This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Simonson, S. J.S. Articles by Lambert, P. F. Search for Related Content PubMed PubMed Citation Articles by Simonson, S. J.S. Articles by Lambert, P. F.

Two Distinct Activities Contribute to Human Papillomavirus 16 E6's Oncogenic Potential

¹ McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin and ² Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Paul F. Lambert, McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Avenue, Madison, WI 53706. Phone: 608-262-8533; Fax: 608-262-2824; E-mail: lambert{at}oncology.wisc.edu.

High-risk human papillomaviruses, such as HPV16, cause cervical cancers, other anogenital cancers, and a subset of head and neck cancers. E6 and E7, two viral oncogenes expressed in these cancers, encode multifunctional proteins best known for their ability to bind and inactivate the tumor suppressors p53 and pRb, respectively. In skin carcinogenesis experiments using E6 transgenic (K14E6^WT) mice, HPV16 E6 was found to contribute to two distinct stages in skin carcinogenesis: promotion, a step involved in the formation of benign papillomas, and progression, the step involved in the malignant conversion of benign tumors to frank cancer. In this study, we compared the tumorigenic properties of K14E6^WT mice with those of K14E6^146-151 mice, which express a mutant form of E6 that cannot bind a family of cellular proteins known as PDZ domain proteins but retains the ability to inactivate p53. In skin carcinogenesis experiments, the K14E6^146-151 transgene failed to contribute to the promotion stage of skin carcinogenesis but retained the ability to contribute to the progression stage. Cytogenetic analysis indicated that, although gains of chromosome 6 are consistently seen in tumors arising on K14E6^WT mice, they are infrequently seen in tumors arising on K14E6^146-151 mice. This observation supports the premise that the nature of cancer development in these two mouse strains is distinct. Based on these studies, we conclude that E6 contributes to cancer through its disruption of multiple cellular pathways, one of which is mediated through its interaction with PDZ domain partners and the other through E6's inactivation of p53.

This article has been cited by other articles:

				W. C. Spanos, A. Hoover, G. F. Harris, S. Wu, G. L. Strand, M. E. Anderson, A. J. Klingelhutz, W. Hendriks, A. D. Bossler, and J. H. Lee The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth J. Virol., March 1, 2008; 82(5): 2493 - 2500. [Abstract] [Full Text] [PDF]

				S. Topffer, A. Muller-Schiffmann, K. Matentzoglu, M. Scheffner, and G. Steger Protein tyrosine phosphatase H1 is a target of the E6 oncoprotein of high-risk genital human papillomaviruses J. Gen. Virol., November 1, 2007; 88(11): 2956 - 2965. [Abstract] [Full Text] [PDF]

				J. P. Maufort, S. M. Genther Williams, H. C. Pitot, and P. F. Lambert Human Papillomavirus 16 E5 Oncogene Contributes to Two Stages of Skin Carcinogenesis Cancer Res., July 1, 2007; 67(13): 6106 - 6112. [Abstract] [Full Text] [PDF]

				A. C. Hoover, W. C. Spanos, G. F. Harris, M. E. Anderson, A. J. Klingelhutz, and J. H. Lee The Role of Human Papillomavirus 16 E6 in Anchorage-Independent and Invasive Growth of Mouse Tonsil Epithelium Arch Otolaryngol Head Neck Surg, May 1, 2007; 133(5): 495 - 502. [Abstract] [Full Text] [PDF]

				C. H. Storrs and S. J. Silverstein PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6 J. Virol., April 15, 2007; 81(8): 4080 - 4090. [Abstract] [Full Text] [PDF]

				A. Shai, T. Brake, C. Somoza, and P. F. Lambert The Human Papillomavirus E6 Oncogene Dysregulates the Cell Cycle and Contributes to Cervical Carcinogenesis through Two Independent Activities Cancer Res., February 15, 2007; 67(4): 1626 - 1635. [Abstract] [Full Text] [PDF]

				P. Kuballa, K. Matentzoglu, and M. Scheffner The Role of the Ubiquitin Ligase E6-AP in Human Papillomavirus E6-mediated Degradation of PDZ Domain-containing Proteins J. Biol. Chem., January 5, 2007; 282(1): 65 - 71. [Abstract] [Full Text] [PDF]