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Gene Review

IREB2  -  iron-responsive element binding protein 2

Homo sapiens

Synonyms: ACO3, IRE-BP 2, IRP2, IRP2AD, Iron regulatory protein 2, ...
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Disease relevance of IREB2


Psychiatry related information on IREB2


High impact information on IREB2

  • Here, c-MYC is shown to repress the expression of the heavy subunit of the protein ferritin (H-ferritin), which sequesters intracellular iron, and to stimulate the expression of the iron regulatory protein-2 (IRP2), which increases the intracellular iron pool [7].
  • This conclusion was confirmed with hybrid proteins in which IRP-1 surface loops were grafted into IRP-2 [8].
  • Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2 [9].
  • Here, we demonstrate that a 73 amino acid sequence that corresponds to a unique exon in IRP2 contains a sequence required for rapid degradation in iron-replete cells [9].
  • Sodium nitroprusside promotes IRP2 degradation via an increase in intracellular iron and in the absence of S nitrosylation at C178 [10].

Chemical compound and disease context of IREB2


Biological context of IREB2

  • Here we describe the consequences of IRP regulation and show that iron homeostasis is regulated in 2 phases during hypoxia: an early phase where IRP1 RNA-binding activity decreases and iron uptake and Ft synthesis increase, and a late phase where IRP2 RNA-binding activity increases and iron uptake and Ft synthesis decrease [1].
  • In mammalian cells, iron homeostasis is largely regulated by post-transcriptional control of gene expression through the binding of iron-regulatory proteins (IRP1 and IRP2) to iron-responsive elements (IREs) contained in the untranslated regions of target mRNAs [12].
  • This second gene product, which we call IRP2, is expressed in many tissues, but its mRNA abundance and tissue distribution are different from IRP1 [13].
  • The Caenorhabditis elegans genome does not contain an IRP2 homolog or identifiable IREs; its IRP1 homolog has aconitase activity but does not bind to mammalian IREs [12].
  • Whereas IRP2 is known to be involved in Fe homeostasis, the role of IRP1 is less clear; it may provide a link between citrate and iron metabolisms and be involved in oxidative stress response [14].

Anatomical context of IREB2

  • In most cell lines tested, levels of IRP2 are inversely regulated by iron levels due to iron-dependent regulation of the half-life of the protein [13].
  • IRP2 levels increased when monocytes differentiated to macrophages [2].
  • INTERPRETATION AND CONCLUSIONS: These findings of the first extensive investigation of the comparative expression of the two IRP in human tissues and blood cells indicate that IRP2 is the major regulator of intracellular iron homeostasis in humans [2].
  • We have investigated changes in activity and expression of both IRP1 and IRP2 during phorbol 12-myristate 13-acetate (PMA)-induced differentiation of HL-60 cells [15].
  • Here, we report that while IRP-1 is present at similar levels in both Alzheimer and control brain tissue, IRP-2 shows striking differences and is associated with intraneuronal lesions, including neurofibrillary tangles, senile plaque neurites and neuropil threads [16].

Associations of IREB2 with chemical compounds


Physical interactions of IREB2


Regulatory relationships of IREB2

  • Furthermore, pVHL is able to promote the ubiquitination and the decay of transfected IRP2 [17].
  • Here we report that purified recombinant IRP2 inhibits translation of ferritin mRNAs with a molar efficacy equal to that of recombinant IRP1 [24].
  • The mRNAs for TfR-1 and, potentially, FPN-1 are posttranscriptionally regulated by iron regulatory protein (IRP)-1 and IRP-2 [25].

Other interactions of IREB2

  • We then examined the biological effect of the interaction of YB-1 and IRP2 on translational regulation [20].
  • As an inappropriate up-regulation of total IRP activity has been found in the duodenum and monocytes of patients with hereditary hemochromatosis (HH), we investigated the respective roles of IRP1 and IRP2 in these settings [2].
  • The concentration and activity of the iron regulatory proteins (IRP1 and IRP2) were analyzed to determine whether there was a functional deficit in the post-transcriptional regulatory mechanism for TfR expression [26].
  • Four 5' flanking sequences, comprising the 5'-UTR and upstream promoter region, have been isolated and cloned from the 1-aminocyclopropane-1-carboxylate (ACC) oxidase gene family of white clover (Trifolium repens L.), and designated TR-ACO1p, TR-ACO2p, TR-ACO3p and TR-ACO4p [27].
  • Cobalt, which mimics hypoxia by activation of hypoxia-inducible factor 1 (HIF-1), also increases IRP2 protein levels; however, cobalt-induced IRP2 lacks RNA binding activity [28].

Analytical, diagnostic and therapeutic context of IREB2

  • Site-directed mutagenesis has demonstrated that specific cysteines within the IRP2 exon are required for iron-dependent degradation [9].
  • Western blot analysis and supershift assays showed that this cytosolic protein is neither IRP1 nor IRP2 [29].
  • RNA-based PCR amplification of ACC oxidase cDNAs from ethylene-treated corollas and wounded leaves revealed transcripts for ACO1, ACO3 and ACO4 indicating that a least three of these genes are transcriptionally active [30].
  • Double immunofluorescence labeling showed that IRP1, IRP2, DMT1 and -IRE DMT1 were mostly expressed in GFAP positive astrocytes [31].


  1. Effects of iron regulatory protein regulation on iron homeostasis during hypoxia. Schneider, B.D., Leibold, E.A. Blood (2003) [Pubmed]
  2. Iron regulatory proteins 1 and 2 in human monocytes, macrophages and duodenum: expression and regulation in hereditary hemochromatosis and iron deficiency. Recalcati, S., Alberghini, A., Campanella, A., Gianelli, U., De Camilli, E., Conte, D., Cairo, G. Haematologica (2006) [Pubmed]
  3. Screening for mutations of the IRP2 gene in Parkinson's disease patients with hyperechogenicity of the substantia nigra. Deplazes, J., Schöbel, K., Hochstrasser, H., Bauer, P., Walter, U., Behnke, S., Spiegel, J., Becker, G., Riess, O., Berg, D. Journal of neural transmission (Vienna, Austria : 1996) (2004) [Pubmed]
  4. What have we learnt from CDNA microarray gene expression studies about the role of iron in MPTP induced neurodegeneration and Parkinson's disease? Youdim, M.B. J. Neural Transm. Suppl. (2003) [Pubmed]
  5. Yersiniabactin production by Pseudomonas syringae and Escherichia coli, and description of a second yersiniabactin locus evolutionary group. Bultreys, A., Gheysen, I., de Hoffmann, E. Appl. Environ. Microbiol. (2006) [Pubmed]
  6. Preliminary demonstration of an allelic association of the IREB2 gene with Alzheimer's disease. Coon, K.D., Siegel, A.M., Yee, S.J., Dunckley, T.L., Mueller, C., Nagra, R.M., Tourtellotte, W.W., Reiman, E.M., Papassotiropoulos, A., Petersen, F.F., Stephan, D.A., Kirsch, W.M. J. Alzheimers Dis. (2006) [Pubmed]
  7. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Wu, K.J., Polack, A., Dalla-Favera, R. Science (1999) [Pubmed]
  8. Identification of RNA-binding surfaces in iron regulatory protein-1. Kaldy, P., Menotti, E., Moret, R., Kühn, L.C. EMBO J. (1999) [Pubmed]
  9. Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2. Iwai, K., Klausner, R.D., Rouault, T.A. EMBO J. (1995) [Pubmed]
  10. Sodium nitroprusside promotes IRP2 degradation via an increase in intracellular iron and in the absence of S nitrosylation at C178. Wang, J., Fillebeen, C., Chen, G., Andriopoulos, B., Pantopoulos, K. Mol. Cell. Biol. (2006) [Pubmed]
  11. Oxygen and iron regulation of iron regulatory protein 2. Hanson, E.S., Rawlins, M.L., Leibold, E.A. J. Biol. Chem. (2003) [Pubmed]
  12. Of two cytosolic aconitases expressed in Drosophila, only one functions as an iron-regulatory protein. Lind, M.I., Missirlis, F., Melefors, O., Uhrigshardt, H., Kirby, K., Phillips, J.P., Söderhäll, K., Rouault, T.A. J. Biol. Chem. (2006) [Pubmed]
  13. Molecular characterization of a second iron-responsive element binding protein, iron regulatory protein 2. Structure, function, and post-translational regulation. Samaniego, F., Chin, J., Iwai, K., Rouault, T.A., Klausner, R.D. J. Biol. Chem. (1994) [Pubmed]
  14. Crystallization and preliminary X-ray diffraction data for the aconitase form of human iron-regulatory protein 1. Dupuy, J., Darnault, C., Brazzolotto, X., Kühn, L.C., Moulis, J.M., Volbeda, A., Fontecilla-Camps, J.C. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. (2005) [Pubmed]
  15. Phosphorylation and activation of both iron regulatory proteins 1 and 2 in HL-60 cells. Schalinske, K.L., Eisenstein, R.S. J. Biol. Chem. (1996) [Pubmed]
  16. Abnormal localization of iron regulatory protein in Alzheimer's disease. Smith, M.A., Wehr, K., Harris, P.L., Siedlak, S.L., Connor, J.R., Perry, G. Brain Res. (1998) [Pubmed]
  17. The pathway for IRP2 degradation involving 2-oxoglutarate-dependent oxygenase(s) does not require the E3 ubiquitin ligase activity of pVHL. Wang, J., Pantopoulos, K. Biochim. Biophys. Acta (2005) [Pubmed]
  18. Differences in the RNA binding sites of iron regulatory proteins and potential target diversity. Butt, J., Kim, H.Y., Basilion, J.P., Cohen, S., Iwai, K., Philpott, C.C., Altschul, S., Klausner, R.D., Rouault, T.A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  19. S-nitrosylation of IRP2 regulates its stability via the ubiquitin-proteasome pathway. Kim, S., Wing, S.S., Ponka, P. Mol. Cell. Biol. (2004) [Pubmed]
  20. Novel translational control through an iron-responsive element by interaction of multifunctional protein YB-1 and IRP2. Ashizuka, M., Fukuda, T., Nakamura, T., Shirasuna, K., Iwai, K., Izumi, H., Kohno, K., Kuwano, M., Uchiumi, T. Mol. Cell. Biol. (2002) [Pubmed]
  21. Multiple, conserved iron-responsive elements in the 3'-untranslated region of transferrin receptor mRNA enhance binding of iron regulatory protein 2. Erlitzki, R., Long, J.C., Theil, E.C. J. Biol. Chem. (2002) [Pubmed]
  22. Increased IRP1 and IRP2 RNA binding activity accompanies a reduction of the labile iron pool in HFE-expressing cells. Roy, C.N., Blemings, K.P., Deck, K.M., Davies, P.S., Anderson, E.L., Eisenstein, R.S., Enns, C.A. J. Cell. Physiol. (2002) [Pubmed]
  23. Translational regulation of mRNAs with distinct IRE sequences by iron regulatory proteins 1 and 2. Menotti, E., Henderson, B.R., Kühn, L.C. J. Biol. Chem. (1998) [Pubmed]
  24. Translational repressor activity is equivalent and is quantitatively predicted by in vitro RNA binding for two iron-responsive element-binding proteins, IRP1 and IRP2. Kim, H.Y., Klausner, R.D., Rouault, T.A. J. Biol. Chem. (1995) [Pubmed]
  25. Influence of gestational age and fetal iron status on IRP activity and iron transporter protein expression in third-trimester human placenta. Bradley, J., Leibold, E.A., Harris, Z.L., Wobken, J.D., Clarke, S., Zumbrennen, K.B., Eisenstein, R.S., Georgieff, M.K. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2004) [Pubmed]
  26. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Connor, J.R., Wang, X.S., Patton, S.M., Menzies, S.L., Troncoso, J.C., Earley, C.J., Allen, R.P. Neurology (2004) [Pubmed]
  27. Expression of 1-aminocyclopropane-1-carboxylate (ACC) oxidase genes during the development of vegetative tissues in white clover (Trifolium repens L.) is regulated by ontological cues. Chen, B.C., McManus, M.T. Plant Mol. Biol. (2006) [Pubmed]
  28. Hypoxia post-translationally activates iron-regulatory protein 2. Hanson, E.S., Foot, L.M., Leibold, E.A. J. Biol. Chem. (1999) [Pubmed]
  29. Regulation of the 75-kDa subunit of mitochondrial complex I by iron. Lin, E., Graziano, J.H., Freyer, G.A. J. Biol. Chem. (2001) [Pubmed]
  30. Organization and structure of the 1-aminocyclopropane-1-carboxylate oxidase gene family from Petunia hybrida. Tang, X., Wang, H., Brandt, A.S., Woodson, W.R. Plant Mol. Biol. (1993) [Pubmed]
  31. Upregulation of iron regulatory proteins and divalent metal transporter-1 isoforms in the rat hippocampus after kainate induced neuronal injury. Huang, E., Ong, W.Y., Go, M.L., Connor, J.R. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. (2006) [Pubmed]
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