Abstract
The binding of the papillomavirus E6 protein to E6AP and the induction of p53 degradation are common features of high-risk genital human papillomaviruses (HPV); cutaneous HPVs, on the other hand, lack these capacities. Nevertheless, several cutaneous HPV types of the beta-genus, such as HPV38 are associated with tumor formation when combined with genetic predisposition, immunosuppression, or UV exposure. In an animal model system, the cottontail rabbit papillomavirus (CRPV) rapidly induces skin cancer without additional cofactors, and CRPVE6 and E7 immortalize rabbit keratinocytes in vitro. However, CRPVE6 neither interacts with E6AP and p53 nor does it induce p53 degradation. In this study, we show that the interaction of CRPVE6, or HPV38E6, with the histone acetyltransferase p300 is crucial to inhibit the ability of p53 to induce apoptosis. Strikingly, E6 mutants deficient for p300 binding are incapable of preventing p53 acetylation, p53-dependent transcription, and apoptosis induction. Moreover, E6 mutants deficient for p300 binding cannot contribute to HPV38-induced immortalization of human keratinocytes or CRPV-induced tumor formation. Our findings highlight changes in the p53 acetylation status mediated by the viral E6 protein as a crucial requirement in the ability of high-risk cutaneous papillomaviruses to immortalize primary keratinocytes and induce tumors. Cancer Res; 70(17); 6913-24. (c)2010 AACR.
Highlights
More than 100 different human papillomaviruses (HPV) have been characterized based on sequence homologies, only a limited number were shown to be associated with cancer development
Β-HPVs have been linked to the development of nonmelanoma skin cancer, which represents the most common malignancy in Caucasians worldwide [3]. β-Papillomaviruses such as HPV5 and HPV8 have been described to be associated with skin carcinogenesis in patients with the rare genetic disorder epidermodysplasia verruciformis
Mutant cottontail rabbit papillomavirus (CRPV) genomes were constructed by replacing the BspEI fragment in pLA2-CRPV with fragments from the respective pMalc2x-CRPVSE6 plasmids. pMal, pcDNA, or pMSCVpuro expression vectors for HPV38E6 and 38E6Ala80–84 were generated by overlap extension PCR
Summary
More than 100 different human papillomaviruses (HPV) have been characterized based on sequence homologies, only a limited number were shown to be associated with cancer development. Consistent with UV as a major risk factor, β-HPV types such as HPV38 were shown to prevent UVB-induced apoptosis by degradation of Bak [19, 20] This activity is surprisingly shared with high-risk genital HPV18, causing cervical cancer, in which UV is not a known cofactor. CRPVE6 interacts neither with p53 nor with E6AP, and is not able to degrade p53 and probably not Bak as well [12, 20, 21] It is not understood why increased p53 levels in CRPVE6/ E7-immortalized cells do not interfere with immortalization or tumor development [12]. Our results imply a novel mechanism for p53 inactivation by β-HPV types and CRPV that is important for skin carcinogenesis
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