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.
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).
Santibáñez
J F
JF
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, 28029-, Spain.
Iglesias
M
M
Frontelo
P
P
Martínez
J
J
Quintanilla
M
M
D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression; D011905:Genes, ras; D015603:Keratinocytes / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D016376:Oligonucleotides, Antisense; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D014568:Urokinase-Type Plasminogen Activator; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one