title: Characterization of a cluster of oncogenic mutations in E6 of a human papillomavirus 83 variant isolated from a high-grade squamous intraepithelial lesion.
abstract: We previously isolated human papillomavirus 83 (HPV83m) from a cervical smear. Sequence analysis of E6 and E7 proteins highlighted five mutations located in the second putative zinc-finger region of E6 (E6m), an important domain for protein-protein or protein-DNA interactions. Here, we show that E6m of HPV83m can trigger human primary cell proliferation and anchorage-independent growth properties, similarly to E6 of HPV16, a high-risk HPV (HR-HPV). Interestingly, we demonstrate that, in contrast to E6 of HPV16, E6m corrupts neither p53 stability nor telomerase activity, but acts as a specific modulator of the transcriptional machinery. By studying E6m reversion mutants, we confirmed the importance of the second zinc-finger domain in triggering the observed upregulation of cell growth and of the transcriptional machinery. Reversion of these mutations in E6m (to yield strain E6r) fully abolished the oncogenic potential of E6m, transforming the phenotype of E6 from a high-risk to a low-risk phenotype. Importantly, our data define the importance of a cluster of mutations in the second zinc finger of E6m in increasing the oncogenic potential of HPV83.
authors.affiliation: INSERM, U895, Centre Méditerranéen de Médecine Moléculaire, C3M, Toxines Microbiennes dans la relation hote pathogènes, Nice, France.|Université de Nice-Sophia-Antipolis, UFR Médecine, Nice, France.|Laboratoire de Virologie, Centre Hospitalier Universitaire de Nice, Hôpital Archet 2, Nice, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cannavo
authors.affiliation: Université de Nice-Sophia-Antipolis, UFR Médecine, Nice, France.|Laboratoire d'Anatomo-Pathologie, Centre Hospitalier Universitaire de Nice, Hôpital Archet 2, Nice, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Benchetrit
authors.affiliation: INSERM, U895, Centre Méditerranéen de Médecine Moléculaire, C3M, Toxines Microbiennes dans la relation hote pathogènes, Nice, France.|Université de Nice-Sophia-Antipolis, UFR Médecine, Nice, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Loubatier
authors.affiliation: INSERM, U895, Centre Méditerranéen de Médecine Moléculaire, C3M, Toxines Microbiennes dans la relation hote pathogènes, Nice, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Michel
authors.affiliation: INSERM, U895, Centre Méditerranéen de Médecine Moléculaire, C3M, Toxines Microbiennes dans la relation hote pathogènes, Nice, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lemichez
authors.affiliation: INSERM, U895, Centre Méditerranéen de Médecine Moléculaire, C3M, Toxines Microbiennes dans la relation hote pathogènes, Nice, France.|Université de Nice-Sophia-Antipolis, UFR Médecine, Nice, France.|Laboratoire de Virologie, Centre Hospitalier Universitaire de Nice, Hôpital Archet 2, Nice, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Giordanengo
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology / Q000821:virology; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D016335:Zinc Fingers; D002578:Uterine Cervical Dysplasia / Q000821:virology*
chemical_list: D004279:DNA, Viral; D009856:Oncogene Proteins, Viral