Two distinct activities contribute to human papillomavirus 16 E6's oncogenic potential.
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(delta146-151) 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(delta146-151) 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(delta146-151) 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.
Simonson
Sara J S
SJ
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706, USA.
Difilippantonio
Michael J
MJ
Lambert
Paul F
PF
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002472:Cell Transformation, Viral / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000821:virology*; D013755:Tetradecanoylphorbol Acetate
C068651:E6 protein, Human papillomavirus type 16; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D004247:DNA; D013755:Tetradecanoylphorbol Acetate