HPV16 E6 natural variants exhibit different activities in functional assays relevant to the carcinogenic potential of E6.
Genetic studies have revealed natural amino acid variations within the human papillomavirus (HPV) type 16 E6 oncoprotein. To address the functional significance of E6 polymorphisms, 10 HPV16 E6 variants isolated from cervical lesions of Swedish women were evaluated for their activities in different in vitro and in vivo assays relevant to the carcinogenic potential of E6. Small differences between E6 prototype and variants, and among variants, were observed in transient expression assays that assessed p53 degradation, Bax degradation, and inhibition of p53 transactivation. More variable levels of activities were exhibited by the E6 proteins in assays that evaluated binding to the E6-binding protein (E6BP) or the human discs large protein (hDlg). The E6 prototype expressed moderate to high activity in the above assays. The L83V polymorphism, previously associated with risk for cancer progression in some populations, expressed similar levels of activity as that of the E6 prototype in most functional assays. On the other hand, L83V displayed more efficient degradation of Bax and binding to E6BP, but lower binding to hDlg. Results of this study indicate that naturally occurring amino acid variations in HPV16 E6 can alter activities of the protein important for its carcinogenic potential.
Lichtig
Hava
H
Department of Human Microbiology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel, and Thunder Bay Regional Health Sciences Centre, Regional Cancer Care Program, Ontario, Canada.
Algrisi
Meirav
M
Botzer
Liat Edri
LE
Abadi
Tal
T
Verbitzky
Yulia
Y
Jackman
Anna
A
Tommasino
Massimo
M
Zehbe
Ingeborg
I
Sherman
Levana
L
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D000074288:Discs Large Homolog 1 Protein; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C494826:BAX protein, human; D002135:Calcium-Binding Proteins; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; C068651:E6 protein, Human papillomavirus type 16; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; C088393:RCN2 protein, human; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein