Inhibition of protein synthesis in LLC-PK1 cells increases calcitonin-induced plasminogen-activator gene transcription and mRNA stability.
The peptide hormone calcitonin induces the accumulation of urokinase-type plasminogen activator (uPA) mRNA in pig kidney LLC-PK1 cells. By itself, inhibition of protein synthesis had a negligible effect on uPA mRNA accumulation. Inhibition of protein synthesis led to two superinductive effects: an increase in calcitonin-induced uPA mRNA accumulation over time, and a shift in the dose-response curve so that lower calcitonin doses became more potent. To explain these two superinductive effects of protein-synthesis inhibition on calcitonin treatment, we demonstrated that the inhibition of protein synthesis increased both calcitonin-induced uPA-gene transcription and uPA-mRNA stability. Different protein-synthesis inhibitors had similar actions, arguing against the possibility that the results were attributable to an anomalous action of a particular inhibitor. The superinductive effects of protein-synthesis inhibition could not be mimicked when a tumour promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA), was used instead of calcitonin as an inducer. Calcitonin and TPA exert their effects through different pathways, suggesting a clue to the mechanism of superinduction. Although inhibition of protein synthesis has been reported to increase transcription and mRNA stability in a number of other systems, the one described here appeared unique in combining both effects in the context of hormonal regulation.
D000818:Animals; D002116:Calcitonin / Q000494:pharmacology*; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D046911:Macromolecular Substances; D010960:Plasminogen Activators / Q000235:genetics*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*; D013552:Swine; D014158:Transcription, Genetic / Q000187:drug effects*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D046911:Macromolecular Substances; D012333:RNA, Messenger; D002116:Calcitonin; D003513:Cycloheximide; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator