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 kerati ns, This study shows that TPA induces a dyssynchronous effect on kerat in expression in stratified squamous epithelium. The effect of TPA on the separate expression of the maturation-associated keratins K1 and K 10 was studied by immunohistochemistry in an unperturbed replicative k eratinocyte population of hairless mice epidermis in relation to chang es in the cell cycle time during regeneration, Keratinocytes in DNA sy nthesis were pulse-labeled by intraperitoneal injection of the thymidi ne analogue 5-bromodeoxyuridine (BrdUrd) 1 h before a single topical a pplication of TPA. The BrdUrd-labeled cell cohort, representing an ori ginally unperturbed replicative keratinocyte population exposed to TPA mainly in the postreplicative period, was followed for up to 97 h, Th e results suggested unaltered timing of the onset of K1 and K10 expres sion compared with normal epidermis (18 and 24 h, respectively, follow ing DNA synthesis), This indicates that the synthesis of both keratins was programmed before the keratinocytes entered their last DNA. synth esis. A reduction in K10 expression from about 30 h compared with that of K1 expression was observed. Mathematical modeling suggested a dela y in K10 expression related to the second and third rounds of cell div isions after pulse-labeling, How TPA induces such dyssynchrony in K1 a nd K10 regulation remains unknown. (C) 1995 Wiley-Liss, Inc.