Tumor promoter-induced MMP-13 gene expression in a model of initiated epidermis.
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.
Zeliadt
Nicholette A
NA
Division of Environmental Health Sciences, University of Minnesota, Minneapolis, MN, USA.
Warmka
Janel K
JK
Winston
Susanna E
SE
Kahler
Rachel
R
Westendorf
Jennifer J
JJ
Mauro
Laura J
LJ
Wattenberg
Elizabeth V
EV
D000818:Animals; D002460:Cell Line; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
D018808:Transcription Factor AP-1; D020928:Mitogen-Activated Protein Kinases; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D013755:Tetradecanoylphorbol Acetate