Transgenic expression of cyclin-dependent kinase 4 results in epidermal hyperplasia, hypertrophy, and severe dermal fibrosis

In a previous report we have described the effects of expression of D-type cyclins in epithelial tissues of transgenic mice. To study the involvement of the D-type cyclin partner cyclin-dependent kinase 4 (CDK4) In epithelial growth and differentiation, transgenic mice were generated carrying the CD K4 gene under the control of a keratin 5 promoter. As expected, transgenic mice showed expression of CDK4 in the epidermal basal-cell layer. Epidermal proliferation increased dramatically and basal cell hyperplasia and hypert rophy were observed. The hyperproliferative phenotype of these transgenic m ice was independent of D-type cyclin expression because no overexpression o f these proteins was detected. CDK4 and CDK2 kinase activities increased in transgenic animals and were associated with elevated binding of p27(Kip1) to CDK4. Expression of CDK4 in the epidermis results in an increased spinou s layer compared with normal epidermis, and a mild hyperkeratosis in the co rnified layer. In addition to epidermal changes, severe dermal fibrosis was observed and part of the subcutaneous adipose tissue was replaced by conne ctive tissue. Also, abnormal expression of keratin 6 associated with the hy perproliferative phenotype was observed in transgenic epidermis. This model provides in vivo evidence for the rot of CDK4 as a mediator of proliferati on in epithelial cells independent of D-type cyclin expression.