The E5a gene of human papillomavirus type 11 (HPV-11) is a transforming oncogene. In this study, we investigated the mechanism of E5a induced transformation. Our results show that the expression of c-jun and junB, but not junD, was activated by HPV-11 E5a in NIH 3T3 cells and human epidermal keratinocytes. However, the expression of c-fos was activated by E5a in NIH 3T3 cells, but not in keratinocytes. We further investigated the mechanism of c-jun and junB induction by E5a. The amount of c-jun and junB RNAs correlated with the amount of E5a RNA in the heavy metal inducible system. E5a constitutively activated the expression of c-jun and junB at the initiation of transcription level. In addition, analyses of the effect of serum on c-jun expression in E5a transformed human epidermal keratinocytes show that EGF might have a stimulatory effect on c-jun gene expression in E5a expressing keratinocytes.