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Differentiation modulates the response of guinea pig epidermal keratinocytes to the stimulation of DNA synthesis by TPA.

Repeated applications of the phorbol ester 12-0-Tetradecanoyl-phorbol-13-acetate (TPA) to adult mouse skin initiated with a polycyclic hydrocarbon results in permanent epidermal hyperplasia and leads to tumor promotion. One application of TPA induces both DNA synthesis in the epidermis and morphological changes in suprabasal normally nondividing epidermal cells that have been interpreted as reprograming of maturing keratinocytes that would be sent back into cycle. To investigate whether DNA synthesis is directly linked with promotion, single doses of TPA (20 nmol) were applied to the skin of guinea pig, an animal in which TPA does not promote tumor. A fourfold increase in DNA synthesis was detected at 24 h by liquid scintillation counting after 3H-TdR in vivo incorporation. A 10–15-fold increase was noted at the same time by autoradiography. To see if TPA is able to initiate DNA synthesis in suprabasal keratinocytes, basal cells were isolated from suprabasal elements by the sequential action of trypsin. Basal cells in suspension were detected by immunofluorescence using bullous pemphigoid (BP) antibodies. Basal and suprabasal cell suspensions contained 70 ± 4.5 and 23 ± 8% BP-positive cells, respectively. Both cell suspensions were cultured in vitro 4–5 days. TPA (10−7 M) was added to the culture medium 20 h after seeding the cells and removed 24 h later. The incorporation of 3H-TdR into DNA was measured daily. A tenfold increase in DNA synthesis was observed 3 days after treatment in basal cell cultures, whereas no significant effect could be detected in suprabasal cultures from day 1–4. It is concluded that: (i) if DNA synthesis is necessary for promotion to occur, it is not sufficient; (ii) the effect of TPA on epidermal DNA synthesis is probably the result of an increase in the number of basal cells entering S phase, and not the consequence of the reprograming of suprabasal maturing keratinocytes.