Mechanisms of human papillomavirus E6/E7 expression during cellular differentialtion of cervical cancer

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To clarify the molecular mechanisms through which human papillomavirus E6/E7 expression is activated during the process of cellular differentiation in stratified epithelial cells of uterine cervix, we identified core enhancer of upstream regulatory region of HPV3 1 b E6/E7 genes using transient expression assays. DNA foot print analyses and gel shift analyses identified sevral nuclear factors which bind core enhancer and regulate transcription of E6/E7 genes. In particular, Ap1 was found to be the most potent transactivator. In situ hybridization analyses revealed that E6/E7 mRNA was expressed mainly in the undifferentiated basal layers of stratified epithelial cells in uterine cervix, which was co-localized with AP1 expression determined by immunohistochemical analyses. These findings suggest that AP1 is the critical determinant of HPV oncogene expression. In addition, we found that cellular factor YY1 cooperates with API to achieve full activation of HPV oncogene expression. These results may provide insight into molecular targets for gene therapies against cervical cancer induced by HPV infection.