The role of nitric-oxide synthase in the regulation of UVB light-induced phosphorylation of the α subunit of eukaryotic initiation factor 2

Wei Lu, Csaba F. László, Zhixin Miao, Hao Chen, Shiyong Wu

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

UV light induces phosphorylation of the α subunit of the eukaryotic initiation factor 2 (eIF2α) and inhibits global protein synthesis. Both eIF2 kinases, protein kinase-like endoplasmic reticulum kinase (PERK) and general control of nonderepressible protein kinase 2 (GCN2), have been shown to phosphorylate eIF2α in response to UV irradiation. However, the roles of PERK and GCN2 in UV-induced eIF2α phosphorylation are controversial. The one or more upstream signaling pathways that lead to the activation of PERK or GCN2 remain unknown. In this report we provide data showing that both PERK and GCN2 contribute to UV-induced eIF2α phosphorylation in human keratinocyte (HaCaT) and mouse embryonic fibroblast cells. Reduction of expression of PERK or GCN2 by small interfering RNA decreases phosphorylation of eIF2α after UV irradiation. These data also show that nitric-oxide synthase (NOS)-mediated oxidative stress plays a role in regulation of eIF2α phosphorylation upon UV irradiation. Treating the cells with the broad NOS inhibitor NG-methyl-L-arginine, the free radical scavenger N-acetyl-L-cysteine, or the NOS substrate L-arginine partially inhibits UV-induced eIF2α phosphorylation. The results presented above led us to propose that NOS mediates UV-induced eIF2α phosphorylation by activation of both PERK and GCN2 via oxidative stress and L-arginine starvation signaling pathways.

Original languageEnglish (US)
Pages (from-to)24281-24288
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number36
DOIs
StatePublished - Sep 4 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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