Differential mechanisms of plasminogen activator inhibitor-1 gene activation by transforming growth factor-beta and tumor necrosis factor-alpha in endothelial cells
| Autor: | Y Q, Chen, J, Sloan-Lancaster, D T, Berg, M A, Richardson, B, Grinnell, J, Tseng-Crank |
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| Rok vydání: | 2002 |
| Předmět: |
Mitogen-Activated Protein Kinase 1
Transcriptional Activation Mitogen-Activated Protein Kinase 3 MAP Kinase Signaling System Tumor Necrosis Factor-alpha Recombinant Fusion Proteins JNK Mitogen-Activated Protein Kinases NF-kappa B p38 Mitogen-Activated Protein Kinases Enzyme Activation Transforming Growth Factor beta1 Gene Expression Regulation Genes Reporter Transforming Growth Factor beta Plasminogen Activator Inhibitor 1 Humans Endothelium Vascular RNA Messenger Mitogen-Activated Protein Kinases Luciferases Promoter Regions Genetic Cells Cultured |
| Zdroj: | Thrombosis and haemostasis. 86(6) |
| ISSN: | 0340-6245 |
| Popis: | Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (SERPIN) specific for tissue-type and urokinase-like plasminogen activators. High plasma PAI-1 activity is a risk factor for thrombotic diseases. Due to the short half-life of PAI-1, regulation of PAI-1 gene expression and secretion of active PAI-1 into the blood stream is important for hemostatic balance. We have investigated transcriptional control of PAI-1 gene expression in bovine aortic endothelial cells (BAECs) and human cell lines using PAI-1 5' promoter-luciferase reporter assays. Contrary to the cytokine-induced up-regulation of PAI-1 mRNA and protein levels, we found that only transforming growth factor-beta (TGF-beta) was efficient in inducing PAI-1 promoter activation. Tissue necrosis factor-alpha (TNF-alpha) induced a small luciferase activity with the 2.5 kb PAI-1 promoter, but not with the PAI-800/4G/5G and p3TP-lux promoters. Next we investigated whether a lack of response to TNF-alpha was due to deficient signaling pathways. BAECs responded to TNF-alpha with robust NFkappaB promoter activation. TGF-beta activated the p38 MAP kinase, while TNF-alpha activated both the SAPK/JNK and p38 MAP kinases. The ERK1/2 MAP kinases were constitutively activated in BAECs. BAEC therefore responded to TNF-alpha stimulation with activation of the MAP kinases and the NFkappaB transcriptional factors. We further measured the messenger RNA stability under the influence by TGF-beta and TNF-alpha and found no difference. PAI-1 gene activation by TNF-alpha apparently is yet to be defined for the location of the response element and/or the signaling pathway, while TGF-beta is the most important cytokine for PAI-1 transcriptional activation through its 5' proximal promoter. |
| Databáze: | OpenAIRE |
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