sub:provenance {
  beldoc: dce:description "Approximately 61,000 statements." ;
    dce:rights "Copyright (c) 2011-2012, Selventa. All rights reserved." ;
    dce:title "BEL Framework Large Corpus Document" ;
    pav:authoredBy sub:_4 ;
    pav:version "20131211" .
  sub:_3 prov:value "With the use of fibroblasts, hepatoma cells, and macrophages in culture, NO has been shown to increase IRP RNA-binding activity, resulting in increased TfR-1 expression and reduced ferritin translation.1-5 The mechanism behind this increase in IRP RNA- binding activity may be a result of the NO-mediated depletion of cellular iron or the ability of NO to directly disassemble the [4Fe-4S] cluster of IRP-1 to increase RNA-binding activity.1,2 However, these studies con- flict with other investigations involving macrophages showing that inflammation or incubation with interferon /lipopolysaccharide leads to marked NO production that stimulates ferritin synthesis and decreases TfR-1 mRNA levels.6-10 This effect was caused by NO as inhibitors of nitric oxide synthase prevented the response. 10 Moreover, the increase in ferritin and decrease in TfR-1 expression were mediated by IRP-2, evidenced by a marked decrease in its RNA-binding activity.8-10 The findings of recent studies9,10 have suggested that the different effects of NO described above are a result of the various redox-related states of this molecule generated under different conditions, eg, the nitrosonium ion [NO+] and nitric oxide [NO-]. For instance, the effect of NO in mediating increased IRP RNA binding activity may be mediated by NO-; as it avidly binds iron and could result in iron release from IRP-1 and the cell.10 Exposure of macrophages to inflammatory cytokines may generate NO, which then S-nitrosylates IRP-2 and results in its degradation, leading to increased ferritin translation.10 However, further studies are required to confirm this hypothesis, as there is no direct evidence that IRP-2 is S-nitrosylated by NO The effects of hypoxia on iron metabolism can also be at least partly linked to the changes in RNA-binding activity of the IRPs. Indeed, IRP-1 RNA-binding activity has been shown to decrease in macrophages and hepatoma cells during hypoxia,11,12 and these conditions are known to increase ferritin expression.13" ;
    prov:wasQuotedFrom pubmed:12761471 .
  sub:_4 rdfs:label "Selventa" .
  sub:assertion prov:hadPrimarySource pubmed:12761471 ;
    prov:wasDerivedFrom beldoc: , sub:_3 .
}