Translational Control of Inducible Nitric Oxide Synthase by p38 MAPK in Islet β-Cells

摘要: The MAPKs are transducers of extracellular signals such as proinflammatory cytokines. In islet β-cells, cytokines acutely activate expression the Nos2 gene encoding inducible nitric oxide synthase (iNOS), which ultimately impairs insulin release. Because iNOS production can also be regulated posttranscriptionally, we asked whether participate in posttranscriptional regulatory events β-cells and primary islets response to cytokine signaling. We show that reduce cellular oxygen consumption rate impair aconitase activity. Inhibition with l-NMMA or inhibition mRNA translation GC7 [an inhibitor eukaryotic initiation factor 5A (eIF5A) activity] reversed these defects, did p38 MAPK by PD169316. Although had no effect on nuclear translocation κB abundance transcripts during immediate period after exposure, its knockdown resulted significant reduction protein, a finding suggestive permissive role for translation. Polyribosomal profiling experiments using INS-1 revealed remained associated polyribosomes setting inhibition, manner similar seen blockade translational elongation cycloheximide. Consistent elongation, activity is required part activation eIF5A promoting hypusination. Our results suggest novel signaling pathway promotes via regulation