A keratinocyte-specific transcription factor, KRF-1, interacts with AP-1 to activate expression of human papillomavirus type 18 in squamous epithelial cells

Human papillomavirus type 18 (HPV-18) infects genital squamous epithelium and is an etiological agent of cervical cancer. Cell-type-specific expression of HPV-18 is directed by the region upstream of the viral early genes that contains a transcriptional enhancer whose function is dependent solely on cellular factors. This element directs expression to high levels in squamous epithelial cells but is only weakly active in other cell types. We demonstrate by gel mobility-shift, methylation interference, and mutational analysis that the binding of two distinct factors to the enhancer is necessary for cell-type-specific transcriptional activation. One of these factors is identified as a keratinocyte-specific transcriptional activator, which we call KRF-1, while the other is a member of the AP-1 family. We also find that Oct-1 competes with KRF-1 for binding to enhancer sequences though it does not contribute to transcriptional activation. These results suggest a complex interplay of ubiquitous and cell-type-restricted transcriptional factors in the tissue- and differentiation-specific expression of HPV-18.