title: Transforming growth factor beta 1 inhibits mitogen-activated protein kinase induced by basic fibroblast growth factor in smooth muscle cells.
abstract: 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.
authors.affiliation: Laboratoire de Physiopathologie Cellulaire et Moléculaire, INSERM 348, Hôpital Lariboisière, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Berrou
authors.forename: M
authors.initials: M
authors.lastname: Fontenay-Roupie
authors.forename: R
authors.initials: R
authors.lastname: Quarck
authors.forename: F R
authors.initials: FR
authors.lastname: McKenzie
authors.forename: S
authors.initials: S
authors.lastname: Lévy-Toledano
authors.forename: G
authors.initials: G
authors.lastname: Tobelem
authors.forename: M
authors.initials: M
authors.lastname: Bryckaert
mesh_terms: 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*
chemical_list: D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D004247:DNA; D003513:Cycloheximide; D017871:Calcium-Calmodulin-Dependent Protein Kinases