Tumor promoter-induced ornithine decarboxylase gene expression occurs independently of AP-1 activation

• Published in: Oncogene Vol. 18; no. 42; pp. 5806 - 5813
• Main Authors: JANSEN, A. P, COLBURN, N. H, VERMA, A. K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 14.10.1999; Nature Publishing Group
• Subjects: 12-O-Tetradecanoylphorbol-13-acetate; Acetic acid; Activator protein 1; Animals; Biological and medical sciences; c-Jun protein; Carcinogens - pharmacology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - drug effects; Cells, Cultured; Eflornithine; Eflornithine - pharmacology; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic transformation; Kinases; Mice; Molecular and cellular biology; Ornithine decarboxylase; Ornithine Decarboxylase - biosynthesis; Ornithine Decarboxylase - genetics; Ornithine Decarboxylase Inhibitors; Proto-Oncogene Proteins c-jun - antagonists & inhibitors; Proto-Oncogene Proteins c-jun - biosynthesis; Proto-Oncogene Proteins c-jun - genetics; Tetradecanoylphorbol Acetate - antagonists & inhibitors; Tetradecanoylphorbol Acetate - pharmacology; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - biosynthesis; Transcription Factor AP-1 - metabolism; Transcription factors; Tumorigenesis; Enzyme; Rodentia; Lyases; Activation; Ornithine decarboxylase; Gene expression; Cell transformation; Carcinogenesis; Carbon-carbon lyases; Vertebrata; Regulation(control); Mammalia; Cell line; Gene; Mouse; Carboxy-lyases; Epithelial cell; Tumor promotion
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1202965

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.