TARGETED EXPRESSION OF THE E6 AND E7 ONCOGENES OF HUMAN PAPILLOMAVIRUS TYPE-16 IN THE EPIDERMIS OF TRANSGENIC MICE ELICITS GENERALIZED EPIDERMAL HYPERPLASIA INVOLVING AUTOCRINE FACTORS

The E6 and E7 early genes of human papillomavirus type 16 have been sh own in vitro to play a central role in the transforming capability of this virus. To explore their effects on differentiating epithelial cel ls in vivo, we used a bovine cytokeratin 10 (K10) promoter to target t he expression of E6 and E7 to the suprabasal layers of the epidermis o f transgenic mice. In two different lines of mice efficiently expressi ng the transgene, animals displayed generalized epidermal hyperplasia, hyperkeratosis and parakeratosis in the skin and the forestomach, bot h known to be sites of K10 expression. Northern (RNA) blot analysis re vealed high levels of E6 and E7 transcripts, and in situ hybridization s localized these transcripts to the suprabasal strata of epidermis. I n vivo labeling of proliferating cells showed two distinct effects of E6 and E7 expression in the epidermis: (i) an increase in the number o f growing cells in the undifferentiated basal layer and (ii) abnormal proliferation of differentiated cells in the suprabasal strata. The ex pression of c-myc in the skin of transgenics was higher than that in c ontrol animals. The induction of c-myc transcription by topical applic ation of tetradecanoyl phorbol acetate was prevented by simultaneous t reatment with transforming growth factor beta 1 in nontransgenic skin but not in transgenic skin. In addition, transforming growth factor or was found to be overexpressed in the suprabasal layers of the transge nic epidermis. These findings suggest that autocrine mechanisms are in volved in the development and maintenance of epidermal hyperplasia. An imals of both lines developed papillomas in skin sites exposed to mech anical irritation and wounding, suggesting that secondary events are n ecessary for progression to neoplasia. Collectively, these results pro vide new insights into the tumor promoter activities of human papillom avirus type 16 in epithelial cells in vivo.