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PMID: 7504627 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway.

The EMBO journal ·Vol. 12 ·No. 9 ·1993-09-00 ·Pages 3651-7

Weiss G, Goossen B, Doppler W, Fuchs D, Pantopoulos K, Werner-Felmayer G, Wachter H, Hentze MW

Abstract

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.

MeSH Terms
Amino Acid Oxidoreductases/biosynthesis,metabolism Animals Arginine/metabolism Base Sequence Cell Line Chloramphenicol O-Acetyltransferase/metabolism Gene Expression Regulation, Enzymologic Humans Iron/metabolism Iron-Regulatory Proteins Leukemia, Erythroblastic, Acute Macrophage Activation Macrophages/metabolism Mice Models, Biological Molecular Sequence Data Nitric Oxide/biosynthesis Nitric Oxide Synthase Oligodeoxyribonucleotides Protein Biosynthesis RNA Probes RNA, Messenger/biosynthesis,metabolism RNA-Binding Proteins/biosynthesis,metabolism Recombinant Fusion Proteins/metabolism Tumor Cells, Cultured
Chemicals
Iron-Regulatory Proteins Oligodeoxyribonucleotides RNA Probes RNA, Messenger RNA-Binding Proteins Recombinant Fusion Proteins Nitric Oxide Arginine Iron Nitric Oxide Synthase Amino Acid Oxidoreductases Chloramphenicol O-Acetyltransferase
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Weiss G
Gene Expression Programme, European Molecular Biology Laboratory, Heidelberg, Germany.
Goossen B
Doppler W
Fuchs D
Pantopoulos K
Werner-Felmayer G
Wachter H
Hentze M W
References (62)
62 references, click to expand
  1. Inactivation of macrophage nitric oxide synthase activity by NG-methyl-L-arginine.
    Biochem Biophys Res Commun. 1991 Jun 14;177(2):828-33 PMID: 2049105
  2. Progress in understanding the pathogenesis of the anemia of chronic disease.
    Blood. 1992 Oct 1;80(7):1639-47 PMID: 1391934
  3. Binding of apotransferrin to K562 cells: explanation of the transferrin cycle.
    Proc Natl Acad Sci U S A. 1983 Apr;80(8):2263-6 PMID: 6300904
  4. Iron withholding: a defense against infection and neoplasia.
    Physiol Rev. 1984 Jan;64(1):65-102 PMID: 6420813
  5. Hemin, chelatable iron, and the regulation of transferrin receptor biosynthesis.
    J Biol Chem. 1985 Nov 25;260(27):14862-6 PMID: 2997226
  6. Regulation of intracellular iron distribution in K562 human erythroleukemia cells.
    J Biol Chem. 1986 Apr 5;261(10):4587-93 PMID: 3457008
  7. Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible.
    J Clin Invest. 1986 Sep;78(3):790-7 PMID: 3745439
  8. Synthesis of nitrite and nitrate in murine macrophage cell lines.
    Cancer Res. 1987 Nov 1;47(21):5590-4 PMID: 3117354
  9. Oligoribonucleotide synthesis using T7 RNA polymerase and synthetic DNA templates.
    Nucleic Acids Res. 1987 Nov 11;15(21):8783-98 PMID: 3684574
  10. Identification of the iron-responsive element for the translational regulation of human ferritin mRNA.
    Science. 1987 Dec 11;238(4833):1570-3 PMID: 3685996
  11. Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5' untranslated region of ferritin heavy- and light-subunit mRNAs.
    Proc Natl Acad Sci U S A. 1988 Apr;85(7):2171-5 PMID: 3127826
  12. Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells.
    J Immunol. 1988 Apr 15;140(8):2829-38 PMID: 2451695
  13. Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation.
    Science. 1988 May 13;240(4854):924-8 PMID: 2452485
  14. A stem-loop in the 3' untranslated region mediates iron-dependent regulation of transferrin receptor mRNA stability in the cytoplasm.
    Cell. 1988 Jun 3;53(5):815-25 PMID: 3370673
  15. Binding of a cytosolic protein to the iron-responsive element of human ferritin messenger RNA.
    Science. 1988 Sep 2;241(4870):1207-10 PMID: 3413484
  16. Interactions of cationic lipid vesicles with negatively charged phospholipid vesicles and biological membranes.
    Biochemistry. 1988 May 31;27(11):3917-25 PMID: 3415963
  17. Nitric oxide: a cytotoxic activated macrophage effector molecule.
    Biochem Biophys Res Commun. 1988 Nov 30;157(1):87-94 PMID: 3196352
  18. The iron-responsive element is the single element responsible for iron-dependent translational regulation of ferritin biosynthesis. Evidence for function as the binding site for a translational repressor.
    J Biol Chem. 1988 Dec 15;263(35):19048-52 PMID: 3198610
  19. A model for the structure and functions of iron-responsive elements.
    Gene. 1988 Dec 10;72(1-2):201-8 PMID: 3266604
  20. Oxidation-reduction and the molecular mechanism of a regulatory RNA-protein interaction.
    Science. 1989 Apr 21;244(4902):357-9 PMID: 2711187
  21. Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation.
    Blood. 1989 Aug 1;74(2):844-51 PMID: 2502204
  22. A specific mRNA binding factor regulates the iron-dependent stability of cytoplasmic transferrin receptor mRNA.
    Cell. 1989 Jul 28;58(2):373-82 PMID: 2752428
  23. Purification of a specific repressor of ferritin mRNA translation from rabbit liver.
    J Biol Chem. 1989 Aug 15;264(23):13765-9 PMID: 2569464
  24. Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3' untranslated region of the mRNA.
    EMBO J. 1989 Dec 1;8(12):3693-9 PMID: 2583116
  25. Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor.
    J Biol Chem. 1989 Nov 25;264(33):19654-8 PMID: 2584186
  26. Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages.
    J Biol Chem. 1989 Dec 5;264(34):20496-501 PMID: 2584226
  27. Nitric oxide from L-arginine stimulates the soluble guanylate cyclase in adrenal glands.
    Biochem Biophys Res Commun. 1989 Dec 15;165(2):802-9 PMID: 2480784
  28. EPR demonstration of iron-nitrosyl complex formation by cytotoxic activated macrophages.
    Proc Natl Acad Sci U S A. 1990 Feb;87(3):1223-7 PMID: 2153975
  29. IFN-gamma-activated macrophages: detection by electron paramagnetic resonance of complexes between L-arginine-derived nitric oxide and non-heme iron proteins.
    Biochem Biophys Res Commun. 1990 Jan 15;166(1):119-25 PMID: 2154196
  30. Regulation of ferritin and transferrin receptor mRNAs.
    J Biol Chem. 1990 Mar 25;265(9):4771-4 PMID: 2156853
  31. Structural requirements of iron-responsive elements for binding of the protein involved in both transferrin receptor and ferritin mRNA post-transcriptional regulation.
    Nucleic Acids Res. 1990 Apr 11;18(7):1819-24 PMID: 2336358
  32. Manipulations of cellular iron metabolism for modulating normal and malignant cell proliferation: achievements and prospects.
    Blood. 1990 May 15;75(10):1903-19 PMID: 2186818
  33. Translational repression by a complex between the iron-responsive element of ferritin mRNA and its specific cytoplasmic binding protein is position-dependent in vivo.
    EMBO J. 1990 Dec;9(12):4127-33 PMID: 1701143
  34. Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts.
    J Exp Med. 1990 Dec 1;172(6):1599-607 PMID: 2124251
  35. Purification of a soluble isoform of guanylyl cyclase-activating-factor synthase.
    Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):365-9 PMID: 1703296
  36. Immune activation and the anaemia associated with chronic inflammatory disorders.
    Eur J Haematol. 1991 Feb;46(2):65-70 PMID: 1899833
  37. Signal transduction mechanisms involving nitric oxide.
    Biochem Pharmacol. 1991 Feb 15;41(4):485-90 PMID: 1847633
  38. Structural relationship between an iron-regulated RNA-binding protein (IRE-BP) and aconitase: functional implications.
    Cell. 1991 Mar 8;64(5):881-3 PMID: 2001588
  39. Homology between IRE-BP, a regulatory RNA-binding protein, aconitase, and isopropylmalate isomerase.
    Nucleic Acids Res. 1991 Apr 25;19(8):1739-40 PMID: 1903202
  40. Nitric oxide: physiology, pathophysiology, and pharmacology.
    Pharmacol Rev. 1991 Jun;43(2):109-42 PMID: 1852778
  41. Brain nitric oxide synthase is a biopterin- and flavin-containing multi-functional oxido-reductase.
    FEBS Lett. 1991 Aug 19;288(1-2):187-91 PMID: 1715290
  42. Inactivation of ribonucleotide reductase by nitric oxide.
    Biochem Biophys Res Commun. 1991 Aug 30;179(1):442-8 PMID: 1652957
  43. Iron depletion: a defense against intracellular infection and neoplasia.
    Life Sci. 1992;50(18):1289-97 PMID: 1560730
  44. Position is the critical determinant for function of iron-responsive elements as translational regulators.
    Mol Cell Biol. 1992 May;12(5):1959-66 PMID: 1569933
  45. Synthesis of nitric oxide from L-arginine: a recently discovered pathway induced by cytokines with antitumour and antimicrobial activity.
    Res Immunol. 1991 Sep;142(7):565-9; discussion 596-8 PMID: 1812549
  46. Modulation of the RNA-binding activity of a regulatory protein by iron in vitro: switching between enzymatic and genetic function?
    Proc Natl Acad Sci U S A. 1992 May 15;89(10):4554-8 PMID: 1584791
  47. Coordination of cellular iron metabolism by post-transcriptional gene regulation.
    J Inorg Biochem. 1992 Aug 15-Sep;47(3-4):183-95 PMID: 1431880
  48. Cloned, expressed rat cerebellar nitric oxide synthase contains stoichiometric amounts of heme, which binds carbon monoxide.
    Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11141-5 PMID: 1280819
  49. Purification and characterization of cytosolic aconitase from beef liver and its relationship to the iron-responsive element binding protein.
    Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11730-4 PMID: 1334546
  50. Cellular regulation of the iron-responsive element binding protein: disassembly of the cubane iron-sulfur cluster results in high-affinity RNA binding.
    Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11735-9 PMID: 1281544
  51. Biochemistry of nitric oxide and its redox-activated forms.
    Science. 1992 Dec 18;258(5090):1898-902 PMID: 1281928
  52. Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide-mediated formation of cyclic GMP.
    J Biol Chem. 1993 Jan 25;268(3):1842-6 PMID: 7678411
  53. Regulating the fate of mRNA: the control of cellular iron metabolism.
    Cell. 1993 Jan 15;72(1):19-28 PMID: 8380757
  54. Ca2+/calmodulin-dependent nitric oxide synthase activity in the human cervix carcinoma cell line ME-180.
    Biochem J. 1993 Jan 15;289 ( Pt 2):357-61 PMID: 7678733
  55. Translational control of 5-aminolevulinate synthase mRNA by iron-responsive elements in erythroid cells.
    J Biol Chem. 1993 Mar 15;268(8):5974-8 PMID: 8449958
  56. Iron regulatory factor expressed from recombinant baculovirus: conversion between the RNA-binding apoprotein and Fe-S cluster containing aconitase.
    Nucleic Acids Res. 1993 Mar 25;21(6):1457-61 PMID: 8464737
  57. Translational regulation by mRNA/protein interactions in eukaryotic cells: ferritin and beyond.
    Bioessays. 1993 Feb;15(2):85-90 PMID: 8471060
  58. Iron modulates interferon-gamma effects in the human myelomonocytic cell line THP-1.
    Exp Hematol. 1992 Jun;20(5):605-10 PMID: 1587306
  59. Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster.
    Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7536-40 PMID: 1502165
  60. Nitric oxide, a novel biologic messenger.
    Cell. 1992 Sep 4;70(5):705-7 PMID: 1381285
  61. Nitric oxide as a secretory product of mammalian cells.
    FASEB J. 1992 Sep;6(12):3051-64 PMID: 1381691
  62. Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA.
    EMBO J. 1991 Jul;10(7):1903-9 PMID: 2050126
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1993-09-00
Pages
3651-7
Language
English
Region
England
NLM ID
8208664
PMCID
PMC413641
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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