High-risk human papillomavirus type 16 (HPV-16) and HPV-18 are associated with 
the majority of human cervical carcinomas, and two viral genes, HPV E6 and E7, 
are commonly found to be expressed in these cancers. The presence of HPV-16 E7 
is sufficient to induce epidermal hyperplasia and epithelial tumors in 
transgenic mice. In this study, we have performed experiments in transgenic mice 
to determine which domains of E7 contribute to these in vivo properties. The 
human keratin 14 promoter was used to direct expression of mutant E7 genes to 
stratified squamous epithelia in mice. The E7 mutants chosen had either an 
in-frame deletion in the conserved region 2 (CR2) domain, which is required for 
binding of the retinoblastoma tumor suppressor protein (pRb) and pRb-like 
proteins, or an in-frame deletion in the E7 CR1 domain. The CR1 domain 
contributes to cellular transformation at a level other than pRb binding. Four 
lines of animals transgenic for an HPV-16 E7 harboring a CR1 deletion and five 
lines harboring a CR2 deletion were generated and were observed for overt and 
histological phenotypes. A detailed time course analysis was performed to 
monitor acute effects of wild-type versus mutant E7 on the epidermis, a site of 
high-level expression. In the transgenic mice with the wild-type E7 gene, 
age-dependent expression of HPV-16 E7 correlated with the severity of epidermal 
hyperplasia. Similar age-dependent patterns of expression of the mutant E7 genes 
failed to result in any phenotypes. In addition, the transgenic mice with a 
mutant E7 gene did not develop tumors. These experiments indicate that binding 
and inactivation of pRb and pRb-like proteins through the CR2 domain of E7 are 
necessary for induction of epidermal hyperplasia and carcinogenesis in mouse 
skin and also suggest a role for the CR1 domain in the induction of these 
phenotypes through as-yet-uncharacterized mechanisms.