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Journal of Virology, March 2004, p. 2749-2757, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2749-2757.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Cul7/p185/p193 Binding to Simian Virus 40 Large T Antigen Has a Role in Cellular Transformation

Syed Hamid Ali, Jocelyn S. Kasper, Takehiro Arai,{dagger} and James A. DeCaprio*

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Received 4 September 2003/ Accepted 10 November 2003

Simian virus 40 large T antigen (TAg) is a viral oncoprotein that can promote cellular transformation. TAg's transforming activity results in part by binding and inactivating key tumor suppressors, including p53 and the retinoblastoma protein (pRb). We have identified a TAg-associated 185-kDa protein that has significant homology to the cullin family of E3 ubiquitin ligases. TAg binds to an SCF-like complex that contains p185/Cul7, Rbx1, and the F box protein Fbw6. This SCF-like complex binds to an N-terminal region of TAg. Several p185/Cul7-binding-deficient mutants of TAg were generated that retained binding to pRb and p53 and were capable of overcoming Rb-mediated repression of E2F transcription. Despite binding to pRb and p53, these p185/Cul7-binding-defective mutants of TAg were unable to transform primary mouse embryo fibroblasts. Cells expressing p185/Cul7-binding-defective mutants of TAg were unable to grow to high density or grow in an anchorage-independent manner as determined by growth in soft agar. Considering the significance of other TAg-interacting proteins in regulation of the cell cycle, p185/Cul7 may also regulate an important growth control pathway.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Mayer 457, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3825. Fax: (617) 632-4760. E-mail: james_decaprio{at}dfci.harvard.edu.

{dagger} Present address: Department of Surgical Oncology, Tokyo Medical and Dental University, 113-8519 Tokyo, Japan.

Journal of Virology, March 2004, p. 2749-2757, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2749-2757.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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