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Mechanisms for Induction and Rerepression of Ferritin Synthesis

  • Chapter
Metal Ions in Gene Regulation

Part of the book series: Chapman & Hall Microbiology Series ((CHMBS))

Abstract

An iron responsive element (IRE) located within the 5′ untranslated region (5′ UTR) of certain mRNAs (e.g., ferritin) serves as a binding site for a class of specific binding proteins [referred to as the iron regulatory proteins (IRPs)] which, when bound to an IRE, repress translation of those mRNAs [reviewed in Leibold and Guo (1992), Melefors and Hentze (1993), Klausner et al. (1993), Munro (1993), Theil (1993), Mascotti et al. (1995)]. Binding of an IRP to an IRE located proximally to the 5′ end of an mRNA is believed to prevent access of eIF-4F (the cap binding protein) to the 5′ cap structure, resulting in a blockage of initiation (Goossen et al. 1990; Bhasker et al. 1993; Gray and Hentze 1994). When chelatable iron levels are increased in the cell, an IRP is induced to dissociate from the IRE and allow initiation of translation of ferritin [reviewed in Leibold and Guo (1992), Melefors and Hentze (1993), Klausner et al. (1993), Munro (1993), Theil (1993)]. Messages that contain functional IREs in their 5′ UTRs code for ferritin (Leibold and Guo 1992; Melefors and Hentze 1993; Klausner et al. 1993; Munro 1993; Theil 1993), erythroid δ-aminolevulinic acid synthase (δ-ALAS) (Cox et al. 1991; Bhasker et al. 1993), mitochondrial aconitase (m-acon) (Dandekar et al. 1991), Drosophila melanogaster succinate dehydrogenase (Kohler et al. 1995; Gray et al. 1996), and possibly transferrin (Tf) (Cox and Adrian 1993; Cox et al. 1995).

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References

  • Balla G., H. S. Jacob, J. Balla, M. Rosenberg, K. Nath, F. Apple, J. W. Eaton, and G. M. Vercellotti. 1992. Ferritin: A cytoprotective antioxidant strategem of endothelium. J. Biol. Chem. 267: 18148–18153.

    PubMed  CAS  Google Scholar 

  • Balla J., H. Jacob, G. Balla, K. Nath, J. W. Eaton, and G. M. Vercellotti. 1993. Endothelialcell heme uptake from heme proteins: Induction of sensitization and desensitization to oxidant damage. Proc. Natl Acad. Sci. 90: 9285–9289.

    Article  PubMed  CAS  Google Scholar 

  • Basilion J. P., T. A. Rouault, C. M. Massinople, R. D. Klausner, and W. H. Burgess. 1994 a. The iron-responsive element-binding protein: Localization of the RNA-binding site to the aconitase active-site cleft. Proc. Natl Acad. Sci. 91: 574–578.

    Article  PubMed  CAS  Google Scholar 

  • Basilion J. P., M. C. Kennedy, H. Beinert, C. M. Massinople, R. D. Klausner, and T. A. Rouault. 1994 b. Overexpression of iron-responsive element-binding protein and its analytical characterization as the RNA-binding form, devoid of an iron-sulfur cluster. Arch. Biochem. Biophys. 311: 517–522.

    Article  PubMed  CAS  Google Scholar 

  • Battistini A. B., E-M. Coccia, G. Marziali, D. Bulgarini, S. Scalzo, G. Fiorucci, G. Romeo, E. Affabris, U. Testa, G. B. Rossi, and C. Peschle. 1991. Intracellular heme coordinately modulates globin chain synthesis, transferrin receptor number, and ferritin content in differentiating friend erythroleukemia cells. Blood 78: 2098–2103.

    PubMed  CAS  Google Scholar 

  • Beinert H., and M. C. Kennedy. 1993. Aconitase, a two-faced protein: Enzyme and iron regulatory factor. FASEB J. 7: 1442–1449.

    PubMed  CAS  Google Scholar 

  • Bhasker C. R., G. Burgiel, B. Neupert, A. Emery-Goodman, L. C. Kuhn, and B. K. May. 1993. The putative iron-responsive element in the human erythroid 5-aminolevulinate synthase mRNA mediates translational control. J. Biol. Chem. 268: 12699–12705.

    PubMed  CAS  Google Scholar 

  • Cairo, G. and A. Pietrangelo. 1994. Transferrin receptor gene expression during rat liver regeneration: Evidence for post-translational regulation by iron regulatory factorB, a second iron-responsive element-binding protein. J. Biol. Chem. 269: 6405–6409.

    PubMed  CAS  Google Scholar 

  • Cairo G., L. Tacchini, G. Pogliaghi, E. Anzon, A. Tomasi and A. Bernelli-Zazzera. 1995. Induction of ferritin synthesis by oxidative stress: Transcriptional and post-transcriptional regulation by expansion of the “free” iron pool. J. Biol. Chem. 270: 700–703.

    Article  PubMed  CAS  Google Scholar 

  • Casey J. L., M. W. Hentze, D. M. Koeller, S. W. Caughman, T. A. Rouault, R. D. Klausner, and J. B. Harford. 1988. Iron responsive elements: Regulatory RNA sequences that control mRNA levels and translation. Science 240: 924–928.

    Article  PubMed  CAS  Google Scholar 

  • Casey J. L., D. M. Koeller, V. C. Ramin, R. D. Klausner, and J. B. Harford. 1989. Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3’ untranslated region of the mRNA. EMBO J. 8: 3693–3699.

    PubMed  CAS  Google Scholar 

  • Constable A., S. Quick, N. K. Gray, and M. W. Hentze. 1992. Modulation of the RNA-binding activity of a regulatory protein by iron in vitro: Switching between enzymatic and genetic function? Proc. Natl. Acad. Sci. 89: 4554–4558.

    Article  PubMed  CAS  Google Scholar 

  • Cox L. A., and G. S. Adrian. 1993. Posttranscriptional regulation of chimeric human transferrin genes by iron. Biochem. 32: 4738–4745.

    Article  CAS  Google Scholar 

  • Cox L. A., M. C. Kennedy, and G. S. Adrian. 1995. The 5’-untranslated region of human transferrin mRNA, which contains a putative iron-regulatory element, is bound by purified iron-regulatory protein in a sequence-specific manner. Biochem. Biophys. Res. Comm. 212: 925–932.

    Article  PubMed  CAS  Google Scholar 

  • Cox T. C., M. J. Bawden, A. Martin, and B. K. May. 1991. Human erythroid 5-aminolevulinate synthase: Promoter analysis and identification of an iron-responsive element in the mRNA. EMBO J. 10: 1891–1902.

    PubMed  CAS  Google Scholar 

  • Dandekar T., R. Stripecke, N. K. Gray, B. Goossen, A. Constable, H. E. Johansson, and M. W. Hentze. 1991. Identification of a novel iron-responsive element in murine and human erythroid δ-aminolevulinic acid synthase mRNA. EMBO J. 10: 1903–1909.

    PubMed  CAS  Google Scholar 

  • Daniels-McQueen S., L. S. Goessling, and R. E. Thach. 1992. Inducible expression bovine papilloma virus shuttle vectors containing ferritin translational regulatory elements. Gene 122: 271–279.

    Article  PubMed  CAS  Google Scholar 

  • Drapier, J-C, H. Hirling, J. Wietzerbin, P. Kaldy, and L. C. Kuhn. 1993. Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J. 12: 3643–3649.

    PubMed  CAS  Google Scholar 

  • Eisenstein R. S., D. Garcia-Mayol, W. Pettingell and H. N. Munro. 1991. Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. Proc. Natl Acad. Sci. 88: 688–692.

    Article  PubMed  CAS  Google Scholar 

  • Eisenstein R. S., and H. N. Munro. 1990/91. Translational regulation of ferritin synthesis by iron. Enzyme 44: 42–58.

    PubMed  CAS  Google Scholar 

  • Eisenstein R. S., P. T. Tuazon, K. L. Schalinske, S. A. Anderson, and J. A. Traugh. 1993. Iron-responsive element-binding protein: Phosphorylation by protein kinase C. J. Biol Chem. 268: 27363–27370.

    PubMed  CAS  Google Scholar 

  • Emery-Goodman A., H. Hirling, L. Scarpellino, B. Henderson, and L. C. Kuhn. 1993. Iron regulatory factor expressed from recombinant baculovirus: Conversion between the RNA-binding apoprotein and Fe-S cluster containing aconitase. Nucl Acid Res. 21: 1457–1461.

    Article  CAS  Google Scholar 

  • Goessling L. S., S. Daniels-McQueen, M. Bhattacharyya-Pakrasi, J.-J. Lin, and R. E. Thach. 1992. Enhanced degradation of the ferritin repressor protein during induction of ferritin messenger RNA translation. Science 256: 670–673.

    Article  PubMed  CAS  Google Scholar 

  • Goessling L. S., D. P. Mascotti, M. Bhattacharyya-Pakrasi, H. Gang, and R. E. Thach. 1994. Irreversible steps in the ferritin synthesis induction pathway. J. Biol Chem. 269: 4343–4348.

    PubMed  CAS  Google Scholar 

  • Goossen B., S. W. Caughman, J. B. Harford, R. D. Klausner and M. W. Hentze. 1990. Translational repression by a complex between the iron-responsive element of ferritin mRNA and its specific cytoplasmic binding protein is position-dependents. in vivo. EMBO J. 9: 4127–4133.

    CAS  Google Scholar 

  • Gray N. K., and M. W. Hentze. 1994. Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs. EMBO J. 13: 3882–3891.

    PubMed  CAS  Google Scholar 

  • Gray N. K., K. Pantopoulos, T. Dandekar, B. A. Ackrell, and M. W. Hentze. 1996. Translational regulation of mammalian and Drosophila citric acid cycle enzymes via iron-responsive elements. Proc. Natl. Acad. Sci. 93: 4925–4930.

    Article  PubMed  CAS  Google Scholar 

  • Guo B., J. D. Phillips, Y. Yu, and E. A. Leibold. 1995. Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J. Biol. Chem. 270: 21645–21651.

    Article  PubMed  CAS  Google Scholar 

  • Guo B., Y. Yu, and E. A. Leibold. 1994. Iron regulates cytoplasmic levels of a novel iron-responsive element-binding protein without aconitase activity. J. Biol Chem. 269: 24252–24260.

    PubMed  CAS  Google Scholar 

  • Haile D. J., T. A. Rouault, J. B. Harford, and R. D. Klausner. 1990. The inhibition of the iron responsive element RNA-protein interaction by heme does not mimic in vivo iron regulation. J. Biol. Chem. 265: 12786–12789.

    PubMed  CAS  Google Scholar 

  • Haile D. J., T. A. Rouault, J. B. Harford, M. C. Kennedy, G. A. Blondin, H. Beinert, and R. D. Klausner. 1992 a. Cellular regulation of the iron-responsive element binding protein: Disassembly of the cubane iron-sulfur cluster results in high-affinity RNA binding. Proc. Natl. Acad. Sci. 89: 11735–11739.

    Article  PubMed  CAS  Google Scholar 

  • Haile D. J., T. A. Rouault, C. K. Tang, J. Chin, J. B. Harford, and R. D. Klausner. 1992 b. Reciprocal control of RNA binding and aconitase activity in the regulation of the iron responsive element binding protein: Role of the iron-sulfur cluster. Proc. Natl. Acad. Sci. 89: 7536–7540.

    Article  PubMed  CAS  Google Scholar 

  • Henderson B. R., C. Seiser, and L. C. Kuhn. 1993. Characterization of a second RNA-binding protein in rodents with specificity for iron-responsive elements. J. Biol. Chem. 268: 27327–27334.

    PubMed  CAS  Google Scholar 

  • Henderson B. R., E. Menotti, C. Bonnard, and L. C. Kuhn. 1994. Optimal sequence and structure of iron-responsive elements: Selection of RNA stem loops with high affinity for iron regulatory factor. J. Biol. Chem. 269: 17481–17489.

    PubMed  CAS  Google Scholar 

  • Hirling H., B. R. Henderson, and L. C. Kuhn. 1994. Mutational analysis of the [4Fe-4S]-cluster converting iron regulatory factor from its RNA-binding form to cytoplasmic aconitase. EMBO J. 13: 453–461.

    PubMed  CAS  Google Scholar 

  • Hoffman R., N. Ibrahim, M. J. Murnane, A. Diamond, B. G. Forget, and R. D. Levere. 1980. Hemin control of heme biosynthesis and catabolism in a human leukemia cell line. Blood 56: 567–570.

    PubMed  CAS  Google Scholar 

  • Jungmann J., H. A. Reins, C. Schobert, and S. Jentsch. 1993. Resistance to cadmium mediated by ubiquitin-dependent proteolysis. Nature 361: 369–371.

    Article  PubMed  CAS  Google Scholar 

  • Kaptain S., W. E. Downey, C. Tang, C. Philpott, D. Haile, D. G. Orloff, J. B. Harford, T. A. Rouault, and R. D. Klausner. 1991. A regulated RNA binding protein also possesses aconitase activity. Proc. Natl. Acad. Sci. 88: 10109–10113.

    Article  PubMed  CAS  Google Scholar 

  • Kennedy M. C., L. Mende-Mueller, G. A. Blondin, and H. Beinert. 1992. Purification and characterization of cytosolic aconitase from beef liver and its relationship to the iron-responsive element binding protein. Proc. Natl. Acad. Sci. 89: 11730–11734.

    Article  PubMed  CAS  Google Scholar 

  • Klausner R. D., and T. A. Rouault. 1993. A double life: Cytosolic aconitase as a regulatory RNA binding protein. Molec. Biol. 4: 1–5.

    CAS  Google Scholar 

  • Klausner R. D., T. A. Rouault, and J. B. Harford. 1993. Regulating the fate of mRNA: The control of cellular iron metabolism.Cell 72: 19–2

    Article  PubMed  CAS  Google Scholar 

  • Koeller D. M., J. L. Casey, M. W. Hentze, E. M. Gerhaardt, L-N.L. Chan, R. D. Klausner, and J. B. Harford. 1989. A cytosolic protein binds to structural elements within the iron regulatory region of the transferrin receptor mRNA. Proc. Natl. Acad. Sci. 86: 3574–3578.

    Article  PubMed  CAS  Google Scholar 

  • Koeppen A. H., A. C. Dickson, R. C. Chu, and R. E. Thach. 1993. The pathogenesis of superficial siderosis of the central nervous system. Ann. Neurol. 34: 646–653.

    Article  PubMed  CAS  Google Scholar 

  • Koeppen A. H., C. G. Hurwitz, R. E. Dearborn, A. C. Dickson, R. C. Borke, and R. C. Chu. 1992. Experimental superficial siderosis of the central nervous system: Biochemical correlates. J. Neurol. Sci. 112: 38–45.

    Article  PubMed  CAS  Google Scholar 

  • Kohler S. A., B. R. Henderson, and L. C. Kuhn. 1995. Succinate dehydrogenase b mRNA of Drosophila melanogaster has a functional iron-responsive element in its 5’-untranslated region. J. Biol. Chem. 270: 30781–30786.

    Article  PubMed  CAS  Google Scholar 

  • Leibold E. A., and B. Guo. 1992. Iron-dependent regulation of ferritin and transferrin receptor expression by the iron-responsive element binding protein. Ann. Rev. Nutr. 12: 345–368.

    Article  CAS  Google Scholar 

  • Lin, J-J., S. Daniels-McQueen, L. Gaffield, M. M. Patino, W. E. Walden, and R. E. Thach. 1990 b. Specificity of the induction of ferritin synthesis by hemin. Biochim. Biophys. Acta 1050: 146–150.

    Article  PubMed  CAS  Google Scholar 

  • Lin, J-J., S. Daniels-McQueen, M. M. Patino, L. Gaffield, W. E. Walden, and R. E. Thach. 1990a. Derepression of ferritin messenger RNA translation by hemin in vitro. Science 247: 74–77.

    CAS  Google Scholar 

  • Lin, J-J., M. M. Patino, L. Gaffield, W. E. Walden, A. Smith, and R. E. Thach. 1991. Crosslinking of hemin to a specific site on the 90-kDa ferritin repressor protein. Proc. Natl Acad. Sci. 88: 6068–6071.

    Article  PubMed  CAS  Google Scholar 

  • Lin, J-J., W. E. Walden, and R. E. Thach. 1990/91. Induction of ferritin synthesis in vitro: Problems of specificity inherent in the use of iron compounds. Enzyme 44: 59–67.

    PubMed  CAS  Google Scholar 

  • Mascotti D. P., D. Rup, and R. E. Thach. 1995. Regulation of iron metabolism: Translational effects mediated by iron, heme and cytokines. Ann. Rev. Nutr. 15: 239–261.

    Article  CAS  Google Scholar 

  • Melefors O., and M. W. Hentze. 1993. Translational regulation by mRNA/protein interactions in eukaryotic cells: Ferritin and beyond. Bioessays 15: 85–90.

    Article  PubMed  CAS  Google Scholar 

  • Mullner E. W., and L. C. Kuhn. 1988. A stem-loop in the 3’ untranslated region mediates iron-dependent regulation of transferrin receptor mRNA stability in the cytoplasm. Cell 53: 815–825.

    Article  PubMed  CAS  Google Scholar 

  • Mullner E. W., B. Neupert, and L. C. Kuhn. 1989. A specific mRNA binding factor regulates the iron-dependent stability of cytoplasmic transferrin receptor mRNA. Cell 58: 373–382.

    Article  PubMed  CAS  Google Scholar 

  • Mullner E. W., S. Rothenberger, A. M. Muller, and L. C. Kuhn. 1992. In vivo and in vitro modulation of the mRNA-binding activity of iron-regulatory factor: Tissue distribution and effects of cell proliferation, iron levels and redox state. Eur. J. Biochem. 208: 597–605.

    Article  PubMed  CAS  Google Scholar 

  • Munro, H. 1993. The ferritin genes: Their response to iron status. Nutr. Rev. 51: 65–73.

    Article  PubMed  CAS  Google Scholar 

  • Murakami Y., S. Matsufuji, T. Kameji, S.-I. Hayashi, K. Igarashi, T. Tamura, K. Tanaka, and A. Ichihara. 1992. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitation. Nature 360: 597–599.

    Article  PubMed  CAS  Google Scholar 

  • Philpott C. C., D. Haile, T. A. Rouault, and R. D. Klausner. 1993. Modification of a free Fe-S cluster cysteine residue in the active iron-responsive element-binding protein prevents RNA binding. J. Biol. Chem. 268: 17655–17658.

    PubMed  CAS  Google Scholar 

  • Rice-Evans C. A., and R. H. Burdon. 1994. In Free Radical Damage and its Control. Elsevier, New York.

    Google Scholar 

  • Rogers J. T., and H. N. Munro. 1987. Translation of ferritin light and heavy subunit mRNAs is regulated by intracellular chelatable iron levels in rat hepatoma cells. Proc. Natl. Acad. Sci. 84: 2277–2281.

    Article  PubMed  CAS  Google Scholar 

  • Samaniego F., J. Chin, K. Iwai, T. A. Rouault, and R. D. Klausner. 1994. Molecular characterization of a second iron-responsive element binding protein, iron regulatory protein vn2: Structure, function, and post-translational regulation. J. Biol. Chem. 269: 30904–30910.

    PubMed  CAS  Google Scholar 

  • Tang C. K., J. Chin, J. B. Harford, R. D. Klausner, and T. A. Rouault. 1992. Iron regulates the activity of the iron-responsive element binding protein without changing its rate of synthesis or degradation. J. Biol. Chem. 267: 24466–24470.

    PubMed  CAS  Google Scholar 

  • Theil, E. C. 1993. The IRE (iron regulatory element) family: Structures which regulate mRNA translation or stability. Biofactors 4: 87–93.

    PubMed  CAS  Google Scholar 

  • Weiss G., B. Goossen, W. Doppler, D. Fuchs, K. Pantopoulos, G. Werner-Felmayer, H. Wachter, and M. W. Hentze. 1993. Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway. EMBO J. 12: 3651–3657.

    PubMed  CAS  Google Scholar 

  • Yu Y., E. Radisky, and E. A. Leibold. 1992. The iron-responsive element binding protein. J. Biol Chem. 267: 19005–19010.

    PubMed  CAS  Google Scholar 

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  1. David P. Mascotti
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  2. Lisa S. Goessling
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  3. Diane Rup
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  4. Robert E. Thach
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Mascotti, D.P., Goessling, L.S., Rup, D., Thach, R.E. (1998). Mechanisms for Induction and Rerepression of Ferritin Synthesis. In: Silver, S., Walden, W. (eds) Metal Ions in Gene Regulation. Chapman & Hall Microbiology Series. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5993-1_8

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