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Inhibition of Tumor Promoter 12-O-Tetradecanoylphorbol-13-acetate-induced Synthesis of Epidermal Ornithine Decarboxylase Messenger RNA and Diacylglycerol-promoted Mouse Skin Tumor Formation by Retinoic Acid¹

Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792

Evidence is presented that inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC; EC 4.1.1.17) by retinoic acid may involve inhibition of protein kinase C-mediated synthesis of ODC mRNA. A single application of 10 nmol of TPA to intact mouse skin led to an increase in the steady state levels of epidermal ODC mRNA; a maximal level of ODC mRNA occurred at about 3.5 h after TPA treatment. TPA-induced increase in ODC mRNA preceded the increase in epidermal ODC activity. Application of 17 nmol of retinoic acid 1 h before application of TPA to mouse skin inhibited the induction of both ODC mRNA and ODC activity. Using the DNA-excess filter hybridization technique, we found that TPA-increased steady state levels of ODC mRNA in primary culture of newborn mouse epidermal cells were the result of enhanced accumulation of newly synthesized ODC mRNA. Furthermore, in a pulse-chase experiment, we could not detect any difference in the half-life of ODC mRNA in epidermal cells after TPA or the vehicle dimethyl sulfoxide treatments; the half-life of ODC mRNA was about 7 h in both cases. Exposure of primary cultures of newborn epidermal cells to retinoic acid, in conjunction with TPA, inhibited the synthesis of ODC mRNA and failed to alter the half-life of ODC mRNA. These results implicate the role of transcription activation in TPA-induced ODC gene expression and indicate that retinoic acid may inhibit TPA-induced ODC gene transcription. We also found that protein kinase C may play a role in the mechanism of inhibition by retinoic acid of ODC gene expression. Supporting evidence is the finding that L--dioctanoylglycerol, an activator of protein kinase C, is a Stage II mouse skin tumor promoter and the application of retinoic acid 1 h before application of L--dioctanoylglycerol to mouse skin inhibited the induction of ODC activity and ODC mRNA as well as tumor promotion by L--dioctanoylglycerol. Taken together, one may conclude that the mechanism of inhibition of TPA-induced ODC by retinoic acid may involve the inhibition of protein kinase C-mediated accumulation of newly synthesized ODC mRNA.

¹ Supported by United States Public Health Service Grant CA-42585 by the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Human Oncology, K4/538, CSC, UW, 600 Highland Avenue, Madison, WI 53792.

Received 9/ 8/87. Revised 1/ 4/88. Accepted 1/19/88.

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