title: Activities of human papillomavirus 16 E6 natural variants in human keratinocytes.
abstract: Genetic variations in the E6 oncogene have been associated with different risk for cancer progression. In the present study, the functional significance of human papillomavirus (HPV) polymorphism in the E6 oncogene was investigated. Ten HPV16 E6 variants containing amino acid substitutions in the N-terminal region of E6 were evaluated for different biological and biochemical activities in human keratinocytes, the target cells for HPV infection. Western blot analyses of primary foreskin human keratinocytes or immortalized human keratinocytes, stably transduced with the E6 variants, revealed reduced p53 and Bax levels in all E6 expressing cultures. The reduction induced by most E6 proteins was at similar levels and comparable to the reduction induced by the E6 prototype. The ability of the proteins to induce serum/calcium-differentiation resistant colonies in primary keratinocytes was more variable. Overall activities of the variants ranged between 0.24- and 2.18-fold of the E6 prototype activity. The I27R/L83V variant showed the lowest activity whereas the R8Q variant showed the highest activity. The L83V polymorphism previously associated with risk for cancer progression in some populations, showed significant activity, comparable to that of the E6 prototype, in reducing p53 and Bax levels. Furthermore, this variant showed enhancement in the ability to induce colonies resistant to serum/calcium-triggered differentiation, however, the difference from the prototype was not statistically significant. This, and augmentation of other described functions might result in differences in L83V pathogenicity.
authors.affiliation: Department of Human Microbiology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Asadurian
authors.forename: Helena
authors.initials: H
authors.lastname: Kurilin
authors.forename: Hava
authors.initials: H
authors.lastname: Lichtig
authors.forename: Anna
authors.initials: A
authors.lastname: Jackman
authors.forename: Pinhas
authors.initials: P
authors.lastname: Gonen
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Zehbe
authors.forename: Levana
authors.initials: L
authors.lastname: Sherman
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D015536:Down-Regulation; D014644:Genetic Variation; D052162:Human papillomavirus 16 / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein