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Lack of an Effect of Tumor-promoting Phorbol Esters and of Epidermal G₁ Chalone on DNA Synthesis in the Epidermis of Newborn Mice¹

Deutsches Krebsforschungszentrum (German Cancer Research Center), Institut für Biochemie, Kirschnerstrasse 6, D 69 Heidelberg, Federal Republic of Germany

An investigation was carried out on the effect of skin and epidermis fractions containing epidermal G₁ chalone and of hyperplasiogenic phorbol esters on precursor incorporation into DNA of dorsal mouse epidermis in vivo. In newborn mice, epidermal DNA synthesis was not inhibited by injections of skin extracts from pigs or from adult and newborn mice, but the responsiveness to the inhibitor was developed with increasing age. In spite of its lack of response, epidermis from newly born mice was shown to contain an inhibitor that may be identical to the epidermal G₁ chalone from adult skin.

The responsiveness of epidermal DNA synthesis to the stimulatory effect of tumor-promoting phorbol esters such as 12-O-tetradecanoyl-phorbol-13-acetate and phorbol-12,13-didecanoate was also age dependent. Whereas in adult mice the DNA synthesis was strongly stimulated, no such effect was observed with newborn animals. However, 1 week after birth an onset of the proliferative response was seen.

By proper control experiments with tritiated 12-O-tetradecanoly-phorbol-13-acetate, "stripped" epidermis, and different phorbol esters, it could be concluded that the lack of a stimulatory effect in newborn mice was not due to hindered penetration or to a too rapid metabolism of the promoting agent. The possibility is discussed that epidermis of newborn mice does not respond to chalones and phorbol esters because its proliferative cells are still in a state of pluripotentiality. During maturation of the animal the pluripotential stem cells are probably replaced by chalone-sensitive committed stem cells. The latter are though to be "rejuvenated" to chaloneinsensitive pluripotential cells by treatment with hyperplasiogenic agents such as the phorbol esters.

¹ This work has been supported by the Deutsche Forschungsgemeinschaft.

² To whom requests for reprints should be addressed.

Received 4/29/74. Accepted 7/ 3/74.

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