Cell- and gene-specific interactions between signal transduction pathways revealed by okadaic acid. Studies on the plasminogen activating system.
The potential contribution of serine/threonine-specific protein phosphatases in the transcriptional regulation of plasminogen activator and plasminogen activator inhibitor gene expression was explored in human HT-1080 fibrosarcoma and U-937 monocyte-like cells using okadaic acid, a potent and specific inhibitor of phosphatases 1 and 2A (PP1 and PP2A). In both cell types okadaic acid induced plasminogen activator type 2 (PAI-2) gene transcription and mRNA and potentiated induction mediated by phorbol-12-myristate-13-acetate and tumor necrosis factor. Okadaic acid-mediated induction of PAI-2 was inhibited by 8-bromo-cAMP in HT-1080 cells but not in U-937 cells. Okadaic acid had opposite effects on urokinase (u-PA) gene expression in the two cell lines; u-PA mRNA and gene transcription was suppressed in HT-1080 cells but transiently induced in U-937 cells. Tissue-type PA (t-PA) mRNA, although undetectable in U-937 cells, was also suppressed by okadaic acid in HT-1080 cells. This effect was selective, as constitutive and phorbol-12-myristate-13-acetate-mediated expression of plasminogen activator inhibitor type 1 mRNA was not modulated by okadaic acid in either cell type. These results indicate that PP1 and PP2A protein phosphatases are involved in signal transduction pathways modulating PAI-2, u-PA, and t-PA, and furthermore, that okadaic acid interaction with the protein kinase C and A pathways are gene- and cell type-specific.
Medcalf
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RL
Central Hematology Laboratory, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D002460:Cell Line; D004988:Ethers, Cyclic / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D003012:Microbial Collagenase / Q000235:genetics; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism*; D015849:Plasminogen Inactivators / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D004988:Ethers, Cyclic; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019319:Okadaic Acid; D015124:8-Bromo Cyclic Adenosine Monophosphate; D010958:Plasminogen; D010749:Phosphoprotein Phosphatases; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D003012:Microbial Collagenase; D013755:Tetradecanoylphorbol Acetate