Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway.
Nitric oxide (NO) produced from L-arginine by NO synthases (NOS) is a transmitter known to be involved in diverse biological processes, including immunomodulation, neurotransmission and blood vessel dilatation. We describe a novel role of NO as a signaling molecule in post-transcriptional gene regulation. We demonstrate that induction of NOS in macrophage and non-macrophage cell lines activates RNA binding by iron regulatory factor (IRFs), the central trans regulator of mRNAs involved in cellular iron metabolism. NO-induced binding of IRF to iron-responsive elements (IRE) specifically represses the translation of transfected IRE-containing indicator mRNAs as well as the biosynthesis of the cellular iron storage protein ferritin. These findings define a new biological function of NO and identify a regulatory connection between the NO/NOS pathway and cellular iron metabolism.
Weiss
G
G
Gene Expression Programme, European Molecular Biology Laboratory, Heidelberg, Germany.
Goossen
B
B
Doppler
W
W
Fuchs
D
D
Pantopoulos
K
K
Werner-Felmayer
G
G
Wachter
H
H
Hentze
M W
MW
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007501:Iron / Q000378:metabolism; D035925:Iron-Regulatory Proteins; D004915:Leukemia, Erythroblastic, Acute; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase; D009838:Oligodeoxyribonucleotides; D014176:Protein Biosynthesis; D015347:RNA Probes; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured
D035925:Iron-Regulatory Proteins; D009838:Oligodeoxyribonucleotides; D015347:RNA Probes; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D009569:Nitric Oxide; D001120:Arginine; D007501:Iron; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D015500:Chloramphenicol O-Acetyltransferase