Tumor promoter-induced MMP-13 gene expression in a model of initiated epidermis

Biochem Biophys Res Commun. 2004 Apr 30;317(2):570-7. doi: 10.1016/j.bbrc.2004.03.081.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Collagenases / genetics
  • Collagenases / metabolism*
  • Epidermis / drug effects
  • Epidermis / metabolism*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • Matrix Metalloproteinase 13
  • Mice
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*


  • Transcription Factor AP-1
  • Mitogen-Activated Protein Kinases
  • Collagenases
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • Tetradecanoylphorbol Acetate