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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.

SUBMITTER: Berrou E 

PROVIDER: S-EPMC1217318 | biostudies-other | 1996 May

REPOSITORIES: biostudies-other

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