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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Muench P,Probst S,Schuetz J,Leiprecht N,Busch M,Wesselborg S,Stubenrauch F,Iftner Tdoi
10.1158/0008-5472.CAN-10-1307subject
Has Abstractpub_date
2010-09-01 00:00:00pages
6913-24issue
17eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-10-1307journal_volume
70pub_type
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