This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Maeda, N.
Right arrow Articles by Fan, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maeda, N.
Right arrow Articles by Fan, H.

 Previous Article  |  Next Article 

Journal of Virology, September 2003, p. 9951-9959, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9951-9959.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Transformation of Mouse Fibroblasts by Jaagsiekte Sheep Retrovirus Envelope Does Not Require Phosphatidylinositol 3-Kinase

Naoyoshi Maeda,1,2 Yasuo Inoshima,1,2 David A. Fruman,1,2 Saskia M. Brachmann,3,4 and Hung Fan1,2*

Cancer Research Institute,1 Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697,2 Freie Universitaet Berlin, Institut fuer Biochemie, 14195 Berlin, Germany,3 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts 021154

Received 27 March 2003/ Accepted 19 June 2003

Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma, a transmissible lung cancer of sheep. The envelope of JSRV may have oncogenic properties, since it can morphologically transform mouse NIH 3T3 cells and other fibroblast lines. Recently, we found that the cytoplasmic tail of the envelope transmembrane (TM) protein is necessary for transformation, and in particular a consensus binding motif (YXXM) for phosphatidylinositol 3-kinase (PI3K) is important. Moreover, JSRV-transformed cells show phosphorylation (activation) of Akt/protein kinase B, a downstream target of PI3K. In these studies, we directly tested for the involvement of PI3K in transformation by JSRV. Contrary to expectations, four different experiments indicated that PI3K is not necessary for JSRV-induced transformation: (i) cotransfection with a dominant negative truncated form of the PI3K regulatory subunit ({Delta}p85) did not affect transformation frequency, (ii) cells stably expressing {Delta}p85 showed the same frequencies of transformation as parental NIH 3T3 cells, (iii) fibroblasts established from double-knockout mice lacking PI3K p85{alpha} and p85ß could be transformed with JSRV envelope, and (iv) incubation of cells with the PI3K inhibitor LY294002 did not specifically inhibit transformation, nor did the drug reverse transformation of JSRV-transformed cells. One alternate explanation for the lack of transformation by YXXM mutants could be that they were defective in intracellular trafficking. However, confocal microscopy of epitope-tagged envelope proteins of both wild-type and nontransforming YXXM mutants showed a cell surface or plasma membrane localization. While PI3K is not required for JSRV-induced transformation of NIH 3T3 cells, the downstream target Akt kinase was found to be activated (phosphorylated) in JSRV-transformed PI3K-negative cells. Therefore, JSRV envelope can induce PI3K-independent phosphorylation of Akt.

* Corresponding author. Mailing address: Cancer Research Institute, Sprague Hall, University of California, Irvine, Irvine, CA 92697-3900. Phone: (949) 824-5554. Fax: (949) 824-4023. E-mail: hyfan{at}uci.edu.

Journal of Virology, September 2003, p. 9951-9959, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9951-9959.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nitta, T., Hofacre, A., Hull, S., Fan, H. (2009). Identification and Mutational Analysis of a Rej Response Element in Jaagsiekte Sheep Retrovirus RNA. J. Virol. 83: 12499-12511 [Abstract] [Full Text]  
  • Hofacre, A., Nitta, T., Fan, H. (2009). Jaagsiekte Sheep Retrovirus Encodes a Regulatory Factor, Rej, Required for Synthesis of Gag Protein. J. Virol. 83: 12483-12498 [Abstract] [Full Text]  
  • Hull, S., Fan, H. (2006). Mutational analysis of the cytoplasmic tail of jaagsiekte sheep retrovirus envelope protein.. J. Virol. 80: 8069-8080 [Abstract] [Full Text]  
  • Dunlap, K. A., Palmarini, M., Adelson, D. L., Spencer, T. E. (2005). Sheep Endogenous Betaretroviruses (enJSRVs) and the Hyaluronidase 2 (HYAL2) Receptor in the Ovine Uterus and Conceptus. Biol. Reprod. 73: 271-279 [Abstract] [Full Text]  
  • Maeda, N., Fu, W., Ortin, A., de las Heras, M., Fan, H. (2005). Roles of the Ras-MEK-Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase-Akt-mTOR Pathways in Jaagsiekte Sheep Retrovirus-Induced Transformation of Rodent Fibroblast and Epithelial Cell Lines. J. Virol. 79: 4440-4450 [Abstract] [Full Text]  
  • Liu, S.-L., Miller, A. D. (2005). Transformation of Madin-Darby Canine Kidney Epithelial Cells by Sheep Retrovirus Envelope Proteins. J. Virol. 79: 927-933 [Abstract] [Full Text]  
  • Hofacre, A., Fan, H. (2004). Multiple Domains of the Jaagsiekte Sheep Retrovirus Envelope Protein Are Required for Transformation of Rodent Fibroblasts. J. Virol. 78: 10479-10489 [Abstract] [Full Text]  
  • Suzuki, A., Lu, J., Kusakai, G.-i., Kishimoto, A., Ogura, T., Esumi, H. (2004). ARK5 Is a Tumor Invasion-Associated Factor Downstream of Akt Signaling. Mol. Cell. Biol. 24: 3526-3535 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»