Involvement of the Ras/MAPK signaling pathway in the modulation of urokinase production and cellular invasiveness by transforming growth factor-beta(1) in transformed keratinocytes

Biochem Biophys Res Commun. 2000 Jul 5;273(2):521-7. doi: 10.1006/bbrc.2000.2946.


Transformed PDV keratinocytes respond to TGF-beta(1) by stimulating cell motility and invasiveness concomitantly to enhancement of the urokinase-type plasminogen activator (uPA) expression/secretion. Depletion of extracellular signal-regulated kinase (ERK1, 2) proteins by treatment of PDV cells with antisense oligonucleotides reduced basal uPA production and abolished stimulation of uPA secreted levels and cell motility by TGF-beta(1). PD098059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase (MEK), decreased TGF-beta(1)-induced uPA mRNA expression, secreted activity in a dose-dependent manner, and abrogated TGF-beta(1)-stimulated cell motility and invasiveness. PDV-derived dominant-negative RasN17 cell transfectants secreted similar amounts of uPA and exhibited similar invasive abilities as the parental cells or control clones, but were unable to respond to TGF-beta(1) for stimulation of uPA-secreted levels and invasiveness. These results suggest that a Ras/MAPK transduction pathway is involved in the invasive response of transformed keratinocytes to TGF-beta(1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line, Transformed
  • Cell Movement / drug effects
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Gene Expression
  • Genes, ras
  • Keratinocytes / drug effects*
  • Keratinocytes / physiology*
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutation
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / pharmacology
  • Signal Transduction
  • Transforming Growth Factor beta / pharmacology*
  • Urokinase-Type Plasminogen Activator / biosynthesis*
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Enzyme Inhibitors
  • Flavonoids
  • Oligonucleotides, Antisense
  • Transforming Growth Factor beta
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Urokinase-Type Plasminogen Activator
  • ras Proteins
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one