Tumor promoter-induced ornithine decarboxylase gene expression occurs independently of AP-1 activation.
Activator protein 1 (AP-1) transactivation and ornithine decarboxylase (ODC) activity have been established as essential downstream effectors of mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). Previous studies have shown that inhibition of either AP-1 transactivation or ODC activity suppressed tumor promoter-induced transformation. By utilizing the JB6 mouse epidermal cell system, the present study determined whether TPA-induced ODC gene expression and activity is independent of AP-1 transactivation. In three independent JB6 (P+) clones, stably expressing dominant negative c-jun, TPA-induced ODC gene expression and activity were similar compared to JB6 P+ cells expressing vector-control alone, while AP-1-dependent transcription was inhibited. Transformation-insensitive JB6 (P-) cells, which lack TPA-inducible c-jun expression, also exhibited similar induction of ODC activity by TPA. alpha-Difluoromethylornithine, an irreversible inhibitor of ODC, attenuated, at an equivalent IC50, both TPA-induced ODC activity and anchorage-independent growth of JB6 P+ cells, despite no inhibition of AP-1 transactivation. Taken together, the results presented indicate that TPA-induced ODC gene expression and activity are independent of AP-1 transactivation. Because inhibition of either AP-1 or ODC precludes TPA-induced transformation, and because ODC is independent of AP-1, we propose that there are at least two pathways to transformation. Each pathway is required but not sufficient for transformation.
Jansen
A P
AP
Department of Human Oncology, Medical School, University of Wisconsin, Madison, Wisconsin, WI 53792, USA.
Colburn
N H
NH
Verma
A K
AK
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D000518:Eflornithine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000235:genetics*; D065108:Ornithine Decarboxylase Inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
D002273:Carcinogens; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate; D000518:Eflornithine