Iron regulatory protein-independent regulation of ferritin synthesis by nitrogen monoxide.
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.
Mikhael
Marc
M
Department of Physiology, McGill University, Montreal, Canada.
Kim
Sangwon F
SF
Schranzhofer
Matthias
M
Soe-Lin
Shan
S
Lin
Shan S
SS
Sheftel
Alex D
AD
Mullner
Ernst W
EW
Ponka
Prem
P
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005290:Ferric Compounds / Q000494:pharmacology; D005293:Ferritins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D035925:Iron-Regulatory Proteins / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D011485:Protein Binding; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis
D005290:Ferric Compounds; D035925:Iron-Regulatory Proteins; D020030:Nitric Oxide Donors; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D009599:Nitroprusside; D009569:Nitric Oxide; D007371:Interferon-gamma; D005293:Ferritins; C013531:ferric ammonium citrate