Translational control of inducible nitric oxide synthase by p38 MAPK in islet β-cells

Yurika Nishiki, Adeola Adewola, Masayuki Hatanaka, Andrew T. Templin, Bernhard Maier, Raghavendra G. Mirmira

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Abstract

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

Original languageEnglish (US)
Pages (from-to)336-349
Number of pages14
JournalMolecular Endocrinology
Volume27
Issue number2
DOIs
StatePublished - Feb 1 2013

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p38 Mitogen-Activated Protein Kinases
Nitric Oxide Synthase Type II
Islets of Langerhans
Cytokines
Aconitate Hydratase
omega-N-Methylarginine
Messenger RNA
Polyribosomes
Protein Biosynthesis
Cycloheximide
Transducers
Oxygen Consumption
Insulin
Gene Expression
eukaryotic translation initiation factor 5A
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Translational control of inducible nitric oxide synthase by p38 MAPK in islet β-cells. / Nishiki, Yurika; Adewola, Adeola; Hatanaka, Masayuki; Templin, Andrew T.; Maier, Bernhard; Mirmira, Raghavendra G.

In: Molecular Endocrinology, Vol. 27, No. 2, 01.02.2013, p. 336-349.

Research output: Contribution to journalArticle

Nishiki, Yurika ; Adewola, Adeola ; Hatanaka, Masayuki ; Templin, Andrew T. ; Maier, Bernhard ; Mirmira, Raghavendra G. / Translational control of inducible nitric oxide synthase by p38 MAPK in islet β-cells. In: Molecular Endocrinology. 2013 ; Vol. 27, No. 2. pp. 336-349.
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