REGULATION OF HUMAN PAPILLOMAVIRUS TRANSCRIPTION BY THE DIFFERENTIATION-DEPENDENT EPITHELIAL FACTOR EPOC-1 SKN-1A/

Human papillomavirus (HPV) early gene expression is closely linked to the differentiation status of infected epithelial cells, Typically, HP V type 16 (HPV16) or HPV18 E6 and E7 transcripts are only barely detec table within the undifferentiated basal cell layer, but their levels i ncrease concomitantly with higher degrees of epithelial cell different iation in suprabasal cells, A similar differentiation-dependent distri bution of expression has been reported for the recently cloned epithel ial cell specific transcription factor Epoc-1/skn-1a, We therefore exa mined whether Epoc-1/skn-1a may be directly involved in the activation of HPV E6/E7 transcription, Transient transfection studies showed tha t Epoc-1/skn-1a specifically stimulated the HPV16 and HPV18 E6/E7 prom oters. Moreover, ectopically expressed Epoc-1/skn-1a was sufficient to stimulate I-IPV transcription also in nonepithelial cells. By deletio n analyses, the Epoc-1/skn-1a-responsive element was mapped to tile pr omoter-proximal portion of the HPV18 transcriptional control region, F ootprint analyses and gel retardation assays demonstrated direct bindi ng of Epoc-1/skn-1a to a hitherto uncharacterized site within this reg ion, Mutation of the Epoc-1/skn-1a recognition site within the context of the complete HPV18 upstream regulatory region inhibited Epoc-1/skn -1a-mediated transactivation, These results show that Epoc-1/skn-1a ca n directly activate the E6/E7 promoter by binding to the viral transcr iptional control region, Thus, Epoc-1/skn-1a may be involved in the di fferentiation-dependent regulation of HPV transcription.