Oncogenic Activity of HPV Genes

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Human papillomaviruses (HPVs) are believed to be the primary causal agents for development of pre-neoplastic and malignant lesions of the uterine cervix and high-risk types such as type 16 and 18 are associated with more than 90 % of all cervical carcinomas. The E6 and E7 genes of HPVs are thought to play causative roles (Cancer Sci. 98:1505-11, 2007. for review). E6 promotes the degradation of p53 through its interaction with E6AP, an E3 ubiquitin ligase, whereas E7 binds to the retinoblastoma protein pRb and disrupts its complex formation with E2F transcription factors. E6 can inhibit differentiation of human keratinocytes. We found that expression of Notch1 is downregulated by E6 through inactivation of p53 and that Notch1 gene is a novel target of p53 in normal human keratinocytes (Mol Cell Biol, 27:3732-3742, 2007). ErbB2 is overexpressed in cervical cancers. We found that HPV16 E6 upregulate ErbB2 expression perhaps through inactivation of p53 and this regulation has an important role in oncogenic transformation of human cervical keratinocytes (Oncogne, 26:2988-2996, 2007). So far the PDZ domian-binding motif located at the carboxy terminus of the E6 protein and the ability to bind E6AP are known to be important for transforming activity of E6. Dlg and Scribble, both of which contain the PDZ domains, are tumor suppressors in Drosophila, and the human orthologues are possible tumor suppressors (J Virol, 81:1379-1389, 2007). We are verifying the hypothesis that the enhanced degradation of these possible tumor suppressors is the mechanism of transformation by E6.