Expression of the early genes of human papillomavirus type 16 (HPV 16) is known to be highly restricted to epithelial cells. This report describes the molecular basis of HPV 16 epitheliotropism at the transcriptional level. A series of 5′-end deletion mutants of the long control region (LCR) located upstream of the HPV 16 early genes were tested in a transient expression assay using various human epithelial and fibroblastic cell lines. The specific region termed the cell-type-dependent regulatory element (CTRE) was found to function as an enhancer in some of HPV-associated human epithelial cell lines, but not at all in HPV-free human epithelial cell lines. No LCR-associated enhancer activity was detectable in fibroblastic cell lines. The CTRE was mapped at a distinct region upstream from the previously proposed proximal keratinocyte dependent enhancer (KD). The CTRE augmented transcription initiated from the autologous P97 promoter as well as from a heterologous promoter in a orientation-independent manner. Within the CTRE, there are three copies of the consensus nuclear factor-1 (NF1) binding site. Using CTRE containing mutations in each of the NF1-sites, it was demonstrated that all of these NF1-sites were necessary for a full enhancer activity in the HPV-associated human epithelial cell line. This suggests that the CTRE plays a critical role in the cell-type specific expression of HPV 16-early gene at the level of transcriptional regulation.
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