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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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