Virus Genes

, Volume 36, Issue 1, pp 147–155 | Cite as

Signal transduction pathways utilized by enzootic nasal tumor virus (ENTV-1) envelope protein in transformation of rat epithelial cells resemble those used by jaagsiekte sheep retrovirus



The ovine β-retroviruses enzootic nasal tumor virus (ENTV) and Jaagsiekte sheep retrovirus (JSRV) are the causative agent of enzootic nasal adenocarcinoma (ENA) and ovine pulmonary adenocarcinoma (OPA), respectively, characterized by neoplastic transformation of secretory epithelial cells. The Envelope (Env) proteins of these related betaretroviruses act as oncogenes, in that they can transform fibroblast and epithelial cell lines in culture. In addition, viral vector-mediated expression of the Env proteins for these viruses causes tumors in animals. Here, we investigated what signaling pathways are required for the ENTV transformation in vitro. We have previously found that Ras–MEK–MAPK and PI3k–Akt–mTOR are involved in JSRV transformation of fibroblast and epithelial cells. In this study, we found that the MEK inhibitor PD98059 and mTOR inhibitor Rapamycin inhibited ENTV transformation in RK3E rat kidney epithelial cells, but the p38 inhibitor SB203580 drastically enhanced transformation, which is quite similar to JSRV transformation. Small molecular inhibitors and dominant negative versions of H-ras and Rac1 indicated a role for both of these molecules in transformation by either virus. These results indicate that the signaling pathways for ENTV and JSRV transformation are quite similar, consistent with the notion that these proteins do not determine the tissue-specificity of the tumors for these viruses.


Retrovirus ENTV JSRV Envelope Transformation Signal transduction 


  1. 1.
    M. De las Heras, L. Gonzalez, J.M. Sharp, Curr. Top. Microbiol. Immunol. 275, 25–54 (2003)Google Scholar
  2. 2.
    M. De las Heras, A. Ortin, C. Cousens, E. Minguijon, J.M. Sharp, Curr. Top. Microbiol. Immunol. 275, 201–223 (2003)Google Scholar
  3. 3.
    A. Ortin, M. Perez de Villarreal, E. Minguijon, C. Cousens, J.M. Sharp, M. De las Heras, J. Comp. Pathol. 131, 253–258 (2004)PubMedCrossRefGoogle Scholar
  4. 4.
    C. Cousens, E. Minguijon, R.G. Dalziel, A. Ortin, M. Garcia, J. Park, L. Gonzalez, J.M. Sharp, M. De las Heras, J. Virol. 73, 3986–3993 (1999)PubMedGoogle Scholar
  5. 5.
    A. Ortin, C. Cousens, E. Minguijon, Z. Pascual, M. Perez de Villarreal, J.M. Sharp, M. De las Heras, J. Gen. Virol. 84, 2245–2252 (2003)PubMedCrossRefGoogle Scholar
  6. 6.
    A. Alberti, C. Murgia, S.L. Liu, M. Mura, C. Cousens, J.M. Sharp, A.D. Miller, M. Palmarini, J. Virol. 76, 5387–5394 (2002)PubMedCrossRefGoogle Scholar
  7. 7.
    T.E. Allen, K.T. Sherill, S.M. Crispel, M.R. Perrot, J.O. Carlson, J.C. DeMartini, J. Gen. Virol. 83, 2733–2742 (2002)PubMedGoogle Scholar
  8. 8.
    S.L. Liu, F.M. Duh, M.I. Lerman, A.D. Miller, J. Virol. 77, 2850–2858 (2003)PubMedCrossRefGoogle Scholar
  9. 9.
    S.L. Liu, M.I. Lerman, A.D. Miller, J. Virol. 77, 7924–7935 (2003)PubMedCrossRefGoogle Scholar
  10. 10.
    N. Maeda, M. Palmarini, C. Murgia, H. Fan, Proc. Natl. Acad. Sci. USA 98, 4449–4454 (2001)PubMedCrossRefGoogle Scholar
  11. 11.
    N. Maeda, Y. Inoshima, D.A. Fruman, S.M. Brachmann, H. Fan, J. Virol. 77, 9951–9959 (2003)PubMedCrossRefGoogle Scholar
  12. 12.
    M. Palmarini, N. Maeda, C. Murgia, C. De-Fraja, A. Hofacre, H. Fan, J. Virol. 75, 11002–11009 (2001)PubMedCrossRefGoogle Scholar
  13. 13.
    S.K. Rai, F.M. Duh, V. Vigdorovich, A. Danilkovitch-Miagkova, M.I. Lerman, A.D. Miller, Proc. Natl. Acad. Sci. USA 98, 4443–4448 (2001)PubMedCrossRefGoogle Scholar
  14. 14.
    G. Zavala, C. Pretto, Y.H. Chow, L. Jones, A. Alberti, E. Grego, M. De las Heras, M. Palmarini, Virology 312, 95–105 (2003)PubMedCrossRefGoogle Scholar
  15. 15.
    A. Danilkovitch-Miagkova, F.M. Duh, I. Kuzmin, D. Angeloni, S.L. Liu, A.D. Miller, M.I. Lerman, Proc. Natl. Acad. Sci. USA 100, 4580–4585 (2003)PubMedCrossRefGoogle Scholar
  16. 16.
    S.L. Liu, A.D. Miller, J. Virol. 79, 927–933 (2005)PubMedCrossRefGoogle Scholar
  17. 17.
    N. Maeda, W. Fu, A. Ortin, M. De las Heras, H. Fan, J. Virol. 79, 4440–4450 (2005)PubMedCrossRefGoogle Scholar
  18. 18.
    M. Varela, Y.H. Chow, C. Sturkie, P. Murcia, M. Palmarini, Virology 350, 347–357 (2006)PubMedCrossRefGoogle Scholar
  19. 19.
    M. Caporale, C. Cousens, P. Centorame, C. Pinoni, M. De las Heras M. Palmarini, J. Virol. 80, 8030–8037 (2006)PubMedCrossRefGoogle Scholar
  20. 20.
    S.K. Wootton, C.L. Halbert, A.D. Miller, Nature 434, 904–907 (2005)PubMedCrossRefGoogle Scholar
  21. 21.
    S.K. Wootton, C.L. Halbert, A.D. Miller, J. Virol. 80, 9322–9325 (2006)PubMedCrossRefGoogle Scholar
  22. 22.
    S.K. Wootton, M.J. Metzger, K.L. Hudkins, C.E. Alpers, D. York, J.C. DeMartini, A.D. Miller, Retrovirology 3, 94 (2006)PubMedCrossRefGoogle Scholar
  23. 23.
    C. Dirks, F.M. Duh, S.K. Rai, M.I. Lerman, A.D. Miller, J. Virol. 76, 2141–2149 (2002)PubMedCrossRefGoogle Scholar
  24. 24.
    S. Hull, H. Fan, J. Virol. 80, 8069–8080 (2006)PubMedCrossRefGoogle Scholar
  25. 25.
    M. Palmarini, C. Hallwirth, D. York, C. Murgia, T. de Oliveira, T. Spencer, H. Fan, J. Virol. 74, 8065–8076 (2000)PubMedCrossRefGoogle Scholar
  26. 26.
    M. De las Heras, A. Ortin, A. Benito, C. Summers, L.M. Ferrer, J.M. Sharp, J. Comp. Pathol. 135, 1–10 (2006)PubMedGoogle Scholar
  27. 27.
    S.J. Leevers, H.F. Paterson, C.J. Marshall, Nature 369, 411–414 (1994)PubMedCrossRefGoogle Scholar
  28. 28.
    D. Stokoe, S.G. Macdonald, K. Cadwallader, M. Symons, J.F. Hancock, Science. 264, 1463–1467 (1994)PubMedCrossRefGoogle Scholar
  29. 29.
    L.A. Feig, G.M. Cooper, Mol. Cell. Biol. 8, 3235–3243 (1988)PubMedGoogle Scholar
  30. 30.
    R. Khosravi-Far, P.A. Solski, G.J. Clark, M.S. Kinch, C.J. Der, Mol. Cell. Biol. 15, 6443–6453 (1995)PubMedGoogle Scholar
  31. 31.
    R.G. Qiu, J. Chen, D. Kirn, F. McCormick, M. Symons, Nature 374, 457–459 (1995)PubMedCrossRefGoogle Scholar
  32. 32.
    Y. Gao, J.B. Dickerson, F. Guo, J. Zheng, Y. Zheng, Proc. Natl. Acad. Sci. USA 101, 7618–7623 (2004)PubMedCrossRefGoogle Scholar
  33. 33.
    K. Wennerberg, C.J. Der, J. Cell Sci. 117, 1301–1312 (2004)PubMedCrossRefGoogle Scholar
  34. 34.
    R.G. Qiu, J. Chen, F. McCormick, M. Symons, Proc. Natl. Acad. Sci. USA 92, 11781–11785 (1995)PubMedCrossRefGoogle Scholar
  35. 35.
    I. Shin, S. Kim, H. Song, H.R. Kim, A. Moon, J. Biol. Chem. 280, 14675–14683 (2005)PubMedCrossRefGoogle Scholar
  36. 36.
    M.T. Uhlik, A.N. Abell, N.L. Johnson, W. Sun, B.D. Cuevas, K.E. Lobel-Rice, E.A. Horne, M.L. Dell’Acqua, G.L. Johnson, Nat. Cell Biol. 5, 1104–1110 (2003)PubMedCrossRefGoogle Scholar
  37. 37.
    M. Palmarini, S. Datta, R. Omid, C. Murgia, H. Fan, J. Virol. 74, 5776–5787 (2000)PubMedCrossRefGoogle Scholar
  38. 38.
    K. Mcgee-Estrada, M. Palmarini, H. Fan, Virology. 292, 87–97 (2002)PubMedCrossRefGoogle Scholar
  39. 39.
    K. Mcgee-Estrada, H. Fan, J. Virol. 80, 332–341 (2006)PubMedCrossRefGoogle Scholar
  40. 40.
    K. Mcgee-Estrada, H. Fan, Virus Genes 35, 303–312 (2007)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Cancer Research InstituteUniversity of California, IrvineIrvineUSA
  2. 2.Department of Molecular Biology and BiochemistryUniversity of California, IrvineIrvineUSA
  3. 3.Division of Host Defense, Research Center for Prevention of Infectious Diseases, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
  4. 4.Division of Bioinformatics, Digital Medicine InitiativeKyushu UniversityFukuokaJapan

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