RETRACTED ARTICLE: E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage

Jackson, Sarah; Storey, Alan

doi:10.1038/sj.onc.1203339

Cited by 184 publications

(136 citation statements)

References 39 publications

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“…Although cutaneous HPV E6 can promote Bak proteolysis in human keratinocytes, the cells used in these experiments are not the natural host for the virus, however, previous studies have shown that the ability of E6 to target the apoptotic machinery is not dependent upon cell type or p53 status. 7,27 Mutations in HPV5 E6 can influence target specificity…”

Section: Identification Of Regions Of Hpv5 E6 Involved In Bak Degradamentioning

confidence: 99%

Identification of the regions of the HPV 5 E6 protein involved in Bak degradation and inhibition of apoptosis

Simmonds

Storey

2008

Intl Journal of Cancer

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UVB induced DNA damage is the major aetiological agent in NMSC development, but mounting evidence suggests a role for human papillomaviruses (HPV) from genus beta, including HPV 5 and HPV 8, in the development of NMSC on sun exposed body sites. We have previously shown that UVB activates Bak, an apoptogenic mitochondrial factor that, following an apoptotic stimulus, undergoes a conformational change that leads to pore formation in the mitochondrial membrane that releases apoptotic factors. The HPV E6 protein effectively inhibits UVB-induced apoptosis and targets Bak for proteolytic degradation. We have now identified the regions of the HPV5 E6 that are required to mediate Bak proteolysis and contribute toward the antiapoptotic activity of the protein. Interestingly, while wild-type HPV5 E6 does not bind or target p53 for proteolysis, we have isolated specific HPV5 E6 mutants that switch target specificity from Bak to p53 in a p53 codon 72 isoform-dependent manner. Furthermore, we demonstrate that the ability of wild-type HPV5 E6 to target Bak or specific E6 mutants to target p53 for proteolysis is not dependent on the E6-AP ubiquitin ligase. ' 2008 Wiley-Liss, Inc.Key words: skin cancer; HPV; Bak; E6; UV; light Chronic exposure to solar UV irradiation has been identified as the primary causative agent in the development of nonmelanoma skin cancer (NMSC).1 The formation of ''sunburn cells'' frequently observed in epidermis treated with UVB display apoptotic characteristic such as condensed nuclei, 2,3 and the response to UVB radiation is in part dependent upon the expression of p53. 4This p53-driven response, often termed ''cellular proofreading'', eliminates rather than repairs severely damaged cells, however p53-independent pathways have also been described. [5][6][7] However, studies indicate that Li Fraumeni patients, who have only one copy of p53, and patients with regions of mutated p53 on sunexposed sites, are not predisposed to tumour development 8,9 indicating that p53-independent mechanisms also play an important role in eliminating damaged cells.Studies on Epidermodysplasia Verruciformis (EV) patients have identified a link between extensive wart infection and the development of skin tumours on sun-exposed sites.10 Epidemiological studies also invoke a role for HPV in NMSC development in both immunocompromised organ transplant recipients and immunocompetent individuals. 11,12 There is increasing evidence that b-HPV types facilitate the persistence of DNA-damaged cells within the epithelium, following UVB-exposure, chiefly through interfering with DNA damage responses and inhibiting apoptotic pathways, reviewed by Akg€ ul et al. 13The Bak protein is a key apoptogenic factor located in the outer mitochondrial membrane.14 Following UV exposure, Bak is activated and stabilized in a p53-independent manner 7 by BH3 domain-containing proteins. 15,16 Bak activation involves a change in conformation at the N-terminus of the prote in 17 leading to Bak multimerization, [18][19][20] that is believed to form pores...

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Section: Identification Of Regions Of Hpv5 E6 Involved In Bak Degradamentioning

confidence: 99%

Identification of the regions of the HPV 5 E6 protein involved in Bak degradation and inhibition of apoptosis

Simmonds

Storey

2008

Intl Journal of Cancer

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“…Having previously demonstrated that HPV E6 interferes with UVB-induced apoptosis in a number of different cell types, we were interested to investigate the consequences on the mitochondrial apoptotic pathway [20,28]. HT1080 cells that express UV-inducible Bak and p53 were transfected with the HPV E6 gene of HPV types 5, a β-papillomavirus found in NMSC, and HPV 18, a mucosal HPV found in anogenital cancers [29].…”

Section: Hpv E6 Inhibits Uv-induced Mitochondrial Morphological Changmentioning

confidence: 99%

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

Leverrier¹,

Bergamaschi²,

Ghali

et al. 2006

Apoptosis

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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

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“…The main risk factors for cutaneous SCC are prolonged sun exposure and pigmentation grade of the skin. Interestingly, several studies have revealed diverse interactions of persisting betapapillomaviruses and UV irradiation, which may be relevant to the multi-step process of skin carcinogenesis (Akgül et al, 2005;Giampieri & Storey, 2004;Jackson & Storey, 2000;Jackson et al, 2002;Underbrink et al, 2008). We therefore evaluated the synergistic effects of UV light in transgenic animals.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous tumour development in human papillomavirus type 8 E6 transgenic mice and rapid induction by UV-light exposure and wounding

Marcuzzi

Hufbauer

Kasper

et al. 2009

Journal of General Virology

114

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Cutaneous human papillomavirus type 8 (HPV8) is carcinogenic in patients with epidermodysplasia verruciformis. Transgenic mice with the complete early region (CER) of HPV8 spontaneously developed papillomas, dysplasia and squamous cell carcinomas of the skin. To characterize the role of individual early genes in carcinogenesis, the E6 and E6/E7 genes were expressed separately in transgenic mice. Nearly all HPV8-E6-positive mice spontaneously developed multifocal tumours, characterized by papillomatosis, hyperkeratosis and varying degrees of epidermal dysplasia. In 6 % of the cases, the tumours became malignant, comparable with HPV8-CER mice. Thus, in the murine epidermis, E6 is the major oncogene necessary and sufficient to induce spontaneous tumour development up to the level of squamous cell carcinoma. To evaluate the synergistic effects of UV light and wound healing, the skin of HPV8 mice was irradiated with UVA/UVB light or wounded with punch biopsies. These treatments induced papillomatosis in HPV8-CER and -E6 mice within 3 weeks. Irradiation with UVA alone did not induce papillomatosis and UVB alone had a weaker effect than UVA/UVB, indicating a synergistic role of UVA in UVB-induced papillomatosis. An HPV8 infection persisting over decades in interaction with sun burns and wound healing processes may be a relevant cause of skin cancer in humans.

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RETRACTED ARTICLE: E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage

Cited by 184 publications

References 39 publications

Identification of the regions of the HPV 5 E6 protein involved in Bak degradation and inhibition of apoptosis

Identification of the regions of the HPV 5 E6 protein involved in Bak degradation and inhibition of apoptosis

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

Spontaneous tumour development in human papillomavirus type 8 E6 transgenic mice and rapid induction by UV-light exposure and wounding

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