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The expression of the proteins encoded by human papillomaviruses (HPVs) is tightly linked to the differentiation program of the infected keratinocytes. The late promoter, expressing the structural proteins, becomes activated in the differentiated keratinocytes, while the early promoter is also active in the basal layers. We have shown previously that the viral transcriptional regulator E2 and the cellular coactivator p300 cooperate in activation of gene expression of HPV8, which infects the skin and is associated with epidermodysplasia verruciformis. Here we demonstrate that this activation is further stimulated after overexpression of the E6 oncoprotein of HPV8 (8E6). RNase protection experiments revealed that 8E6 efficiently cooperates with 8E2 and p300 in activation of the late promoter. In addition, the early promoter, which did not respond to 8E2 and/or p300, was stimulated more than fourfold by 8E6. Our data suggest that both promoters are activated via distinct mechanisms, since the activation of the early promoter was achieved by the N-terminal moiety of 8E6; in contrast, its C-terminal half was sufficient for late promoter activation. This was markedly reduced by the deletion of amino acids 132 to 136 of 8E6, which also abolished the binding to p300, indicating that a direct interaction between 8E6 and p300 is involved. Moreover, a 45-amino-acid segment within the C/H3 region of p300 is required for 8E6 to stimulate the coactivator function of p300. Our results demonstrate for the first time that an E6 oncoprotein of HPV directly contributes to the regulation of HPV gene expression.

The E6 Protein of the Cutaneous Human Papillomavirus Type 8 Can Stimulate the Viral Early and Late Promoters by Distinct Mechanisms