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Journal of Virology, June 2003, p. 6957-6964, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6957-6964.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The PDZ Ligand Domain of the Human Papillomavirus Type 16 E6 Protein Is Required for E6's Induction of Epithelial Hyperplasia In Vivo

Marie L. Nguyen,1 Minh M. Nguyen,2,{dagger} Denis Lee,1 Anne E. Griep,2 and Paul F. Lambert1*

McArdle Laboratory for Cancer Research,1 Department of Anatomy, University of Wisconsin Medical School, Madison, Wisconsin 537062

Received 17 September 2002/ Accepted 21 February 2003

Human papillomaviruses (HPVs) are the causative agent of warts. Infections with high-risk HPVs are associated with anogenital and head and neck cancers. One of the viral genes responsible for HPV's oncogenic activity is E6. Mice expressing the HPV-16 E6 protein in their epidermis (K14E6WT) develop epithelial hyperplasia and squamous carcinomas. Numerous cellular proteins interact with E6, some of which can be grouped based on common amino acid motifs in their E6-binding domains. One such group, the PDZ partners, including hDLG, hSCRIBBLE, MUPP1, and MAGI, bind to the carboxy-terminal four amino acids of E6 through their PDZ domains. E6's interaction with the PDZ partners leads to their degradation. Additionally, E6's binding to PDZ proteins has been correlated with its ability to transform baby rat kidney cells in tissue culture and to confer tumorigenicity onto cells in xenograft experiments. To address whether the ability of E6 to bind PDZ domain partners is necessary for E6 to confer epithelial hyperproliferation in vivo, we generated transgenic mice that express in stratified squamous epithelia a mutant of E6 lacking the last six amino acids at its carboxyl terminus, E6{Delta}146-151, from the human keratin 14 (K14) promoter. The K14E6{Delta}146-151 mice exhibit a radiation response similar to that of the K14E6WT mice, demonstrating that this protein, as predicted, retains an ability to inactivate p53. However, the K14E6{Delta}146-151 mice fail to display epithelial hyperplasia. These results indicate that an interaction of E6 with PDZ partners is necessary for its induction of epithelial hyperplasia.

* Corresponding author. Mailing address: McArdle Laboratory for Cancer Research, 1400 University Ave., Madison, WI 53706. Phone: (608) 262-8533. Fax: (608) 262-2824. E-mail: lambert{at}oncology.wisc.edu.

{dagger} Present address: Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029-6574.

Journal of Virology, June 2003, p. 6957-6964, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6957-6964.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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