1. Tumor promoter-induced MMP-13 gene expression in a model of initiated epidermis.
- Author
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Zeliadt NA, Warmka JK, Winston SE, Kahler R, Westendorf JJ, Mauro LJ, and Wattenberg EV
- Subjects
- Animals, Cell Line, Collagenases genetics, Epidermis drug effects, Gene Expression Profiling methods, Gene Expression Regulation drug effects, Keratinocytes drug effects, Matrix Metalloproteinase 13, Mice, Mitogen-Activated Protein Kinases genetics, Signal Transduction drug effects, Transcription Factor AP-1 genetics, Collagenases metabolism, Epidermis metabolism, Gene Expression Regulation physiology, Keratinocytes metabolism, Mitogen-Activated Protein Kinases metabolism, Signal Transduction physiology, Tetradecanoylphorbol Acetate pharmacology, Transcription Factor AP-1 metabolism
- Abstract
In mouse epidermis in vivo, the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) increases gene expression of matrix metalloproteinase-13 (MMP-13), an enzyme implicated in carcinogenesis. Here we used a keratinocyte cell line (308) derived from initiated mouse skin to investigate TPA-induced MMP-13 gene expression. Use of a pharmacological inhibitor (U0126) demonstrated that extracellular signal regulated kinase (ERK) plays a major role in TPA-induced MMP-13 gene expression. The 5'-flanking sequences of the MMP-13 gene contain binding sites for activator protein-1 (AP-1) and Runx. Both transcription factor families can be modulated by ERK and have been implicated in MMP-13 gene expression. TPA stimulated ERK-dependent increases in c-Fos protein and the c-Fos content of AP-1 complexes. MMP-13 promoter studies indicated that TPA requires AP-1, but not Runx, to induce MMP-13 gene expression. These studies show that in mouse keratinocytes MMP-13 gene expression can be induced through a Runx-independent pathway that involves the ERK-dependent modulation of AP-1.
- Published
- 2004
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