The human papillomavirus type 16 E5 gene cooperates with the E7 gene to stimulate proliferation of primary cells and increases viral gene expression.

The E5 gene from HPV-16 has recently been shown to stimulate anchorage-independent growth of murine 3T3 cells and this phenotype was enhanced in the presence of epidermal growth factor (EGF). Since EGF is capable of stimulating cellular signal transduction, we have compared levels of EGF-induced c-fos and c-jun mRNA in E5-expressing 3T3 cells. We present data showing that the expression of c-fos and c-jun was higher in E5-expressing 3T3 cells than in control cells. Complexes of c-fos/c-jun constitute the AP1 transcription factor and the HPV-16 promoter/enhancer contains AP1 enhancer elements. HPV-16 promoter activity was therefore examined in cells transfected with the E5 gene and data are presented which reveal that the viral enhancer is more active in E5-expressing cells. Since the viral E7 gene product has been shown to cooperate with v-fos and certain growth factors for transformation and stimulation of DNA synthesis, we investigated the possible cooperation between E5 and E7 to induce cell proliferation. Transfection of E5 and E7 genes into primary rodent epithelial cells produced a potent mitogenic response which was enhanced in the presence of EGF. These results suggest that E5 may cooperate with the E7 gene to stimulate cell proliferation in vivo.