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Journal of Virology, May 2001, p. 4459-4466, Vol. 75, No. 9
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.9.4459-4466.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Human Papillomavirus Type 16 E6-Induced Degradation of E6TP1 Correlates with Its Ability To Immortalize Human Mammary Epithelial Cells

Qingshen Gao,1 Latika Singh,1 Ajay Kumar,1 Seetha Srinivasan,1 David E. Wazer,1 and Vimla Band1,2,*

Department of Radiation Oncology, New England Medical Center,1 and Department of Biochemistry, Tufts University School of Medicine,2 Boston, Massachusetts 02111

Received 6 October 2000/Accepted 8 February 2001

Recent analyses have identified a number of binding partners for E6, including E6AP, ERC55, paxillin, hDlg, p300, interferon regulatory factor 3, hMCM7, Bak, and E6TP1. Notably, association with E6 targets p53, E6TP1, myc, hMCM7, and Bak for degradation. However, the relative importance of the various E6 targets in cellular transformation remains unclear. E6 alone can dominantly immortalize normal human mammary epithelial cells (MECs), permitting an assessment of the importance of various E6 targets in cellular transformation. Studies in this system indicate that E6-induced degradation of p53 and E6 binding to ERC55 or hDlg do not correlate with efficient immortalization. Here, we have examined the role of E6TP1, a Rap GTPase-activating protein, in E6-induced immortalization of MECs. We tested a large set of human papillomavirus type 16 E6 mutants for their ability to bind and target E6TP1 for degradation in vitro and in vivo. We observed a strict correlation between the ability of E6 protein to target E6TP1 for degradation and its ability to immortalize MECs. Recent studies have identified telomerase as a target of E6 protein. Previous analyses of E6 mutants have revealed this trait to closely correlate with MEC immortalization. We examined our entire panel of E6 mutants for rapid induction of telomerase activity and found in general a strong correlation with immortalizing ability. The tight correlation between E6TP1 degradation and MEC immortalization strongly supports a critical role of functional inactivation of E6TP1 in E6-induced cellular immortalization.

* Corresponding author. Mailing address: Department of Radiation Oncology, Box 824, New England Medical Center, 750 Washington St., Boston, MA 02111. Phone: (617) 636-4776. Fax: (617) 636-6205. E-mail: VBAND{at}lifespan.org.

Journal of Virology, May 2001, p. 4459-4466, Vol. 75, No. 9
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.9.4459-4466.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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