In a previous study, we showed that synchronized proliferation of mouse epidermis was induced by topical application of 12-O-tetradecanoyl-phorbol 13-acetate. Here, we used this system to study modifications in the cell cycle regulation and kinetics of proliferation in transgenic mice that overexpress cyclin D1 (K5D1 mice). Overexpression of cyclin D1 corresponded with an increase of proliferation in the epidermis of these transgenic mice. After proliferation reached its peak, the labeling index remained high in the transgenics, but not in the wild-type animals. In addition, cyclin D1/cyclin-dependent kinase (CDK) complex formation increased in the transgenic mice and was correlated with elevated CDK4 and CDK6 kinase activities. However, the increased CDK activities were not sufficient to effect mouse skin tumor development. In summary, these results show that cyclin D1 has a unique growth-promoting role in tumor development, but does not act as an oncogene independent of ras activity.