Iron Regulation of Transferrin Receptor and Ferritin Expression in Differentiating Friend Leukemia Cells

  • Eliana Marina Coccia
  • Emilia Stellacci
  • Giovanna Marziali
  • Roberto Orsatti
  • Edvige Perrotti
  • Nicoletta Del Russo
  • Ugo Testa
  • Angela Battistini


Transferrin receptor (TfR) and ferritin expression has been investigated in Friend erythroleukemia cells (FLCs) induced to differentiate by dimethylsulfoxide (Me2SO). In differentiating FLCs, administration of hemin increases the ferritin content approximately 20–25 fold; conversely, iron salts have only mild stimulatory effects on ferritin accumulation and iron chelators only slightly inhibit the stimulatory effect exerted by hemin. Moreover, in Me2SO-induced FLC, the negative feedback reported in a variety of other cell types for the regulation of TfR expression by heme is not operative. We conclude that in FLCs induced to differentiate, hemin acts synergistically with the differentiation inducer increasing ferritin expression and is not able to down modulate the TfR number. These effects appear characteristic of differentiating erythroid cells since they are not observed in other cell types (i.e. fibroblastic cell lines).


Transferrin Receptor Erythroid Cell Erythroid Differentiation Ferric Ammonium Citrate Ferritin Expression 
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  1. 1.
    Klausner RD, Rouault TA, Harford JB: Regulating the fate of mRNA: The control of cellular iron metabolism. Cell 72:15, 1993CrossRefGoogle Scholar
  2. 2.
    Kühn LC, Hentze MW: Coordination of cellular iron metabolism by post-transcriptional gene regulation. J Inorg Biochem 47:183, 1992PubMedCrossRefGoogle Scholar
  3. 3.
    Ward JH, Kushner JP, and Kaplan J: Transferrin receptors of human fibroblasts. Analysis of receptor properties and regulation. Biochem J 208:19, 1982PubMedGoogle Scholar
  4. 4.
    Louache F, Testa U, Pelicci P, Thomopoulos P, Titeux M, and Rochant H: Regulation of transferrin receptors in human haematopoietic cell lines. J Biol Chem 259:11576, 1984PubMedGoogle Scholar
  5. 5.
    Pelosi E, Testa U, Louache F, Thomopoulos P, Salvo G, Samoggia P, Peschle C: Expression of transferrin receptors in phytohemagglutinin-stimulated human T-lymphocytes. Evidence for a three-step model. J Biol Chem 261:3036, 1986PubMedGoogle Scholar
  6. 6.
    Testa U, Petrini M, Quaranta MT, Pelosi-Testa E, Mastroberardino G, Camagna A, Boccoli G, Sargiacomo M, Isacchi G, Cozzi A, Arosio P, Peschle C: Iron upmodulates the expression of TfRs during monocyte-macrophage maturation. J Biol Chem 264:13181, 1989PubMedGoogle Scholar
  7. 7.
    Battistini A, Marziali G, Albertini R, Habetswallner D, Bulgarini D, Coccia EM, Fiorucci G, Romeo G, Orsatti R, Testa U, Affabris E, Peschle C, Rossi GB: Positive modulation of hemoglobin, heme, and transferrin receptor synthesis by murine interferon-alpha and -beta in differentiating Friend cells. Pivotal role of heme synthesis. J Biol Chem 266:528, 1991PubMedGoogle Scholar
  8. 8.
    Reuben RC, Rifkind RA, Marks PA: Chemically induced murine erythroleukemic differentiation. Bio¬chim Biophys Acta 605:325, 1980Google Scholar
  9. 9.
    Orkin SH, Swan D, Leder P: Differential expression of alpha- and beta-globin genes during differentiation of cultured erythroleukemic cells. J Biol Chem 250:8753, 1975PubMedGoogle Scholar
  10. 10.
    Chirgwin JJ, Przybyla AE, MacDonald RJ, Rutter WJ: Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18:5294, 1970CrossRefGoogle Scholar
  11. 11.
    Hentze MW, Rouault TA, Caughman SW, Dancis A, Harford JB, Klausner RD: A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron. Proc Natl Acad Sci USA 84:6730, 1987PubMedCrossRefGoogle Scholar
  12. 12.
    Stearne PA, Pietersz GA, Goding JW: cDNA cloning of the murine TfR: Sequence of trans-membrane and adjacent regions. J. Immunol. 134:3474, 1985PubMedGoogle Scholar
  13. 13.
    Battistini A, Coccia EM, Bulgarini D, Scalzo S, Fiorucci G, Romeo G, Affabris E, Testa U, Rossi GB, Peschle C: Intracellular heme coordinately modulates globin chain synthesis, transferrin receptor number, and ferritin content in differentiating Friend erythroleukemia cells. Blood 78:2098, 1991PubMedGoogle Scholar
  14. 14.
    Ross J, Sautner D: Induction of globin mRNA accumulation by hemin in cultured erythroleukemic cells. Cell 8:513, 1976PubMedCrossRefGoogle Scholar
  15. 15.
    London IM, Clemens MJ, Ranu RS, Levin DH, Cherbas LF, Ernst V: The role of hemin in the regulation of protein synthesis in erythroid cells. Fed Proc 35:2218, 1976PubMedGoogle Scholar
  16. 16.
    Aziz N, Munro HN: Both subunits of rat liver ferritin are regulated at a translational level by iron induction. Nucleic Acids Res 14:915, 1986PubMedCrossRefGoogle Scholar
  17. 17.
    Zahringer J, Bahga BS, Munro HN. Novel mechanism for translational control in regulation of ferritin synthesis by iron. Proc Natl Acad Sci USA 73:857, 1976PubMedCrossRefGoogle Scholar
  18. 18.
    Rouault TA, Hentze MW, Dancis A, Caughman W, Harford JB, Klausner RD: Influence of altered transcription on the translational control of human ferritin expression. Proc Natl Acad Sci USA 84:6335, 1987PubMedCrossRefGoogle Scholar
  19. 19.
    Coccia EM, Profita V, Fiorucci G, Romeo G, Affabris E, Testa U, Hentze MW, Battistini A: Modulation of ferritin H-chain expression in Friend erythroleukemia cells: transcriptional and translational regulation by hemin. Mol Cell Biol 12:3015, 1992PubMedGoogle Scholar
  20. 20.
    Theil EC: Ferritin: structure, gene regulation, and cellular function in animals, plant, and microorganism. Annu Rev Biochem 56:289, 1987PubMedCrossRefGoogle Scholar
  21. 21.
    London IM, Levin DH, Matts RL, Thomas NSB, Petryshyn R, Chen JJ: Regulation of protein synthesis, in Boyer PD (ed): The enzymes, Academic Press, New York, 1987Google Scholar
  22. 22.
    Ponka P, Schulman HM, Cox TM: Iron metabolism in relation to heme synthesis, in Dailey HA (ed): Biosynthesis of heme and chlorophyllis, McGraw-Hill, NY, 1990Google Scholar
  23. 23.
    Ward JH, Kushner JP, Kaplan J: TfRs of human fibroblasts. Analysis of receptor properties and regulation. Biochem J 28:19, 1982Google Scholar
  24. 24.
    Testa U, Louache F, Titeux M, Thomopoulos P, Rochant H: The iron chelating agent picolinic acid enhances TfR expression in human erythroleukemic lines. Br J Haematol 60: 491, 1985PubMedCrossRefGoogle Scholar
  25. 25.
    Ward JH, Jordan I, Kushner JP, Kaplan J: Regulation of Hela cells transferrin receptors. J Biol Chem 259:13235, 1984PubMedGoogle Scholar
  26. 26.
    Muller-Eberhard U, Liem H, Grasso J, Giffhorm-Katz S, De Falco M, Katz N: Increase in surface expression of transferrin receptors on cultured hepatocytes of adult rats in response to iron deficiency. J Biol Chem 263:14753, 1988PubMedGoogle Scholar
  27. 27.
    Chan YY, Seiser C, Schulman HM, Kühn LC, Ponka P: Regulation of transferrin receptor mRNA expression distinct regulatory features in erythroid cells. Eur J Biochem 220:683, 1994PubMedCrossRefGoogle Scholar
  28. 28.
    Rogers J, Munro HN: Translation of ferritin light and heavy subunit mRNAs is regulated by intracellular chelatable iron levels in rat hepatoma cells. Proc Natl Acad Sci USA 84:2277, 1987PubMedCrossRefGoogle Scholar
  29. 29.
    White K, Munro HN: Induction of ferritin subunit synthesis by iron is regulated at both the transcriptional and translational levels. J Biol Chem 263:8938, 1988PubMedGoogle Scholar
  30. 30.
    Lin JJ, Daniels-McQueen S, Gaffield L, Patino MM, Walden WE, Thach RE: Specificity of the induction of ferritin synthesis by hemin. Biochem Biophys Acta 1050:146, 1990PubMedGoogle Scholar
  31. 31.
    Eisenstein RS, Garcia-Mayol D, Pettingell W, Munro HN: Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. Proc Natl Acad Sci USA 88: 688, 1991PubMedCrossRefGoogle Scholar
  32. 32.
    Coccia EM, Goossen B, Hentze MW: Characterization of iron-responsive regulatory elements localized in erythroid 5-aminolevulinic acid synthase mRNAs: Implications for the regulation of heme biosynthe¬sis, in Abraham N et al. (eds): Molecular Biology of Haematopoiesis Andover, Intercept Ltd, 1992Google Scholar
  33. 33.
    Ponka P, Schulman HM, Cox TM: Iron metabolism in relation to haem biosynthesis, in Dailey H (ed): Biosynthesis of Heme and Chlorophyllis, Mc-Graw-Hill. New York, 1990Google Scholar
  34. 34.
    Aziz N, Munro HN: Iron regulates ferritin mRNA translation through a segment of its 5’ untranslated region. Proc Natl Acad Sci USA 84:8478, 1987PubMedCrossRefGoogle Scholar
  35. 35.
    Hentze MW, Caughman SW, Rouault TA, et al: Identification of the iron-responsive element for the translational regulation of human ferritin mRNA. Science 238:1570, 1987PubMedCrossRefGoogle Scholar
  36. 36.
    Caughman SW, Hentze MW, Rouault TA, Harford JB, Klausner RD: The iron-responsive element is the single element responsible for iron-dependent translational regulation of ferritin biosynthesis. Evidence for function as the binding site for a translational repressor. J. Biol Chem 263:19048, 1988PubMedGoogle Scholar
  37. 37.
    Casey JL, Koeller DM, Ramin VC, Klausner RD, Harford JB: 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, 1989PubMedGoogle Scholar
  38. 38.
    Chan L-NL, Gerhardt EM: Transferrin receptor gene is hyperexpressed and transcriptionally regulated in differentiating erythroid cells. J Biol Chem 267:8254, 1992PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • Eliana Marina Coccia
    • 1
  • Emilia Stellacci
    • 1
  • Giovanna Marziali
    • 1
  • Roberto Orsatti
    • 1
  • Edvige Perrotti
    • 1
  • Nicoletta Del Russo
    • 1
  • Ugo Testa
    • 2
  • Angela Battistini
    • 1
    • 3
  1. 1.Laboratory of VirologyInstituto Superiore di SanitàRomeItaly
  2. 2.Laboratory of Hematology and OncologyIstituto Superiore di SanitàRomeItaly
  3. 3.Department of VirologyInstituto Superiore di SanitàRomeItaly

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