Iron regulatory protein-independent regulation of ferritin synthesis by nitrogen monoxide

Marc Mikhael, Sangwon F. Kim, Matthias Schranzhofer, Shan S. Lin, Alex D. Sheftel, Ernst W. Mullner, Prem Ponka

Research output: Contribution to journalArticlepeer-review

Abstract

The discovery of iron-responsive elements (IREs), along with the identification of iron regulatory proteins (IRP1, IRP2), has provided a molecular basis for our current understanding of the remarkable post-transcriptional regulation of intracellular iron homeostasis. In iron-depleted conditions, IRPs bind to IREs present in the 5′-UTR of ferritin mRNA and the 3′-UTR of transferrin receptor (TfR) mRNA. Such binding blocks the translation of ferritin, the iron storage protein, and stabilizes TfR mRNA, whereas the opposite scenario develops when iron in the intracellular transit pool is plentiful. Nitrogen monoxide (commonly designated nitric oxide; NO), a gaseous molecule involved in numerous functions, is known to affect cellular iron metabolism via the IRP/IRE system. We previously demonstrated that the oxidized form of NO, NO+, causes IRP2 degradation that is associated with an increase in ferritin synthesis [Kim, S & Ponka, P (2002) Proc Natl Acad Sci USA99, 12214-12219]. Here we report that sodium nitroprusside (SNP), an NO+ donor, causes a dramatic and rapid increase in ferritin synthesis that initially occurs without changes in the RNA-binding activities of IRPs. Moreover, we demonstrate that the translational efficiency of ferritin mRNA is significantly higher in cells treated with SNP compared with those incubated with ferric ammonium citrate, an iron donor. Importantly, we also provide definitive evidence that the iron moiety of SNP is not responsible for such changes. These results indicate that SNP-mediated increase in ferritin synthesis is, in part, due to an IRP-independent and NO+-dependent post-transcriptional, regulatory mechanism.

Original languageEnglish (US)
Pages (from-to)3828-3836
Number of pages9
JournalFEBS Journal
Volume273
Issue number16
DOIs
StatePublished - Aug 2006
Externally publishedYes

Keywords

  • Ferritin
  • Iron
  • Iron regulatory proteins
  • NO
  • Nitrogen monoxide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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