Effect of elevated levels of ornithine decarboxylase on cell cycle progression in skin

By crossing TG.AC v-Ha-ras and K6/ODC transgenic mice, we found previously that an activated ras and follicular ornithine decarboxylase (ODC) overexpr ession cooperate to generate spontaneous tumors in the skin. Cellular proli feration was dramatically increased in the K6/ODC transgenic skin, as evide nced by elevated proliferating cell nuclear antigen and Ki67 expression com pared with nontransgenic littermates. Keratinocytes isolated from transgeni c skin also displayed increased clonal growth. Paradoxically, expression of the growth inhibition-associated proteins p53, p21(Waf1), p27(Kip1), and B ax was increased with ODC overexpression in the skin. ODC overexpression di d not affect cyclin D/cyclin-dependent kinase 4 (Cdk4)-dependent phosphoryl ation of retinoblastoma protein but stimulated cyclin E/Cdk2 and cyclin A/C dk2-associated kinase activity, with minimal effect on the levels of these proteins. Thus, ODC/polyamine-induced activation of cyclin E/Cdk2 and cycli n A/Cdk2-associated kinase activity may cooperate with the ras induction of cyclin D/Cdk4/6-associated retinoblastoma protein phosphorylation to not o nly stimulate proliferation but ultimately contribute to tumor development.