The E2 proteins regulate papillomavirus (PV) gene expression by sequence-specific DNA binding. However, E2 is also able to activate in the absence of E2 binding sites. We show here that the E2 protein of human PV type 8 (HPV8) can activate the expression of p21(WAF1/CIP1) via promoter-proximal 200 nucleotides, which contain several Sp1 binding sites and no E2 binding sites. HPV8 E2 lacking the activation domain, which is rather conserved among E2 proteins, cooperated with co-expressed Sp1 in stimulation of the p21(WAF1/CIP1) promoter, in contrast to HPV18 E2 lacking the activation domain. We can demonstrate that the internal non-conserved hinge region of HPV8 E2 is sufficient for this functional cooperativity with Sp1. In correlation, the hinge of HPV8 E2 directly binds to Sp1. These results suggest that HPV8 E2 might be able to 'super'-activate Sp1-mediated transcription by a direct interaction via the non-conserved hinge region.