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HPV E6 proteins interact with specific PML isoforms and allow distinctions to be made between different POD structures

Oncogene volume 23, pages 4662–4672 (2004)Cite this article

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.

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Acknowledgements

This work was supported in part by research grants from the Associazione Italiana per la Ricerca sul Cancro to LB and from the Biotechnology and Biological Sciences Research Council (UK) to KNL. We gratefully acknowledge the gift of cDNA clones for PMLIV from R Everett (Inst. of Virology, Glasgow), for PML I, II and VI from E Solomon (Guys Hospital, London), for PML I, II, IV and V from PG Pelicci (European Institute of Oncology, Milan) and for PML III from A Dejean (Inst. Pasteur, Paris). We are also grateful to G Del Sal and PP Pandolfi for the gift of PML−/− fibroblasts, and to Miranda Thomas and David Pim for comments on the manuscript.

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  1. International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, I-34012, Italy

    Ernesto Guccione & Lawrence Banks

  2. Department of Biological Sciences, University of Warwick, Coventry, CV4 7AL, UK

    Katherine J Lethbridge, Neil Killick & Keith N Leppard

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  1. Ernesto Guccione
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Correspondence to Lawrence Banks.

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Guccione, E., Lethbridge, K., Killick, N. et al. HPV E6 proteins interact with specific PML isoforms and allow distinctions to be made between different POD structures. Oncogene 23, 4662–4672 (2004). https://doi.org/10.1038/sj.onc.1207631

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