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Gene Review

Trf  -  transferrin

Mus musculus

Synonyms: AI266983, Beta-1 metal-binding globulin, Cd176, HP, Serotransferrin, ...
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Disease relevance of Trf


Psychiatry related information on Trf

  • Pharmacologic doses of 200 microgram AFP ip three times per week had no effect on either latency period or tumor incidence in mice given injections of MCA and DMBA when compared to albumin-treated and transferrin-treated controls [6].
  • Membrane-bound transferrin-like protein (MTf), a glycosylphosphatidylinositol-anchored protein, is expressed at high levels in many tumors and in several fetal and adult tissues including cartilage and the intestine, as well as in the amyloid plaques of Alzheimer's disease, although its role remains unknown [7].

High impact information on Trf

  • Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tf-bound iron uptake [8].
  • The reduction of iron is an essential step in the transferrin (Tf) cycle, which is the dominant pathway for iron uptake by red blood cell precursors [8].
  • Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells [8].
  • We propose that inactivation of Sec15l1 alters recycling of transferrin cycle endosomes and increases the release of transferrin receptor exocytic vesicles [9].
  • It has been suggested that HFE modulates uptake of transferrin-bound iron by undifferentiated intestinal crypt cells, thereby programming the absorptive capacity of enterocytes derived from these cells; however, this model is unproven and controversial [10].

Chemical compound and disease context of Trf


Biological context of Trf

  • To test the hypothesis that the Trf cycle has unique importance for erythropoiesis, we disrupted the Trfr gene in mice [16].
  • It results from a single point mutation, which alters an invariable nucleotide in the splice donor site after exon 16 of the Trf gene [17].
  • The gene coding for hepatocyte growth factor-like protein has been localized to mouse chromosome 9 at a locus (Hgfl) distal to the Trf locus [18].
  • Our data show that the regulation of Tf uptake by receptor-mediated endocytosis is mediated by PP2A and additionally may occur through regulation of microtubule-based vesicle transport [19].
  • Cells of heme deficient line Fw did not increase the number of Tf binding sites after the induction of differentiation by 5 mM sodium butyrate [20].

Anatomical context of Trf

  • They are born alive, but before weaning, die from severe anemia if they are not treated with exogenous Trf or red blood cell transfusions [17].
  • Moreover, antibody to transferrin, which prevents it binding its receptor, inhibits listericidal macrophages from killing this bacterium [21].
  • Most patients develop iron loading of Kupffer cells with relatively low saturation of plasma transferrin, but others present with high transferrin saturation and iron-loaded hepatocytes [22].
  • The function of HFE protein is unknown, but it is hypothesized that it acts in association with beta(2)-microglobulin and transferrin receptor 1 to regulate iron uptake from plasma transferrin by the duodenum, the proposed mechanism by which body iron levels are sensed [23].
  • Based on these observations, we suggest that oral iron therapy is not the therapy of choice for patients with EPP and that the PPIX-liver transferrin pathway plays a role in the orchestration of iron distribution between peripheral iron stores, the spleen, and the bone marrow [2].

Associations of Trf with chemical compounds


Physical interactions of Trf

  • Transferrin transports iron into cells via the transferrin receptor: thus, iron content of resident cells is low, of peptone- and FCS-elicited cells is intermediate, and of thioglycollate-elicited cells is high [21].
  • The aim of this study was to test this hypothesis by comparing clearance of transferrin-bound iron in Hfe knockout (KO) mice with that observed in C57BL/6 control mice [23].
  • As Nramp2 can transport Fe from non-Tf-bound Fe, the effect of preincubation with DFO and FAC was also examined on Fe uptake from [59Fe]nitrilotriacetate and [59Fe]citrate [25].
  • After anti-CD71 IgG or control IgG was reacted with cells for 20 min on ice, the uptake of transferrin-bound 59Fe by the MEL cells or the mouse bone marrow cells during 2-day incubation without erythropoietin was measured [26].
  • Here, endosomal pH and chloride concentration were measured in proximal tubule cell cultures from wildtype vs. ClC-5 deficient mice using fluorescent sensors coupled to transferrin (early/recycling endosomes) or alpha(2)-macroglobulin (late endosomes) [27].

Co-localisations of Trf


Regulatory relationships of Trf

  • HFE knockout, beta2-microglobulin knockout and C57BL/6J mice were injected with Freund's Complete Adjuvant to induce an acute phase response and hepatic hepcidin expression and serum transferrin saturation was determined 16 h later [29].
  • Nramp2 is a widely expressed metal-ion transporter that is involved in dietary iron absorption in the duodenum and iron uptake from transferrin in peripheral tissues [30].
  • It was concluded from these experiments that the erythropoietin-stimulated rise in transferrin receptors during the final stages of J2E cell maturation is linked to cell division, and is not essential for haemoglobin synthesis [31].
  • Mitogenic stimulation with insulin and transferrin also induced a marked elevation of c-myc but not of N-myc mRNA [32].
  • Transferrin (5 micrograms/ml) slightly stimulated DNA synthesis and potentiated EGF mitogenic action [33].

Other interactions of Trf

  • However, duodenal iron uptake from plasma transferrin was decreased in the Hfe KO mice compared with the control mice [23].
  • Divalent metal transporter 1 (DMT1) is the major transferrin-independent iron uptake system at the apical pole of intestinal cells, but it may also transport iron across the membrane of acidified endosomes in peripheral tissues [34].
  • Significantly, we found that c-Tf is efficiently processed and presented when the TfR is cross-linked, altering its normal cycling [35].
  • Both Cp and Tf genes were found to be syntenic in rodents, occupying with high probability the regions 9D and 9F1-3 in mice and 7q11-13 and 7q31-34 in rats respectively [36].
  • The murine Hyal2 gene is approximately 3.5 kb, contains the coding sequence for the mRNA on four exons, and is localized on chromosome 9 between the microsatellite markers D9Mit183 and D9Mit17 near the genes for dystroglycan and transferrin [37].

Analytical, diagnostic and therapeutic context of Trf

  • CONCLUSION: Receptor-mediated accumulation of [18F]Tf in tumor xenografts is impaired by rate-determining permeability and competition from endogenous Tf and is not achieved in a time frame of 6 h [38].
  • The model might prove useful in guiding site-directed mutagenesis studies, simplifying the experimental elucidation of the antibody structure, and in the use of automatic procedures to dock the interacting molecules as soon as structural information about the structure of the human Tf molecule will be available [39].
  • Through sequence analysis by automated Edman degradation, the N-terminal sequence of the 42 kDa-tryptic fragment was aligned to the N-terminus of mature transferrin (VPDKTVR) [40].
  • The 83-kD protein has been identified as transferrin on the basis of its electrophoretic migration and recognition on Western blots by an antitransferrin antibody [41].
  • Culture of embryos in serum containing 125I-transferrin, followed by autoradiography of embryo sections, shows that transferrin is taken up and localized in the gut beneath the closing neural folds at several levels of the body axis in 8.5- and 9.5-day embryos [41].


  1. Regulation of transferrin receptor 2 protein levels by transferrin. Robb, A., Wessling-Resnick, M. Blood (2004) [Pubmed]
  2. Increased plasma transferrin, altered body iron distribution, and microcytic hypochromic anemia in ferrochelatase-deficient mice. Lyoumi, S., Abitbol, M., Andrieu, V., Henin, D., Robert, E., Schmitt, C., Gouya, L., de Verneuil, H., Deybach, J.C., Montagutelli, X., Beaumont, C., Puy, H. Blood (2007) [Pubmed]
  3. In vivo gene delivery to tumor cells by transferrin-streptavidin-DNA conjugate. Sato, Y., Yamauchi, N., Takahashi, M., Sasaki, K., Fukaura, J., Neda, H., Fujii, S., Hirayama, M., Itoh, Y., Koshita, Y., Kogawa, K., Kato, J., Sakamaki, S., Niitsu, Y. FASEB J. (2000) [Pubmed]
  4. Transferrin and its receptor in the development of genetically determined neural tube defects in the mouse embryo. Hoyle, C., Henderson, D.J., Matthews, D.J., Copp, A.J. Dev. Dyn. (1996) [Pubmed]
  5. Evidence that dystroglycan is associated with dynamin and regulates endocytosis. Zhan, Y., Tremblay, M.R., Melian, N., Carbonetto, S. J. Biol. Chem. (2005) [Pubmed]
  6. Accelerated plasmacytoma formation in mice treated with alpha-fetoprotein. Gershwin, M.E., Castles, J.J., Makishima, R. J. Natl. Cancer Inst. (1980) [Pubmed]
  7. Anti-membrane-bound transferrin-like protein antibodies induce cell-shape change and chondrocyte differentiation in the presence or absence of concanavalin A. Oda, R., Suardita, K., Fujimoto, K., Pan, H., Yan, W., Shimazu, A., Shintani, H., Kato, Y. J. Cell. Sci. (2003) [Pubmed]
  8. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Ohgami, R.S., Campagna, D.R., Greer, E.L., Antiochos, B., McDonald, A., Chen, J., Sharp, J.J., Fujiwara, Y., Barker, J.E., Fleming, M.D. Nat. Genet. (2005) [Pubmed]
  9. A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice. Lim, J.E., Jin, O., Bennett, C., Morgan, K., Wang, F., Trenor, C.C., Fleming, M.D., Andrews, N.C. Nat. Genet. (2005) [Pubmed]
  10. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nicolas, G., Viatte, L., Lou, D.Q., Bennoun, M., Beaumont, C., Kahn, A., Andrews, N.C., Vaulont, S. Nat. Genet. (2003) [Pubmed]
  11. Inhibition of hemoglobin production by transferrin-gallium. Chitambar, C.R., Zivkovic, Z. Blood (1987) [Pubmed]
  12. Differential expression of a Mr approximately 90,000 cell surface transferrin receptor-related glycoprotein on murine B16 metastatic melanoma sublines selected for enhanced brain or ovary colonization. Nicolson, G.L., Inoue, T., Van Pelt, C.S., Cavanaugh, P.G. Cancer Res. (1990) [Pubmed]
  13. Desferal inhibits breast tumor growth and does not interfere with the tumoricidal activity of doxorubicin. Hoke, E.M., Maylock, C.A., Shacter, E. Free Radic. Biol. Med. (2005) [Pubmed]
  14. Release of lactoferrin by polymorphonuclear leukocytes after aerosol challenge with Escherichia coli. LaForce, F.M., Boose, D.S. Infect. Immun. (1987) [Pubmed]
  15. Distribution and number of transferrin receptors in Parkinson's disease and in MPTP-treated mice. Mash, D.C., Pablo, J., Buck, B.E., Sanchez-Ramos, J., Weiner, W.J. Exp. Neurol. (1991) [Pubmed]
  16. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Levy, J.E., Jin, O., Fujiwara, Y., Kuo, F., Andrews, N.C. Nat. Genet. (1999) [Pubmed]
  17. The molecular defect in hypotransferrinemic mice. Trenor, C.C., Campagna, D.R., Sellers, V.M., Andrews, N.C., Fleming, M.D. Blood (2000) [Pubmed]
  18. Assignment of the gene coding for hepatocyte growth factor-like protein to mouse chromosome 9. Degen, S.J., Gilbert, D.J., Jenkins, N.A., Copeland, N.G. Genomics (1992) [Pubmed]
  19. Transferrin receptor recycling in rat hepatocytes is regulated by protein phosphatase 2A, possibly through effects on microtubule-dependent transport. Runnegar, M., Wei, X., Berndt, N., Hamm-Alvarez, S.F. Hepatology (1997) [Pubmed]
  20. Inhibition of heme synthesis decreases transferrin receptor expression in mouse erythroleukemia cells. Hradilek, A., Fuchs, O., Neuwirt, J. J. Cell. Physiol. (1992) [Pubmed]
  21. Role of transferrin, transferrin receptors, and iron in macrophage listericidal activity. Alford, C.E., King, T.E., Campbell, P.A. J. Exp. Med. (1991) [Pubmed]
  22. The molecular basis of ferroportin-linked hemochromatosis. De Domenico, I., Ward, D.M., Nemeth, E., Vaughn, M.B., Musci, G., Ganz, T., Kaplan, J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  23. Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse. Trinder, D., Olynyk, J.K., Sly, W.S., Morgan, E.H. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  24. Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis. Chua, A.C., Olynyk, J.K., Leedman, P.J., Trinder, D. Blood (2004) [Pubmed]
  25. The effect of intracellular iron concentration and nitrogen monoxide on Nramp2 expression and non-transferrin-bound iron uptake. Wardrop, S.L., Richardson, D.R. Eur. J. Biochem. (1999) [Pubmed]
  26. CD71 antibody enhances iron uptake by mouse bone marrow cells and the survival potential of erythroid progenitor cells. Honda, K.I., Ishiko, O., Hato, F., Kitagawa, S., Jikihara, I., Yoshida, H., Ogita, S. Int. J. Mol. Med. (2001) [Pubmed]
  27. Impaired acidification in early endosomes of ClC-5 deficient proximal tubule. Hara-Chikuma, M., Wang, Y., Guggino, S.E., Guggino, W.B., Verkman, A.S. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  28. Receptor mediated and fluid phase pathways for internalization of the ER Hsp90 chaperone GRP94 in murine macrophages. Wassenberg, J.J., Dezfulian, C., Nicchitta, C.V. J. Cell. Sci. (1999) [Pubmed]
  29. Increased hepcidin expression and hypoferraemia associated with an acute phase response are not affected by inactivation of HFE. Frazer, D.M., Wilkins, S.J., Millard, K.N., McKie, A.T., Vulpe, C.D., Anderson, G.J. Br. J. Haematol. (2004) [Pubmed]
  30. Induction of Nramp2 in activated mouse macrophages is dissociated from regulation of the Nramp1, classical inflammatory genes, and genes involved in iron metabolism. Wardrop, S.L., Wells, C., Ravasi, T., Hume, D.A., Richardson, D.R. J. Leukoc. Biol. (2002) [Pubmed]
  31. Haemoglobin synthesis in erythropoietin-stimulated J2E cells does not require increased numbers of transferrin receptors. Callus, B.A., Busfield, S.J., Rossi, E., Tilbrook, P.A., Chappell, D., Morgan, E.H., Klinken, S.P. Eur. J. Biochem. (1997) [Pubmed]
  32. Similarities and differences in the regulation of N-myc and c-myc genes in murine embryonal carcinoma cells. Sejersen, T., Rahm, M., Szabo, G., Ingvarsson, S., Sümegi, J. Exp. Cell Res. (1987) [Pubmed]
  33. Fetal mouse kidney maturation in vitro: coordinated influences of epidermal growth factor, transferrin and hydrocortisone. Chailler, P., Ferrari, J., Brière, N. Anat. Embryol. (1991) [Pubmed]
  34. Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice. Canonne-Hergaux, F., Zhang, A.S., Ponka, P., Gros, P. Blood (2001) [Pubmed]
  35. Antigen entry into early endosomes is insufficient for MHC class II processing. Niebling, W.L., Pierce, S.K. J. Immunol. (1993) [Pubmed]
  36. Chromosomal localization of ceruloplasmin and transferrin genes in laboratory rats, mice and in man by hybridization with specific DNA probes. Baranov, V.S., Schwartzman, A.L., Gorbunova, V.N., Gaitskhoki, V.S., Rubtsov, N.B., Timchenko, N.A., Neifakh, S.A. Chromosoma (1987) [Pubmed]
  37. Structural organization and chromosomal localization of Hyal2, a gene encoding a lysosomal hyaluronidase. Strobl, B., Wechselberger, C., Beier, D.R., Lepperdinger, G. Genomics (1998) [Pubmed]
  38. Targeting of transferrin receptors in nude mice bearing A431 and LS174T xenografts with [18F]holo-transferrin: permeability and receptor dependence. Aloj, L., Jogoda, E., Lang, L., Caracò, C., Neumann, R.D., Sung, C., Eckelman, W.C. J. Nucl. Med. (1999) [Pubmed]
  39. Cloning, characterization, and modeling of a monoclonal anti-human transferrin antibody that competes with the transferrin receptor. Orlandini, M., Santucci, A., Tramontano, A., Neri, P., Oliviero, S. Protein Sci. (1994) [Pubmed]
  40. Partial characterization of the human serum transferrin epitope reactive with the monoclonal antibody TRC-2. Oztürk, S., Cirakoglu, B., Bermek, E. Hybrid. Hybridomics (2003) [Pubmed]
  41. Exogenous transferrin is taken up and localized by the neurulation-stage mouse embryo in vitro. Copp, A.J., Estibeiro, J.P., Brook, F.A., Downs, K.M. Dev. Biol. (1992) [Pubmed]
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