Abnormalities of epidermal differentiation associated with expression of the human papillomavirus type 1 early region in transgenic mice.

Abstract

The promoter region of a keratin 6 (K6) gene was used to regulate expression of the early region of human papillomavirus type 1 (HPV-1e) in transgenic mice. In one line of mice the K6-HPV1e transgene was transcribed in several regions of the skin, the predominant transcript being a 1.1 kb RNA including the E4 open reading frame, and E1-E4 protein was detected in the upper suprabasal layers of the skin in paws and tail. A 1.7 kb RNA corresponding to the E6/E7 transcript was also prominent in tails of homozygous transgenic animals. In young homozygous transgenic mice the epidermis of the tail showed dysplasia and hyperplasia of the suprabasal layers with both hyperkeratosis and focal parakeratosis in the stratum corneum. A similar though milder phenotype was also observed sporadically in hemizygous transgenics. Analysis of the pattern of mouse keratins present in the affected tail skin showed strong up-regulation of the endogenous keratins 6 and 16 throughout the basal and suprabasal layers, suggesting a positive feedback mechanism for the strong transgene activation. Expression of the major differentiation-specific keratins 1 and 10 was repressed. The pattern of E1-E4 expression and the perturbation of normal epithelial differentiation parallel many of the characteristics of HPV-1 warts or verrucae, suggesting that HPV transgenic mice could be useful for analysis of the interactions of HPV gene products with cellular regulatory pathways within an otherwise normal epithelium.