The induction of epidermal transglutaminase and terminal differentiation by tumor promoters in cultured epidermal cells.

Previous studies had indicated that complete skin tumor promoters of the phorbol ester class induce epidermal transglutaminase and cornification in a subpopulation of cultured mouse epidermal basal cells in proportion to their promoting properties. This report describes the effect of promoting agents other than phorbol esters on the differentiation response and explores the pharmacological basis for the heterogeneity of responsiveness among subpopulations. The potent indole alkaloid skin tumor promoter, teleocidin, induces transglutaminase to the same extent or greater than 12-O-tetradecanoylphorbol-13-acetate (TPA). The highly inflammatory and cytotoxic non-promoting agent resiniferotoxin is not an inducer of transglutaminase. Incomplete skin tumor promoters, mezerein and retinyl phorbol acetate, were as potent as TPA as inducers of transglutaminase. Anthralin and benzoyl peroxide, skin tumor promoters which do not bind to the phorbol ester receptor, do not induce transglutaminase. TPA was used to study the influence of the state of epidermal maturation at the time of exposure on the differentiation response. Epidermal basal cells were induced to differentiate by elevating extracellular calcium to 1.2 mM. TPA markedly accelerates the differentiation program when given simultaneous with exposure to 1.2 mM Ca2+ as indicated by measurements of DNA synthesis, transglutaminase activity and cornified cells. Furthermore, epidermal cells committed to differentiate by switching to 1.2 mM Ca2+ medium remain responsive to the differentiative effects of TPA for at least 5 h. These results indicate that the induction of transglutaminase activity and cornification in epidermal basal cells is characteristic of phorbol ester promoters or other agents that bind to the phorbol ester receptor but is not characteristic of all skin tumor promoters. This result suggests that the phorbol ester receptor regulates epidermal differentiation. The state of differentiation of epidermal cells at the time of phorbol ester exposure may determine whether the cellular response will be in a proliferative or differentiative pathway.