Organ-specific activation of activator protien-1 in transgenic mice by 12-O-tetradecanoylphorbol-13-acetate with different administration methods

12-O-Tetradecanoylphorbol-13-acetate (TPA) is widely used as a tumor promot er with organotropy in skin and esophagus. TPA-induced, organ-specific tumo r promotion is not correlated with the distribution of its receptor, protei n kinase C (PKC), Using five administration methods (painting, drinking, ga vage feeding, i.p. injection, and i.v, injection), we analyzed TPA-stimulat ed activator protein-1 (AP-1) activity in various organs (liver, kidney, br ain, lung, spleen, heart, stomach, colon, esophagus, and skin) from transge nic mice expressing the AP-1 luciferase reporter gene. Topical application of TPA by painting the skin on the back of mice raised AP-1 activity 122.6- fold, and the highest peak of AP-I activity was at 12 h after administratio n of TPA. Drinking water containing TPA caused a 25.8-fold induction of AP- I activity in the skin, whereas gavage feeding with TPA caused a 34.2-fold induction of AP-I in the skin. Intraperitoneal or i.v. injection of TPA ind uced a 49.56-fold or 20.4-fold increase in AP-1 activity in the skin, respe ctively. The highest peaks of AP-1 activity in the skin were at 12 h after drinking, feeding, or injection of TPA. More interesting, in the esophagus, i.p. injection of TPA raised AP-1 activity 13.9-fold, drinking TPA raised AP-I activity 8.4-fold, and painting with TPA caused a 2.4-fold induction o f AP-1 activity. In the colon, i.p. injection of TPA raised AP-1 activity 3 .9-fold, drinking TPA induced a 1.2-fold increase in AP-1 activity, but pai nting with TPA had no effect. AP-I activity in other organs was not detecta ble after administration of TPA by painting, drinking, or injection. Phosph orylation of extracellular signal-regulated kinases in the skin increased a t 12 h after painting, drinking, or i.p. injection of TPA. In addition, pho sphorylation of p38 kinase was raised slightly after TPA administration, bu t phosphorylation of c-Jun NH2-terminal kinases was not detected at any tim e point after TPA administration. Similar changes in MAP kinases were also seen in the esophagus after TPA administration. These results indicate that the skin is the most sensitive organ to TPA induction of AP-I activity. Th e data suggest that the organ-specific, tumor-promoting effect of TPA may b e through AP-I activation and phosphorylation of ERKs and p38 kinase.