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Journal of Virology, July 2007, p. 7069-7076, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00115-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The p110{alpha} Isoform of Phosphatidylinositol 3-Kinase Is Essential for Polyomavirus Middle T Antigen-Mediated Transformation{triangledown}

Tamara Utermark,1,2 Brian S. Schaffhausen,4 Thomas M. Roberts,1,2 and Jean J. Zhao1,3*

Department of Cancer Biology, Dana-Farber Cancer Institute,1 Departments of Pathology,2 Surgery, Harvard Medical School, Boston, Massachusetts 02115,3 Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 021114

Received 17 January 2007/ Accepted 9 April 2007

Middle T antigen (MT) of polyomavirus is known to play an important role in virus-mediated cellular transformation. While MT has been extensively examined in spontaneously immortalized rodent fibroblasts, its interactions with cells of other types and species are less well understood. We have undertaken a cross-species and cross-cell-type comparison of MT-induced transformation in cells with genetically defined backgrounds. We tested the transforming abilities of a panel of MT mutants, Y250F, Y315F, and Y322F, that are selectively mutated in the binding sites for the principal effectors of MT—Src homology 2 domain-containing transforming protein, phosphatidylinositol 3-kinase (PI3K), and phospholipase C-{gamma}, respectively—in fibroblasts and epithelial cells of murine or human origin. We found that the Y315F mutation disabled the ability of MT to induce transformation in all cell types and species tested. While Y315F also failed to activate the PI3K pathway in these cells, genetic evidence has indicated Y315 may make other contributions to transformation. To confirm the role of PI3K, the PIK3CA gene, encoding p110{alpha}, the prime effector of PI3K signaling downstream from activated growth factor receptors, was genetically ablated. This abolished the transforming activity of MT, demonstrating the essential role for this PI3K isoform in MT-mediated transformation. The Y250F mutant was able to transform the human, but not the murine, cells that were examined. Interestingly, this mutant fully activates the PI3K pathway in human cells but activated PI3K signaling poorly in the murine cells used in the study. This again points to the importance of PI3K activation for transformation and suggests that the mechanism by which MT activates the PI3K pathway differs in different species.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-2932. Fax: (617) 632-3709. E-mail: jean_zhao{at}dfci.harvard.edu

{triangledown} Published ahead of print on 18 April 2007.

Journal of Virology, July 2007, p. 7069-7076, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00115-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Whalen, K. A., Weber, G. F., Benjamin, T. L., Schaffhausen, B. S. (2008). Polyomavirus Middle T Antigen Induces the Transcription of Osteopontin, a Gene Important for the Migration of Transformed Cells. J. Virol. 82: 4946-4954 [Abstract] [Full Text]  


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