., Messing A., van Dyke T., Levine A. J., Palmiter R. D. Transgenic mice harboring SV40 T-antigen genes develop characteristic brain tumors. Cell. 1984 Jun;37(2):367–379. doi: 10.1016/0092-8674(84)90367-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chowdhury K., Light S. E., Garon C. F., Ito Y., Israel M. A. A cloned polyoma DNA fragment representing the 5' half of the early gene region is oncogenic. J Virol. 1980 Nov;36(2):566–574. doi: 10.1128/jvi.36.2.566-574.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cory S., Adams J. M. Transgenic mice and oncogenesis. Annu Rev Immunol. 1988;6:25–48. doi: 10.1146/annurev.iy.06.040188.000325. [DOI] [PubMed] [Google Scholar]
  8. Crenshaw E. B., 3rd, Russo A. F., Swanson L. W., Rosenfeld M. G. Neuron-specific alternative RNA processing in transgenic mice expressing a metallothionein-calcitonin fusion gene. Cell. 1987 May 8;49(3):389–398. doi: 10.1016/0092-8674(87)90291-1. [DOI] [PubMed] [Google Scholar]
  9. Dawe C. J., Freund R., Mandel G., Ballmer-Hofer K., Talmage D. A., Benjamin T. L. Variations in polyoma virus genotype in relation to tumor induction in mice. Characterization of wild type strains with widely differing tumor profiles. Am J Pathol. 1987 May;127(2):243–261. [PMC free article] [PubMed] [Google Scholar]
  10. Demengeot J., Jacquemier J., Torrente M., Blangy D., Berebbi M. Pattern of polyomavirus replication from infection until tumor formation in the organs of athymic nu/nu mice. J Virol. 1990 Nov;64(11):5633–5639. doi: 10.1128/jvi.64.11.5633-5639.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dubensky T. W., Freund R., Dawe C. J., Benjamin T. L. Polyomavirus replication in mice: influences of VP1 type and route of inoculation. J Virol. 1991 Jan;65(1):342–349. doi: 10.1128/jvi.65.1.342-349.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Freund R., Calderone A., Dawe C. J., Benjamin T. L. Polyomavirus tumor induction in mice: effects of polymorphisms of VP1 and large T antigen. J Virol. 1991 Jan;65(1):335–341. doi: 10.1128/jvi.65.1.335-341.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Freund R., Garcea R. L., Sahli R., Benjamin T. L. A single-amino-acid substitution in polyomavirus VP1 correlates with plaque size and hemagglutination behavior. J Virol. 1991 Jan;65(1):350–355. doi: 10.1128/jvi.65.1.350-355.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Freund R., Mandel G., Carmichael G. G., Barncastle J. P., Dawe C. J., Benjamin T. L. Polyomavirus tumor induction in mice: influences of viral coding and noncoding sequences on tumor profiles. J Virol. 1987 Jul;61(7):2232–2239. doi: 10.1128/jvi.61.7.2232-2239.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Frohman M. A., Dush M. K., Martin G. R. Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8998–9002. doi: 10.1073/pnas.85.23.8998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ge H., Noble J., Colgan J., Manley J. L. Polyoma virus small tumor antigen pre-mRNA splicing requires cooperation between two 3' splice sites. Proc Natl Acad Sci U S A. 1990 May;87(9):3338–3342. doi: 10.1073/pnas.87.9.3338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hanahan D. Dissecting multistep tumorigenesis in transgenic mice. Annu Rev Genet. 1988;22:479–519. doi: 10.1146/annurev.ge.22.120188.002403. [DOI] [PubMed] [Google Scholar]
  18. Hanahan D. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature. 1985 May 9;315(6015):115–122. doi: 10.1038/315115a0. [DOI] [PubMed] [Google Scholar]
  19. Ito Y., Spurr N. Polyoma virus T antigens expressed in transformed cells: significance of middle T antigen in transformation. Cold Spring Harb Symp Quant Biol. 1980;44(Pt 1):149–157. doi: 10.1101/sqb.1980.044.01.017. [DOI] [PubMed] [Google Scholar]
  20. Krippl B., Griep A. E., Mahon K. A., Böhnlein E., Gruss P., Westphal H. Expression and amplification in transgenic mice of a polyoma virus mutant regulatory region. Nucleic Acids Res. 1988 Sep 26;16(18):8963–8976. doi: 10.1093/nar/16.18.8963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lusky M., Botchan M. Inhibition of SV40 replication in simian cells by specific pBR322 DNA sequences. Nature. 1981 Sep 3;293(5827):79–81. doi: 10.1038/293079a0. [DOI] [PubMed] [Google Scholar]
  22. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Noda T., Satake M., Robins T., Ito Y. Isolation and characterization of NIH 3T3 cells expressing polyomavirus small T antigen. J Virol. 1986 Oct;60(1):105–113. doi: 10.1128/jvi.60.1.105-113.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Palmiter R. D., Chen H. Y., Messing A., Brinster R. L. SV40 enhancer and large-T antigen are instrumental in development of choroid plexus tumours in transgenic mice. Nature. 1985 Aug 1;316(6027):457–460. doi: 10.1038/316457a0. [DOI] [PubMed] [Google Scholar]
  25. Pomerantz B. J., Mueller C. R., Hassell J. A. Polyomavirus large T antigen binds independently to multiple, unique regions on the viral genome. J Virol. 1983 Sep;47(3):600–610. doi: 10.1128/jvi.47.3.600-610.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rassoulzadegan M., Cowie A., Carr A., Glaichenhaus N., Kamen R., Cuzin F. The roles of individual polyoma virus early proteins in oncogenic transformation. Nature. 1982 Dec 23;300(5894):713–718. doi: 10.1038/300713a0. [DOI] [PubMed] [Google Scholar]
  27. Rassoulzadegan M., Naghashfar Z., Cowie A., Carr A., Grisoni M., Kamen R., Cuzin F. Expression of the large T protein of polyoma virus promotes the establishment in culture of "normal" rodent fibroblast cell lines. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4354–4358. doi: 10.1073/pnas.80.14.4354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ruley H. E. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature. 1983 Aug 18;304(5927):602–606. doi: 10.1038/304602a0. [DOI] [PubMed] [Google Scholar]
  29. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  30. Small J. A., Khoury G., Jay G., Howley P. M., Scangos G. A. Early regions of JC virus and BK virus induce distinct and tissue-specific tumors in transgenic mice. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8288–8292. doi: 10.1073/pnas.83.21.8288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Treisman R., Cowie A., Favaloro J., Jat P., Kamen R. The structures of the spliced mRNAs encoding polyoma virus early region proteins. J Mol Appl Genet. 1981;1(2):83–92. [PubMed] [Google Scholar]
  32. Treisman R., Novak U., Favaloro J., Kamen R. Transformation of rat cells by an altered polyoma virus genome expressing only the middle-T protein. Nature. 1981 Aug 13;292(5824):595–600. doi: 10.1038/292595a0. [DOI] [PubMed] [Google Scholar]
  33. Van Dyke T., Finlay C., Levine A. J. A comparison of several lines of transgenic mice containing the SV40 early genes. Cold Spring Harb Symp Quant Biol. 1985;50:671–678. doi: 10.1101/sqb.1985.050.01.082. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES