E6 Proteins from Multiple Human Betapapillomavirus Types Degrade Bak and Protect Keratinocytes from Apoptosis after UVB Irradiation

Abstract

Human papillomavirus (HPV) types from the beta genus (beta-HPVs) have been implicated in the development of skin cancer. A potentially important aspect of their carcinogenic role is the ability of the E6 protein to degrade the proapoptotic family member Bak, which gives cells the ability to survive UV damage. However, it is unknown if the ability to degrade Bak is limited to certain beta-HPV types or whether E6 expression in keratinocytes affects other proteins important for apoptosis signaling. We tested the abilities of E6 proteins from several representative members of the beta-HPVs to degrade Bak and protect UV-treated keratinocytes from apoptosis. The E6 proteins of the beta-HPV type 5 (HPV5), -8, -20, -22, -38, -76, -92, and -96, as well as the alpha genus HPV HPV16, all degraded Bak or prevented its accumulation following UV treatment but did not degrade Bak constitutively. In addition, when tested using HPV16 E6 (16E6) and 8E6 as representative E6 proteins from the alpha and beta genera, respectively, Bak degradation was dependent on the E3 ubiquitin ligase, E6AP. Other important regulators of apoptotic signaling were examined and found to be unperturbed by the expression of the beta-HPV E6 proteins. Importantly, the expression of beta-HPV E6 proteins protected keratinocytes from apoptosis to the same extent as 16E6-expressing cells. In conclusion, several of the beta-HPV types possess the ability to protect UV-treated keratinocytes from apoptosis by reducing levels of Bak in those cells, thus blocking the intrinsic apoptotic pathway.Human papillomaviruses (HPVs) are small DNA tumor viruses that infect cutaneous and mucosal epithelia and disseminate by replication in terminally differentiated keratinocytes. So far, over 100 different types have been identified and characterized on the basis of DNA sequence analysis (12). Only a small number of these display a strong association with cancer development. Most notably, the high-risk types (16, 18, 31, 33, etc.) of alpha genus HPVs (alpha-HPVs) play a critical role in the development of cervical cancer. These same types have also been implicated in the majority of other anogenital cancers and a subset of head and neck carcinomas (11,43).Recently, the beta-HPVs, which cause cutaneous lesions in humans, have been linked to the development of skin cancers (32). The association between beta-HPVs and skin cancer was first identified in patients with the rare inherited disorder epidermodysplasia verruciformis (EV) (27). These individuals have a predisposition to the early development of disseminated, persistent flat warts and macular lesions following infection with a specific group of about 20 related beta-HPV genotypes, also known as EV types. About half of EV patients develop premalignant skin lesions and squamous cell carcinomas by age 40, primarily in sun-exposed areas (30). DNA from these lesions was found to harbor HPV genomes, suggesting a cocarcinogenic role of beta-HPVs and UV radiation in the early development of EV cancers (32). By use of sensitive P...

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

“…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.…”

Human Papillomaviruses Oncoproteins

“…the intrinsic pathway, which triggers sensing apoptotic signals that arise within the cell (DNA damage, oxidative stress) [54]. The lr/hrE6 oncoproteins block intrinsic apoptotic signaling interacting with Bak, inducing its proteasomal-dependent degradation [55], or using a mechanism depending or not on E6AP and E3 ubiquitin ligases [56].…”

HPV vaccination for prevention of skin cancer

“…30 Additionally, b-PV E6 targets the pro-apoptotic protein Bak for degradation. 31,32 These effects, usually combined with mechanisms that delay DNA repair (like abrogation of ATR activity 33 ) or impairment of the telomere/ telomerase system 34 may explain b-PV contribution to skin carcinogenesis by favoring the accumulation of UV damaged cells. The oncogenic potential of b-PV has also been shown in in vivo transgenic models which develop SCC in response to b-PV gene expression, either spontaneously or after UV irradiation.…”