A mutant of human papillomavirus type 16 E6 deficient in binding alpha-helix partners displays reduced oncogenic potential in vivo.
Human papillomaviruses (HPVs) are small DNA tumor viruses that are the causative agent of warts and are associated with many anogenital cancers. The viral gene encoding the E6 protein has been found to be involved in HPV oncogenesis. E6 is known to inactivate the cellular tumor suppressor, p53. In addition, E6 has been shown to bind to a variety of other cellular proteins. The focus of this study was to determine what role the interactions of E6 with a subset of cellular proteins which contain a common alpha-helical domain in their E6 binding region (alpha-helix partners) play in E6-mediated phenotypes. We generated transgenic mice expressing a mutant of E6, E6(I128T), which is defective for binding at least a subset of the alpha-helix partners, including E6AP, the ubiquitin ligase that mediates E6-dependent degradation of the p53 protein, to determine whether binding of alpha-helix partners plays a role in E6-mediated activities in vivo. Unlike mice expressing the wild-type E6 (strain K14E6(WT)), the mice expressing E6(I128T) lacked the ability to alter the radiation-induced block to DNA synthesis and promote the formation of benign skin tumors in conjunction with chemical carcinogens. Additionally, they displayed reduced levels of skin hyperplasia, spontaneous skin tumors, and tumor progression activity compared to those of the K14E6(WT) mice. From these results, we conclude that a domain in E6 that mediates alpha-helix partner binding is critical for E6-induced phenotypes in transgenic mice.
Nguyen
Marie
M
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Avenue, Madison, WI 53706, USA.
Song
Shiyu
S
Liem
Amy
A
Androphy
Elliot
E
Liu
Yun
Y
Lambert
Paul F
PF
D000818:Animals; D004247:DNA / Q000096:biosynthesis / Q000528:radiation effects; D018450:Disease Progression; D004848:Epithelium / Q000473:pathology; D006965:Hyperplasia; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000737:chemistry* / Q000502:physiology*; D010212:Papilloma / Q000517:prevention & control; D017433:Protein Structure, Secondary; D012097:Repressor Proteins; D012878:Skin Neoplasms / Q000517:prevention & control; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA