Disease relevance of Ireb2

• Differential regulation of IRP1 and IRP2 by nitric oxide in rat hepatoma cells [1].

High impact information on Ireb2

• Our data indicate that IRP1 and IRP2 are differentially regulated by NO. in rat hepatoma cells, suggesting a role for IRP1 in the regulation of iron homeostasis in vivo during hepatic inflammation [1].
• The role of NO. in the regulation of IRP1 and IRP2 in rat hepatoma cells was investigated by using the NO.-generating compound S-nitroso-N-acetylpenicillamine (SNAP), or by stimulating cells with multiple cytokines and lipopolysaccharide (LPS) to induce NO. production [1].
• Transferrin receptor (TfR) and ferritin, key proteins of cellular iron metabolism, are coordinately and divergently controlled by cytoplasmic proteins (iron regulatory proteins, IRP-1 and IRP-2) that bind to conserved mRNA motifs called iron-responsive elements (IRE) [2].
• Under these circumstances, growth-dependent signals may activate ferritin gene transcription and at the same time hamper the ability of activated IRP-2 to repress translation of ferritin mRNAs, thus preserving for growing liver cells an essential iron-storage compartment [2].
• Because RNA bandshift assays showed a fourfold increase in IRP-2 binding activity after CCl4 administration, activated IRP in regenerating liver seemed unable to prevent ferritin mRNAs binding to polysomes [2].

Chemical compound and disease context of Ireb2

• Given the important relationship between O2 and iron (Fenton chemistry) a study was undertaken to characterize the effects of hypoxia, as well as subsequent reoxygenation, on the iron-regulatory proteins 1 and 2 (IRP1 and IRP2) in a rat hepatoma cell line [3].

Biological context of Ireb2

• The 3'-untranslated region of rat IRP2 contains multiple polyadenylation signals, two of which could account for the 4.0-kb and 3.7-kb mRNAs [4].
• The derived amino acid sequence of rat IPR2 is 93% identical with that of human IRP2 and is present in lower eukaryotes, indicating that IRP2 is highly conserved [4].
• A considerable increase in ferritin mRNA levels showed that DOX acted at transcriptional level, but an additional potential mechanism was identified as the down-regulation of iron regulatory protein-2, post-transcriptional inhibitor of ferritin synthesis [5].
• Ferritin expression is regulated mainly at post-transcriptional level by iron regulatory proteins (IRP1 and IRP2) that bind specific RNA sequences (IREs) in the 5'untranslated region of ferritin mRNA [6].
• Glial and neuronal expression of IRP1, IRP2, DMT-1, and TfR in cortex, hippocampal subareas and striatum increased over time, but showed variability in cell number and intensity of expression based on brain region, cell type, and age [7].

Anatomical context of Ireb2

• IRP2 is ubiquitously expressed in rat tissues, the highest amounts present in skeletal muscle and heart [4].
• In iron-deficient tissues and cultured cells, both IRP1 and IRP2 are activated for high affinity IRE binding [8].
• Converse modulation of IRP1 and IRP2 by immunological stimuli in murine RAW 264.7 macrophages [9].
• To determine the mechanism by which iron decreases IRP2 levels, we studied IRP2 regulation by iron in rat hepatoma and human HeLa cells [10].
• The cerebral blood vessels and ependymal cells strongly expressed IRP1, IRP2, and DMT-1 as early as PND 5 [7].

Associations of Ireb2 with chemical compounds

• Manganese exposure altered the dynamics of IRP-1 binding and the intracellular abundance of IRP-2, and altered the cellular abundance of transferrin receptor, ferritin, and mitochondrial aconitase protein levels [11].
• The decrease in IRP1 RNA binding activity occurs by a switch between apoprotein and 4Fe-4S forms, without changes in IRP1 levels, whereas the decrease in IRP2 RNA binding activity reflects a reduction in IRP2 levels [10].
• We show that stimulation of mouse RAW 264.7 macrophage-like cells increased IRP1 IRE binding activity 4-fold, whereas IRP2 activity decreased 2-fold 8 h after interferon-gamma/lipopolysaccharide treatment [9].
• Mobility shift assays with liver extracts and IRP1 or IRP2-specific probes indicate that only IRP1 responds to H(2)O(2) [8].
• Like IRP1, the RNA-binding activity of IRP2 was sensitive to inactivation by N-ethylmaleimide (NEM) or 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), indicating IRP2 contains a cysteine(s) that is (are) necessary for RNA binding [12].

Regulatory relationships of Ireb2

• Such increases in tissue iron content may be attributed to the stabilisation of IRP-2 by aluminium thereby promoting transferrin receptor synthesis while blocking ferritin synthesis [13].

References