High-risk human papillomaviruses (HPV) cause certain anogenital and head and
neck cancers. E6, one of three potent HPV oncogenes that contribute to the development of these
malignancies, is a multifunctional
protein with many biochemical activities. Among these activities are its ability to bind and inactivate the cellular
tumor suppressor p53, induce expression of
telomerase, and bind to various other
proteins, including Bak, E6BP1, and
E6TP1, and
proteins that contain PDZ domains, such as hScrib and hDlg. Many of these activities are thought to contribute to the role of E6 in
carcinogenesis. The interaction of E6 with many of these cellular
proteins, including p53, leads to their destabilization. This property is mediated at least in part through the ability of E6 to recruit the
ubiquitin ligase E6-associated
protein (E6AP) into complexes with these cellular
proteins, resulting in their
ubiquitin-mediated degradation by the
proteasome. In this study, we address the requirement for E6AP in mediating acute and oncogenic phenotypes of E6, including induction of epithelial
hyperplasia, abrogation of DNA damage response, and induction of
cervical cancer. Loss of E6AP had no discernible effect on the ability of E6 to induce
hyperplasia or abrogate DNA damage responses, akin to what we had earlier observed in the mouse epidermis. Nevertheless, in cervical
carcinogenesis studies, there was a complete loss of the oncogenic potential of E6 in mice nulligenic for E6AP. Thus, E6AP is absolutely required for E6 to cause
cervical cancer.