Iron
Iron metabolism is intimately related to heme synthesis, in that the rate of iron acquisition is limiting for heme synthesis 1. Activation of GATA-1 resulted in transcriptional down-modulation of two nuclearly encoded mitochondrial proteins putatively related to erythroid iron metabolism: frataxin 2 and sideroflexin 3. Mutation of both genes is associated with mitochondrial iron-overload 3,4. These transcripts declined prior to the acceleration of globin mRNA and heme synthesis at the midpoint of the time course. Frataxin transcripts were reported to decline in DMSO-differentiated Friend cells 5. Its decline may be associated with mitochondrial iron-retention for heme synthesis.
The mitochondrial ABC transport protein Abcf2, which had a transcriptional profile similar to frataxin, was identified using subtraction screening for transcripts repressed by iron 6. Abcf2 is closely related to GCN20 (Abcf1), a positive regulator of GCN2 (Eif2ak4) activity 7. When activated, Eif2ak4 phosphorylates and inactivates Eif2 which is required for globin synthesis. Abcf2 may be an iron sensor, linking iron availability to protein synthesis.
Nramp2 (DMT1, DCT2) is believed to transport iron into the erythrocyte from the transferrin-containing endosome, but it was not transcriptionally upregulated during the time course, consistent with findings in MEL cells 5.
Time course of iron-related transcripts frataxin (Frda), sideroflexin (Sfxn1), Abcf2, and Nramp2 (Slc11a2). Time points are 0, 3, 7, 14, 21, and 30 hours after activation of GATA-1.
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Copper
This divalent cation has been known for many years to be important for erythroid development. Copper deficiency causes anemia 8, at least in part by interfering with iron uptake and heme synthesis in erythroid precursors 9. Copper-containing enzymes are important for interconversion of iron redox states coupled to its transport 10-13. In addition, copper is a necessary component of the antioxidants metallothionein 1 and 2 (Mt1, Mt2) 14 and Cu/Zn superoxide dismutase (Sod1) 15, abundant erythroid proteins that protect against injury from iron-catalyzed formation of free radicals. Therefore, erythroid precursors may have particularly high requirements for copper uptake. We found that the high-affinity copper transporter Ctr1 (Slc31a1) was strongly upregulated during G1E-ER4 cell maturation, implying a specialized role for this protein in erythropoiesis. While examination of erythroid development in Ctrl-null mice was obscured by early embryonic lethality 16,17 more detailed investigations are indicated by our current findings.
Time course of copper-related transcripts Metallotheins 1 and 2 (Mt1, Mt2) with their unique biphasic transcript profiles, Cu-Zn superoxide dismutase 1 (Sod1) and Ctr1 (Slc31a1) metal transporter. Time points are 0, 3, 7, 14, 21, and 30 hours after activation of GATA-1.
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Selenium
See Antioxidants regarding selenium and selenium binding protein.
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References
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| 1. Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms of erythroid cells. Blood. 1997;89:1-25
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| 2. Koutnikova H, Campuzano V, Foury F, Dolle P, Cazzalini O, Koenig M. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nature Genetics. 1997;16:345-351 |
| 3. Fleming M, Campagna D, Haslett J, Trenor C, Andrews N. A mutation in a mitochondrial transmembrane protein is responsible for the pleiotropic hematological and skeletal phenotype of flexed-tail (f/f) mice. Genes Dev. 2001;15:652-657 |
| 4. Becker E, Richardson D. Frataxin: its role in iron metabolism and the pathogenesis of Friedrich's ataxia. International Journal of Biochemistry & Cell Biology. 2001;33:1-10 |
| 5. Becker E, Greer J, Ponka P, Richardson D. Erythroid differentiation and protoporphyrin IX down-regulate frataxin expression in Friend cells: characterization of frataxin expression compared to molecules involved in iron metabolism and hemoglobininization. Blood. 2002;99:3813-3822 |
| 6. Ye Z, Connor J. Identification of iron responsive genes by screen cDNA libraries from suppression subtractive hybridization with antisense probes from three iron conditions. Nucleic Acids Research. 2000;28:1802-1807 |
| 7. Vazquez de Aldana C, Marton M, Hinnebusch A. GCN20, a novel ATP binding cassette protein, and a GCN1 reside in a complex that mediates activation of the eIF-2 alpha kinase GCN2 in amino acid-starved cells. EMBO J. 1995;14:3184-3199 |
| 8. Hart E, Steenbock H, Waddell J, Elvehjem C, van Donk E, Riising B. Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. J Biol Chem. 1928;77:797-833 |
| 9. Williams D, Loukopoulous D, Lee G, Cartwright G. Role of copper in mitochondrial iron metabolism. Blood. 1976;76:77-85 |
| 10. Frieden E. The copper connection. Semin Hematol. 1983;20:114 |
| 11. Dancis A, Yuan D, Askwith C, Eide D, Moehle C, Kaplan J, Klausner R. Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell. 1994;76:393-402 |
| 12. Fox P. The copper-iron chronicles: the story of an intimate relationship. Biometals. 2003;16:9-40 |
| 13. Vulpe C, Kuo Y-M, Murphy T, Cowley L, Askwith C, Libina N, Gitschier J, Anderson G. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defect in the sla mouse. Nature Genetics. 1999;21:195-199 |
| 14. Lyons B, Lynes M, Burzenski L, Joliat M, Hadjout N, Shultz L. Mechanisms of anemia in SHIP-1 protein tyrosine phosphatase-deficient "viable motheaten" mice. Exp Hematol. 2003;31:234-243 |
| 15. Cousins R. Absorption, transport, and hepatic metabolisms of copper and zinc: special reference to metallothionein and ceruloplasmin. Physiol Rev. 1985;65:238-309 |
| 16. Lee J, Prohaska J, Thiele D. Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embyronic development. Proc Natl Acad Sci USA. 2001;98:6842-6847 |
| 17. Kuo Y-M, Zhou B, Cosco D, Gitschier J. The copper transporter Ctr1 provides an essential function in mammalian embryonic development. Proc Natl Acad Sci USA. 2001;98:6836-6841
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