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Role of HPV E6 proteins in preventing UVB-induced release of pro-apoptotic factors from the mitochondria

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Abstract

Apoptotic elimination of UV-damaged cells from the epidermis is an important step in preventing both the emergence and expansion of cells with carcinogenic potential. A pivotal event in apoptosis is the release of apoptogenic factors from the mitochondria, although the mechanisms by which the different proteins are released are not fully understood. Here we demonstrate that UV radiation induced the mitochondrial to nuclear translocation of apoptosis inducing factor (AIF) in normal skin. The human papillomavirus (HPV) E6 protein prevented release of AIF and other apoptotic factors such as cytochrome c and Omi from mitochondria of UV-damaged primary epidermal keratinocytes and preserved mitochondrial integrity. shRNA silencing of Bak, a target for E6-mediated proteolysis, demonstrated the requirement of Bak for UV-induced AIF release and mitochondrial fragmentation. Furthermore, screening non-melanoma skin cancer biopsies revealed an inverse correlation between HPV status and AIF nuclear translocation. Our results indicate that the E6 activity towards Bak is a key factor that promotes survival of HPV-infected cells that facilitates tumor development.

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Acknowledgments

The authors are grateful to Drs C.A. Harwood and C.M. Proby (University of London, UK) for tissue biopsies, and to Dr. S. Basu (Cancer Research UK, UK) for critical reading of the manuscript. We also thank Prof. H. Pfister (University of Cologne, Germany) for providing us the retroviral construct pLXSN-8-E6, and Dr. F.A. Rassendren (CNRS, France) for shRNA expression plasmids nd helpful advice. This work was supported by funding from Cancer Research UK. B.A. was the recipient of a grant from the Dr. Mildred Scheel Stiftung / Deutsche Krebshilfe.

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Correspondence to Alan Storey.

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Leverrier, S., Bergamaschi, D., Ghali, L. et al. Role of HPV E6 proteins in preventing UVB-induced release of pro-apoptotic factors from the mitochondria. Apoptosis 12, 549–560 (2007). https://doi.org/10.1007/s10495-006-0004-1

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  • DOI: https://doi.org/10.1007/s10495-006-0004-1

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