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Mol Cell Biol, March 1998, p. 1746-1756, Vol. 18, No. 3
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Novel Mechanisms of E2F Induction by BK Virus Large-T Antigen: Requirement of Both the pRb-Binding and the J Domains

Kimya F. Harris,1 Joan B. Christensen,2 Eric H. Radany,3,4 and Michael J. Imperiale1,2,4,*

Graduate Program in Cellular and Molecular Biology,1 Department of Microbiology and Immunology,2 Department of Radiation Oncology,3 and Comprehensive Cancer Center,4 University of Michigan Medical School, Ann Arbor, Michigan 48109-0942

Received 17 September 1997/Returned for modification 21 November 1997/Accepted 15 December 1997

E2F activity is regulated in part by the retinoblastoma family of tumor suppressor proteins. Viral oncoproteins, such as simian virus 40 (SV40) large-T antigen (TAg), adenovirus E1A, and human papillomavirus E7, can disrupt the regulation of cellular proliferation by binding to pRb family members and dissociating E2F-pRb family protein complexes. BK virus (BKV), which infects a large percentage of the human population and has been associated with a variety of human tumors, encodes a TAg homologous to SV40 TAg. It has been shown that BKV TAg, when expressed at low levels, does not detectably bind to pRb family members, yet it induces a serum-independent phenotype and causes a decrease in the overall levels of pRb family proteins. The experiments presented in this report show that, despite the lack of TAg-pRb interactions, BKV TAg can induce transcriptionally active E2F and that this induction does in fact require an intact pRb-binding domain as well as an intact J domain. In addition, E2F-pRb family member complexes can be detected in both BKV and SV40 TAg-expressing cells. These results suggest the presence of alternate cellular mechanisms for the release of E2F in addition to the well-established model for TAg-pRb interactions. These results also emphasize a role for BKV TAg in the deregulation of cellular proliferation, which may ultimately contribute to neoplasia.

* Corresponding author. Mailing address: Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109-0942. Phone: (313) 763-9162. Fax: (313) 647-9271. E-mail: imperial{at}umich.edu.




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