Synchronized proliferation induced by 12-O-tetradecanoylphorbol- 13- acetate treatment of mouse skin: An in vivo model for cell cycle regulation

Much of what is known about the mammalian cell cycle comes from studies using established cell lines in culture. In this study, cell cycle-regulatory events were analyzed in vivo after treatment of mouse epidermis with 12-O- tetradecanoylphorbol-13-acetate. A synchronized wave of basal keratinocyte proliferation occurred; over 80% of the cells were in S phase 15 h after treatment. c-myc protein expression was induced, and p57(Kip2) protein levels dropped early after stimulation. Before S phase, cyclin D1 and cyclin- dependent kinase (CDK) 6 levels increased, and expression of cyclins E and A was induced. Rb was phosphorylated in late G₁, and this correlates with the formation of cyclin D1/CDK4 and cyclin D1/CDK6 complexes. At the end of S phase, the p57(Kip2) and p21(Cip1) protein levels increased. These findings demonstrate that stimulation of basal epidermal cells by 12-O- tetradecanoylphorbol-13-acetate results in several classic cell cycle events and suggests that p57(Kip2) plays a key role in regulating proliferation in the epidermis.