title: HPV E6 proteins interact with specific PML isoforms and allow distinctions to be made between different POD structures.
abstract: Mucosal human papillomaviruses (HPVs) are the causative agents of a number of human pathologies, including benign condylomas, as well as of the majority of cervical cancers and their high-grade precursor lesions. Although the viral E6 protein is known to be essential for driving malignant progression of HPV-infected cells, there are still many uncertainties about its mode of action. In this study, we have analysed the intracellular distribution of the E6 oncoproteins from the high-risk HPV-18 and the low-risk HPV-11. We show that both E6 proteins localize within the nucleus in nuclear bodies that are confocal with the promyelocytic leukaemia (PML) protein. Using a panel of different PML isoforms, we demonstrate specific co-localization between the E6 proteins and PML isoforms I-IV, but not with PML isoforms V and VI. We also demonstrate the interaction between E6 and a subset of PML isoforms in vivo. As a consequence of this interaction, the insoluble form of PML IV is destabilized by HPV-18 E6 through a proteasome-dependent pathway. Interestingly, both HPV-11 E6 and HPV-18 E6 can readily overcome PML IV-induced cellular senescence in primary cells. These results show separable functions for different PML isoforms that are specifically targeted by the HPV E6 oncoproteins.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, I-34012 Trieste, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Lethbridge
authors.forename: Neil
authors.initials: N
authors.lastname: Killick
authors.forename: Keith N
authors.initials: KN
authors.lastname: Leppard
authors.forename: Lawrence
authors.initials: L
authors.lastname: Banks
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D018613:Microscopy, Confocal; D009097:Multienzyme Complexes / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000378:metabolism*; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D000911:Antibodies, Monoclonal; D009097:Multienzyme Complexes; D009856:Oncogene Proteins, Viral; D020033:Protein Isoforms; D012333:RNA, Messenger; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex