Topical application of 12-O-tetradecanoylphorbol-13-acetate induces dyssynchronous expression of keratins K1 and K10 in mouse epidermis.

12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent tumor promoter that causes severe alterations in the biosynthesis of epidermal keratins. This study shows that TPA induces a dyssynchronous effect on keratin expression in stratified squamous epithelium. The effect of TPA on the separate expression of the maturation-associated keratins K1 and K10 was studied by immunohistochemistry in an unperturbed replicative keratinocyte population of hairless mice epidermis in relation to changes in the cell cycle time during regeneration. Keratinocytes in DNA synthesis were pulse-labeled by intraperitoneal injection of the thymidine analogue 5-bromodeoxyuridine (BrdUrd) 1 h before a single topical application of TPA. The BrdUrd-labeled cell cohort, representing an originally unperturbed replicative keratinocyte population exposed to TPA mainly in the postreplicative period, was followed for up to 97 h. The results suggested unaltered timing of the onset of K1 and K10 expression compared with normal epidermis (18 and 24 h, respectively, following DNA synthesis). This indicates that the synthesis of both keratins was programmed before the keratinocytes entered their last DNA synthesis. A reduction in K10 expression from about 30 h compared with that of K1 expression was observed. Mathematical modeling suggested a delay in K10 expression related to the second and third rounds of cell divisions after pulse-labeling. How TPA induces such dyssynchrony in K1 and K10 regulation remains unknown.