Article: article from journal or magazin.
Okadaic acid-dependent induction of the urokinase-type plasminogen activator gene associated with stabilization and autoregulation of c-Jun.
Journal of Biological Chemistry
We have previously shown that the tumor promoter okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A, transcriptionally induces the urokinase-type plasminogen activator (uPA) gene in LLC-PK1 cells. This induction occurs independently of the protein kinase C- and cAMP-dependent signaling pathways. Here we show that a sequence located 2.0 kilobases upstream of the uPA gene, which resembles an AP-1-recognition sequence, mediates the action of OA. DNA-protein interaction studies, together with mRNA and protein analyses, indicate that c-Jun, but not c-Fos, is involved in OA-dependent uPA gene induction. The appearance of high levels of uPA mRNA and DNA binding activity of c-Jun to the AP-1-like site correspond to the appearance of c-Jun accumulation, suggesting that c-Jun accumulation is a critical event in OA-dependent uPA gene induction. c-Jun protein levels increase significantly between 100 and 160 min following OA treatment, whereas c-Jun translation increases only slightly in this time frame, suggesting that post-translation mechanisms are also involved in c-Jun accumulation. Pulse-chase analyses shows that OA specifically stabilizes c-Jun. We discuss our results with respect to the possibility that protein phosphatase 2A maintains c-Jun in its down-regulated state in LLC-PK1 cells.
8-Bromo Cyclic Adenosine Monophosphate/pharmacology, Animals, Base Sequence, Binding Sites, Blotting, Southern, Blotting, Western, Cell Line, Chloramphenicol O-Acetyltransferase/biosynthesis, Chloramphenicol O-Acetyltransferase/metabolism, Colchicine/pharmacology, Cycloheximide/pharmacology, DNA Mutational Analysis, DNA-Binding Proteins/metabolism, Enzyme Induction, Ethers, Cyclic/pharmacology, Gene Expression Regulation, Enzymologic/drug effects, Genes, Regulator, Homeostasis, Kinetics, Molecular Sequence Data, Nuclear Proteins/isolation & purification, Nuclear Proteins/metabolism, Okadaic Acid, Oligodeoxyribonucleotides/chemistry, Oligodeoxyribonucleotides/metabolism, Oxazoles/pharmacology, Phosphorylation, Protein Phosphatase 2, Protein Tyrosine Phosphatases/antagonists & inhibitors, Proto-Oncogene Proteins c-jun/biosynthesis, Proto-Oncogene Proteins c-jun/metabolism, Time Factors, Transcriptional Activation, Transfection, Urokinase-Type Plasminogen Activator/biosynthesis, Urokinase-Type Plasminogen Activator/genetics
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