Comparative analysis of 19 genital human papillomavirus types with regard to p53 degradation, immortalization, phylogeny, and epidemiologic risk classification.
We have analyzed E6 proteins of 19 papillomaviruses able to infect genital tissue with regard to their ability to degrade p53 and the thus far unknown immortalization potential of the genomes of human papillomaviruses (HPV) 53, 56, 58, 61, 66, and 82 in primary human keratinocytes. E6 proteins of HPV types 16, 18, 33, 35, 39, 45, 51, 52, 56, 58, and 66, defined as high-risk types, were able to induce p53 degradation in vitro, and HPV18-, HPV56-, and HPV58-immortalized keratinocytes revealed markedly reduced levels of p53. In contrast, the E6 proteins of HPV6 and 11 and HPV44, 54, and 61, regarded as possible carcinogenic or low-risk HPV types, respectively, did not degrade p53. Interestingly, the E6 proteins of HPV 53, 70, and 82 inconsistently risk classified in the literature were also found to induce p53 degradation. The genomes of HPV53 and 82 immortalized primary human keratinocytes that revealed almost absent nuclear levels of p53. These data suggest a strict correlation between the biological properties of certain HPV types with conserved nucleotide sequence (phylogeny), which is largely coherent with epidemiologic risk classification. HPV types 16, 18, 33, 35, 39, 45, 51, 52, 56, 58, and 66, generally accepted as high-risk types, behaved in our assays biologically different from HPV types 6, 11, 44, 54, and 61. In contrast, HPV70, regarded as low-risk type, and HPV53 or HPV82, with inconsistent described risk status, were indistinguishable with respect to p53 degradation and immortalization from prototype high-risk HPV types. This could imply that other important functional differences exist between phylogenetically highly related viruses displaying similar biological properties in tissue culture that may affect their carcinogenicity in vivo.
Hiller
Thomas
T
Sektion Experimentelle Virologie, Universitaetsklinikum Tuebingen, Germany. tsiftner@med.uni-tuebingen.de
Poppelreuther
Sven
S
Stubenrauch
Frank
F
Iftner
Thomas
T
D000818:Animals; D015153:Blotting, Western; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000821:virology; D005455:Fluorescent Antibody Technique; D005836:Genitalia, Female / Q000821:virology*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009856:Oncogene Proteins, Viral / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000145:classification / Q000502:physiology*; D030361:Papillomavirus Infections / Q000453:epidemiology* / Q000378:metabolism / Q000821:virology; D010802:Phylogeny; D010957:Plasmids; D046988:Proteasome Endopeptidase Complex; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012867:Skin / Q000821:virology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D009856:Oncogene Proteins, Viral; D012367:RNA, Viral; D016159:Tumor Suppressor Protein p53; D046988:Proteasome Endopeptidase Complex