The human papillomavirus type 8 E2 protein suppresses beta4integrin expression in primary human keratinocytes

The papillomavirus life cycle parallels keratinocyte differentiation in stratifying epithelia. We have previ-ously shown that the human papillomavirus type 8 (HPV8) E2 protein downregulates 4-integrin expression in normal human keratinocytes, which may trigger subsequent differentiation steps. Here, we demonstrate that the DNA binding domain of HPV8 E2 is sufficient to displace a cellular factor from the 4-integrin promoter. We identified the E2-displaceable factor as activator protein 1 (AP-1), a heteromeric transcription factor with differentiation-specific expression in the epithelium. 4-Integrin-positive epithelial cells displayed strong AP-1 binding activity. Both AP-1 binding activity and 4-integrin expression were coregulated during keratinocyte differentiation suggesting the involvement of AP-1 in 4-integrin expression. In normal human keratinocytes the AP-1 complex was composed of JunB and Fra-1 subunits. Chromatin immunoprecipitation assays con-firmed that JunB/Fra-1 proteins interact in vivo with the 4-integrin promoter and that JunB/Fra-1 promoter occupancy is reduced during keratinocyte differentiation as well as in HPV8 E2 positive keratinocytes. Ectopic expression of the tethered JunB/Fra-1 heterodimer in normal human keratinocytes activated the 4-integri