Linked Life Data

12044177

Source:http://linkedlifedata.com/resource/pubmed/id/12044177

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2002-6-4
pubmed:abstractText
Posttranscriptional regulation of iron homeostasis involves, among other factors, a reversible conversion of the Fe-S enzyme cytoplasmic aconitase to a mRNA-binding iron regulatory protein (IRP-1) that lacks an Fe-S cluster. Previous studies have shown that aconitase/IRP-1 may be a target of *NO or peroxynitrite (ONOO(-)), formed after reaction of *NO with superoxide anion (O(2)(*-)); however, the mechanisms and consequences of such interactions have remained uncertain. In this study, recombinant aconitase/IRP-1 was exposed to SIN-1, whose thermal decomposition releases *NO and O(2)(*-). Results showed that SIN-1 was able to induce concomitant inactivation of aconitase and activation of IRP-1, attributable to cluster disassembly induced by ONOO(-). SIN-1 was used also in lysates of J774A.1 mouse macrophages grown under control conditions, or subjected to iron loading or starvation by treatment with hemin or desferrioxamine, respectively. Three lines of evidence confirmed that ONOO(-) activated IRP-1 by removing iron from the Fe-S cluster of cytoplasmic aconitase. First, IRP-1 activation was accompanied by iron release and loss of aconitase activity. Second, aconitase activity was recovered by reassembling Fe-S clusters with cysteine and ferrous ammonium sulfate. Third, iron release and IRP-1 activation were observed in lysates from control or iron-loaded macrophages, containing increasing levels of Fe-S clusters, but not in lysates from iron-starved macrophages, in which aconitase had already undergone cluster disassembly and switched to IRP-1. *NO was less efficient than ONOO(-) in attacking the Fe-S cluster of cytoplasmic aconitase; in fact, SIN-1-dependent iron release and IRP-1 activation were diminished by superoxide dismutase, which scavenged O(2)(*-) before it reacted with *NO to form ONOO(-). Under comparable conditions, however, both *NO and ONOO(-) inactivated an IRP-2 unable to assemble an Fe-S cluster. These results indicate that *NO and ONOO(-) may activate IRP-1 by attacking the Fe-S cluster of cytoplasmic aconitase, while also inactivating the cluster-deficient IRP-2. Such divergent actions offer clues to explain links between iron homeostasis and reactive nitrogen species in macrophages involved in inflammation or other pathophysiologic conditions.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/3-morpholino-sydnonimine, http://linkedlifedata.com/resource/pubmed/chemical/Aconitate Hydratase, http://linkedlifedata.com/resource/pubmed/chemical/Ferrous Compounds, http://linkedlifedata.com/resource/pubmed/chemical/Ferrozine, http://linkedlifedata.com/resource/pubmed/chemical/Iron Regulatory Protein 1, http://linkedlifedata.com/resource/pubmed/chemical/Iron Regulatory Protein 2, http://linkedlifedata.com/resource/pubmed/chemical/Iron-Regulatory Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Iron-Sulfur Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Molsidomine, http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide, http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide Donors, http://linkedlifedata.com/resource/pubmed/chemical/Peroxynitrous Acid, http://linkedlifedata.com/resource/pubmed/chemical/RNA-Binding Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Superoxides
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
11
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7435-42
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:12044177-Aconitate Hydratase, pubmed-meshheading:12044177-Animals, pubmed-meshheading:12044177-Cell Line, pubmed-meshheading:12044177-Cell-Free System, pubmed-meshheading:12044177-Cytoplasm, pubmed-meshheading:12044177-Escherichia coli, pubmed-meshheading:12044177-Ferrous Compounds, pubmed-meshheading:12044177-Ferrozine, pubmed-meshheading:12044177-Iron Regulatory Protein 1, pubmed-meshheading:12044177-Iron Regulatory Protein 2, pubmed-meshheading:12044177-Iron-Regulatory Proteins, pubmed-meshheading:12044177-Iron-Sulfur Proteins, pubmed-meshheading:12044177-Macrophages, pubmed-meshheading:12044177-Mice, pubmed-meshheading:12044177-Molsidomine, pubmed-meshheading:12044177-Nitric Oxide, pubmed-meshheading:12044177-Nitric Oxide Donors, pubmed-meshheading:12044177-Peroxynitrous Acid, pubmed-meshheading:12044177-Protein Processing, Post-Translational, pubmed-meshheading:12044177-RNA-Binding Proteins, pubmed-meshheading:12044177-Recombinant Proteins, pubmed-meshheading:12044177-Superoxides
pubmed:year
2002
pubmed:articleTitle
Nitric oxide and peroxynitrite activate the iron regulatory protein-1 of J774A.1 macrophages by direct disassembly of the Fe-S cluster of cytoplasmic aconitase.
pubmed:affiliation
Institute of General Pathology, University of Milan, via Mangiagalli 31, 20133 Milan, Italy. gaetano.cairo@unimi.it
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't