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Journal of Virology, September 2005, p. 11685-11692, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11685-11692.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Simian Virus 40 Large T Antigen's Association with the CUL7 SCF Complex Contributes to Cellular Transformation

Jocelyn S. Kasper, Hiroshi Kuwabara, Takehiro Arai, Syed Hamid Ali, and James A. DeCaprio^*

Dana-Farber Cancer Institute Department of Medical Oncology and Harvard Medical School, Boston, Massachusetts

Received 12 March 2005/ Accepted 24 June 2005

Simian virus 40 large T antigen (T Ag) is capable of immortalizing and transforming rodent cells. The transforming activity of T Ag is due in large part to perturbation of the tumor suppressor proteins p53 and the retinoblastoma (pRB) family members. Inactivation of these tumor suppressors may not be sufficient for T Ag-mediated cellular transformation. It has been shown that T Ag associates with an SCF-like complex that contains a member of the cullin family of E3 ubiquitin ligases, CUL7, as well as SKP1, RBX1, and an F-box protein, FBXW8. We identified T Ag residues 69 to 83 as required for T Ag binding to the CUL7 complex. We demonstrate that 69-83 T Ag, while it lost its ability to associate with CUL7, retained binding to p53 and pRB family members. In the presence of CUL7, wild-type (WT) T Ag but not 69-83 T Ag was able to induce proliferation of mouse embryo fibroblasts, an indication of cellular transformation. In contrast, WT and 69-83 T Ag enabled mouse embryo fibroblasts to proliferate to similarly high densities in the absence of CUL7. Our data suggest that, in addition to p53 and the pRB family members, T Ag serves to bind to and inactivate the growth-suppressing properties of CUL7. In addition, these results imply that, at least in the presence of T Ag, CUL7 may function as a tumor suppressor.

Present address: Tokatsu-Tsujinaka Hospital, 946-1 Neda, Abiko-shi, Chiba 270-1168, Japan.

Present address: The Aga Khan University Hospital, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan.

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