Transforming growth factor beta 1 inhibits mitogen-activated protein kinase induced by basic fibroblast growth factor in smooth muscle cells.
Stimulation of smooth muscle cells with basic fibroblast growth factor (bFGF) results in the activation of the mitogen-activated protein kinase (MAP kinase) cascade and leads to cell proliferation. We show that transforming growth factor beta 1 (TGF-beta 1), at concentrations that completely inhibited bFGF-induced mitogenic activity, decreased bFGF-induced MAP kinase activity. Under these conditions, tyrosine and threonine phosphorylations of MAP kinase were differentially affected depending on the time period of TGF-beta 1 pretreatment. After a short (30 min) TGF-beta 1 pretreatment, the bFGF-mediated increase in phosphorylation of p42mapk on threonine was inhibited, with no effect on the level of phosphotyrosine or decrease in the electrophoretic mobility of p42mapk. This suggests that TGF-beta 1 inhibited MAP kinase activity through the action of a serine/threonine phosphatase. In contrast, a longer TGF-beta 1 pretreatment (4 h) partly inhibited the bFGF-induced MAP kinase mobility shift and correlated with the inhibition of phosphorylation on both threonine and tyrosine, suggesting that long-term TGF-beta 1 treatment prevented activation of the MAP kinase cascade or directly blocked MAP kinase. The ability of long-term (4 h) but not short-term (30 min) TGF-beta 1 pretreatment to inhibit MAP kinase activity was completely dependent on protein synthesis and suggests that TGF-beta 1 inhibits MAP kinase activity by two distinct mechanisms. These findings provide a molecular basis for the growth-inhibitory action TGF-beta 1 on bFGF-induced mitogenic activity.
Berrou
E
E
Laboratoire de Physiopathologie Cellulaire et Moléculaire, INSERM 348, Hôpital Lariboisière, Paris, France.
Fontenay-Roupie
M
M
Quarck
R
R
McKenzie
F R
FR
Lévy-Toledano
S
S
Tobelem
G
G
Bryckaert
M
M
D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D013552:Swine; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D004247:DNA; D003513:Cycloheximide; D017871:Calcium-Calmodulin-Dependent Protein Kinases