Transforming growth factor-beta1 modulates matrix metalloproteinase-9 production through the Ras/MAPK signaling pathway in transformed keratinocytes

Biochem Biophys Res Commun. 2002 Aug 16;296(2):267-73. doi: 10.1016/s0006-291x(02)00864-1.


Mouse transformed keratinocytes cultured in the presence of transforming growth factor-beta1 (TGF-beta1) acquire a set of morphological and functional properties giving rise to a more motile phenotype that expresses mesenchymal markers. In this work, we present evidence showing that TGF-beta1 stimulates cellular production of MMP-9 (Gelatinase B), a metalloproteinase that plays an important role in tumoral invasion. Our results demonstrate that TGF-beta1stimulates MMP-9 production and MMP-9 promoter activity in a process that depends of the activation of the Ras-ERK1,2 MAP kinase pathway. The latter was demonstrated by cellular transfection of TGF-beta1-sensitive cells with a RasN17 mutant gene, using PD 098059, a MEK 1,2 inhibitor, and treating cells with anti-sense oligodeoxinucleotides. The enhanced MMP-9 production proved to be an important factor in the acquisition of migratory and invasive properties as shown by the use of a specific inhibitor of MMP-9 (GM6001) that inhibits the TGF-beta1-stimulated invasive and migratory properties of these transformed keratinocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic
  • Curcumin / pharmacology
  • Dipeptides / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Genes, Reporter
  • Humans
  • Imidazoles / pharmacology
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Keratinocytes / enzymology*
  • MAP Kinase Signaling System / physiology*
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinase Inhibitors
  • Mice
  • Oligodeoxyribonucleotides, Antisense / metabolism
  • Promoter Regions, Genetic
  • Pyridines / pharmacology
  • Recombinant Proteins / pharmacology
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology*
  • Transforming Growth Factor beta1
  • Tumor Cells, Cultured
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Dipeptides
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Matrix Metalloproteinase Inhibitors
  • N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
  • Oligodeoxyribonucleotides, Antisense
  • Pyridines
  • Recombinant Proteins
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Matrix Metalloproteinase 9
  • ras Proteins
  • Curcumin
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one