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Gene Review

Ireb2  -  iron responsive element binding protein 2

Rattus norvegicus

Synonyms: IRE-BP 2, IRP2, Iron regulatory protein 2, Iron-responsive element-binding protein 2, Irp2
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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


  1. Differential regulation of IRP1 and IRP2 by nitric oxide in rat hepatoma cells. Phillips, J.D., Kinikini, D.V., Yu, Y., Guo, B., Leibold, E.A. Blood (1996) [Pubmed]
  2. Lack of coordinate control of ferritin and transferrin receptor expression during rat liver regeneration. Cairo, G., Tacchini, L., Pietrangelo, A. Hepatology (1998) [Pubmed]
  3. Regulation of iron regulatory protein 1 during hypoxia and hypoxia/reoxygenation. Hanson, E.S., Leibold, E.A. J. Biol. Chem. (1998) [Pubmed]
  4. Characterization and expression of iron regulatory protein 2 (IRP2). Presence of multiple IRP2 transcripts regulated by intracellular iron levels. Guo, B., Brown, F.M., Phillips, J.D., Yu, Y., Leibold, E.A. J. Biol. Chem. (1995) [Pubmed]
  5. Doxorubicin paradoxically protects cardiomyocytes against iron-mediated toxicity: role of reactive oxygen species and ferritin. Corna, G., Santambrogio, P., Minotti, G., Cairo, G. J. Biol. Chem. (2004) [Pubmed]
  6. Divergent modulation of iron regulatory proteins and ferritin biosynthesis by hypoxia/reoxygenation in neurones and glial cells. Irace, C., Scorziello, A., Maffettone, C., Pignataro, G., Matrone, C., Adornetto, A., Santamaria, R., Annunziato, L., Colonna, A. J. Neurochem. (2005) [Pubmed]
  7. Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain. Siddappa, A.J., Rao, R.B., Wobken, J.D., Leibold, E.A., Connor, J.R., Georgieff, M.K. J. Neurosci. Res. (2002) [Pubmed]
  8. IRP1 activation by extracellular oxidative stress in the perfused rat liver. Mueller, S., Pantopoulos, K., Hübner, C.A., Stremmel, W., Hentze, M.W. J. Biol. Chem. (2001) [Pubmed]
  9. Converse modulation of IRP1 and IRP2 by immunological stimuli in murine RAW 264.7 macrophages. Bouton, C., Oliveira, L., Drapier, J.C. J. Biol. Chem. (1998) [Pubmed]
  10. Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. Guo, B., Phillips, J.D., Yu, Y., Leibold, E.A. J. Biol. Chem. (1995) [Pubmed]
  11. Temporal responses in the disruption of iron regulation by manganese. Kwik-Uribe, C., Smith, D.R. J. Neurosci. Res. (2006) [Pubmed]
  12. Expression and biochemical characterization of iron regulatory proteins 1 and 2 in Saccharomyces cerevisiae. Phillips, J.D., Guo, B., Yu, Y., Brown, F.M., Leibold, E.A. Biochemistry (1996) [Pubmed]
  13. Aluminium toxicity and iron homeostasis. Ward, R.J., Zhang, Y., Crichton, R.R. J. Inorg. Biochem. (2001) [Pubmed]
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