Control of transferrin receptor expression via nitric oxide-mediated modulation of iron-regulatory protein 2.
Cellular iron storage and uptake are coordinately regulated post-transcriptionally by cytoplasmic factors, iron-regulatory proteins 1 and 2 (IRP-1 and IRP-2). When iron in the intracellular transit pool is scarce, IRPs bind to iron-responsive elements (IREs) in the 5'-untranslated region of the ferritin mRNA and 3'-untranslated region of the transferrin receptor (TfR) mRNA. Such binding inhibits translation of ferritin mRNA and stabilizes the mRNA for TfR, whereas the opposite scenario develops when iron in the transit pool is plentiful. However, we (Richardson, D. R., Neumannova, V., Nagy, E., and Ponka, P. (1995) Blood 86, 3211-3219) and others reported that the binding of IRPs to IREs can also be modulated by nitric oxide (NO). In this study, we showed that a short exposure of RAW 264.7 cells (a murine macrophage cell line) to the NO(+) donor, sodium nitroprusside (SNP), caused a significant decrease in IRP-2 binding to the IREs followed by IRP-2 degradation and that these changes occurred without affecting IRP-1 binding. The SNP-mediated degradation of IRP-2 in RAW 264.7 cells could be prevented by MG-132 or lactacystin, known inhibitors of proteasome-dependent protein degradation. A SNP-mediated decrease in IRP-2 binding and levels was associated with a dramatic decrease in TfR mRNA levels and an increase in ferritin synthesis. Importantly, the proteasome inhibitor MG-132 prevented the SNP-mediated decrease in TfR mRNA levels. These observations suggest that IRP-2 can play an important role in controlling transferrin receptor expression.
Kim
S
S
Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2.
Ponka
P
P
D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007501:Iron / Q000378:metabolism; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics*; D013997:Time Factors; D051154:Wnt2 Protein
D005290:Ferric Compounds; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011518:Proto-Oncogene Proteins; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011990:Receptors, Transferrin; C110881:S-nitro-N-acetylpenicillamine; D051154:Wnt2 Protein; D009599:Nitroprusside; D009569:Nitric Oxide; D007501:Iron; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D010396:Penicillamine; D003676:Deferoxamine; C013531:ferric ammonium citrate