Histone phosphorylation and synthesis of DNA and RNA during phases of proliferation and differentiation induced in mouse epidermis by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate.

The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induces discrete waves of proliferation and differentiation when applied to mouse epidermis. The aim of this study was to elucidate the temporal relationship between histone phosphorylation and synthesis of DNA and RNA in mouse epidermis during the process of tumor promotion. This investigation as facilitated by choosing a low but nevertheless strongly tumor-promoting dose of TPA (0.002 micronmole/mouse), which induced the epidermal cells to go through only one round of DNA synthesis and cell division. Histones were isolated from mouse epidermis, and the rates of phosphorylation of the individual histone species were determined at different times after treatment with TPA. The results demonstrated that the phosphorylation of H1 histone was initiated at about the same time as the synthesis of DNA but continued past the S phase and reached a maximum simultaneously with the maximum in the epidermal mitotic rate. The only other histone that phosphorylated to any significant extent was Histone H2A. From the results obtained, it was concluded that histone phosphorylation in the epidermis is related to the processes of DNA replication and mitosis after stimulation with TPA. Positive evidence for the activation of specific genes, which has been proposed by other authors to be important in the promotion of epidermal tumors, was not found in this investigation.