Nitric oxide signaling to iron-regulatory protein: direct control of ferritin mRNA translation and transferrin receptor mRNA stability in transfected fibroblasts.
Iron-regulatory protein (IRP) is a master regulator of cellular iron homeostasis. Expression of several genes involved in iron uptake, storage, and utilization is regulated by binding of IRP to iron-responsive elements (IREs), structural motifs within the untranslated regions of their mRNAs. IRP-binding to IREs is controlled by cellular iron availability. Recent work revealed that nitric oxide (NO) can mimic the effect of iron chelation on IRP and on ferritin mRNA translation, whereas the stabilization of transferrin receptor mRNA following NO-mediated IRP activation could not be observed in gamma-interferon/lipopolysaccharide-stimulated murine macrophages. In this study, we establish the function of NO as a signaling molecule to IRP and as a regulator of mRNA translation and stabilization. Fibroblasts with undetectable levels of endogenous NO synthase activity were stably transfected with a cDNA encoding murine macrophage inducible NO synthase. Synthesis of NO activates IRE binding, which in turn represses ferritin mRNA translation and stabilizes transferrin receptor mRNA against targeted degradation. Furthermore, iron starvation and NO release are shown to be independent signals to IRP. The posttranscriptional control of iron metabolism is thus intimately connected with the NO pathways.
Pantopoulos
K
K
Gene Expression Programme, European Molecular Biology Laboratory, Heidelberg, Germany.
Hentze
M W
MW
D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D005293:Ferritins / Q000235:genetics*; D005347:Fibroblasts; D005786:Gene Expression Regulation; D007501:Iron / Q000502:physiology; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000502:physiology*; D011990:Receptors, Transferrin / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D014162:Transfection
D004268:DNA-Binding Proteins; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011990:Receptors, Transferrin; D009569:Nitric Oxide; D005293:Ferritins; D007501:Iron; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases