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Gene Review

TFRC  -  transferrin receptor (p90, CD71)

Gallus gallus

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Disease relevance of TFRC

  • V-ErbA, a mutated thyroid hormone receptor (TR) alpha cooperates with tyrosine kinase oncoproteins to induce fatal erythroleukemia in chicks [1].
  • In this study, we show that the adenovirus E1A oncoprotein functions as a strong coactivator for the thyroid hormone receptor (TR), and that TR and E1A synergistically activate transcription via direct (DR4) or palindromic (IRO) hormone-responsive sites [2].
  • Chicken transferrin receptor expression during erythroid differentiation and by retrovirus transformed cells [3].
  • Antiserum prepared against sucrose gradient purified reticuloendotheliosis virus (REV) recognized the chicken transferrin receptor [3].
  • Three murine monoclonal antibodies (mAbs) against the 61-residue amino-terminal cytoplasmic tail of the human transferrin receptor (TR) have been produced by immunization of mice with recombinant human TR produced in a baculovirus expression system [4].

High impact information on TFRC

  • A monoclonal antibody to the chicken transferrin receptor (JS-8) blocked temperature-induced and spontaneous differentiation of avian erythroid cells transformed by ts- and wt-retroviral oncogenes [5].
  • Endocytic cargo such as the transferrin receptor is incorporated into clathrin-coated pits by associating, via tyrosine-based motifs, with the AP2 complex [6].
  • To study thyroid hormone receptor (TR) action on neuronal cells in vitro, we expressed the chicken c-erbA/TR alpha-1 as well as its oncogenic variant v-erbA in the adrenal medulla progenitor cell line PC12 [7].
  • In contrast, TR alpha-1 allows normal differentiation and neuronal gene expression to occur in the presence of T3 [7].
  • A similar differentiation induction by NGF plus T3 was observed in a central nervous system-derived neuronal cell line (E 18) expressing exogenous TR alpha-1 [7].

Biological context of TFRC


Anatomical context of TFRC

  • Thyroid hormones are essential for correct brain development, and since vertebrates express two thyroid hormone receptor genes (TR alpha and beta), we investigated TR gene expression during chick brain ontogenesis [11].
  • In contast, expression of TR beta mRNA was restricted, occurring notably in brain, eye, lung, yolk sac and kidney, and was subject to striking developmental control, especially in brain where levels increased 30-fold upon hatching [12].
  • Surprisingly, both TR genes were expressed in early cerebellar outgrowth at E9, before known hormone requirements, with TR beta mRNA restricted to the ventricular epithelium of the metencephalon and TR alpha expressed in migrating cells and the early granular layer [11].
  • Antiserum against oviduct transferrin receptor did not stain erythrocytes, either from embryos or from mature animals [9].
  • Transferrin receptor hyperexpression in primary erythroblasts is lost on transformation by avian erythroblastosis virus [13].

Associations of TFRC with chemical compounds

  • In vitro-expressed TR beta protein bound thyroid hormone with similar affinity as the chicken TR alpha [12].
  • In GC cells stably transfected with a plasmid containing F2-TRE-TK-CAT or TRalpha, chloramphenicol acetyltransferase expression was T3 inducible and DMS footprinting revealed both F2 TRE TR-binding half sites in a pattern suggesting the binding of TR homodimers before and during T3 exposure [10].
  • Instead, we show that the mechanism of repression could occur at three different levels: (a) active silencing of transcription and dual competition for; (b) occupancy of DNA binding sites; and (c), heterodimer formation with retinoid X receptor, the coregulator of VDR, TR, and RAR [14].
  • It seems apparent from our studies that the NH2- and COOH-terminal half-molecules each contain a recognition region both of which are necessary for binding to the transferrin receptor and iron donation to the chick embryo red blood cell [15].
  • We show that TR endocytosis is not affected by tyrosine kinase or protein kinase C inhibitors, but is inhibited by one serine/threonine kinase inhibitor, H-89 [16].

Other interactions of TFRC


Analytical, diagnostic and therapeutic context of TFRC


  1. Mechanism of transformation by v-ErbA: substitution for steroid hormone receptor function in self renewal induction. Bauer, A., Ulrich, E., Andersson, M., Beug, H., von Lindern, M. Oncogene (1997) [Pubmed]
  2. The adenovirus E1A protein is a potent coactivator for thyroid hormone receptors. Wahlström, G.M., Vennström, B., Bolin, M.B. Mol. Endocrinol. (1999) [Pubmed]
  3. Chicken transferrin receptor expression during erythroid differentiation and by retrovirus transformed cells. Kline, K., Plante, L.A., Morgan, T.J., Sanders, B.G. Dev. Comp. Immunol. (1989) [Pubmed]
  4. Monoclonal antibodies against defined epitopes of the human transferrin receptor cytoplasmic tail. White, S., Miller, K., Hopkins, C., Trowbridge, I.S. Biochim. Biophys. Acta (1992) [Pubmed]
  5. Control of erythroid differentiation: possible role of the transferrin cycle. Schmidt, J.A., Marshall, J., Hayman, M.J., Ponka, P., Beug, H. Cell (1986) [Pubmed]
  6. Clathrin promotes incorporation of cargo into coated pits by activation of the AP2 adaptor micro2 kinase. Jackson, A.P., Flett, A., Smythe, C., Hufton, L., Wettey, F.R., Smythe, E. J. Cell Biol. (2003) [Pubmed]
  7. Thyroid hormone receptor/c-erbA: control of commitment and differentiation in the neuronal/chromaffin progenitor line PC12. Muñoz, A., Wrighton, C., Seliger, B., Bernal, J., Beug, H. J. Cell Biol. (1993) [Pubmed]
  8. Receptor-mediated endocytosis of transferrin-polycation conjugates: an efficient way to introduce DNA into hematopoietic cells. Zenke, M., Steinlein, P., Wagner, E., Cotten, M., Beug, H., Birnstiel, M.L. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  9. Differential tissue localization of oviduct and erythroid transferrin receptors. Fuernkranz, H.A., Schwob, J.E., Lucas, J.J. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  10. In vivo genomic footprinting of thyroid hormone-responsive genes in pituitary tumor cell lines. Kim, S.W., Ahn, I.M., Larsen, P.R. Mol. Cell. Biol. (1996) [Pubmed]
  11. Distinct functions for thyroid hormone receptors alpha and beta in brain development indicated by differential expression of receptor genes. Forrest, D., Hallböök, F., Persson, H., Vennström, B. EMBO J. (1991) [Pubmed]
  12. Contrasting developmental and tissue-specific expression of alpha and beta thyroid hormone receptor genes. Forrest, D., Sjöberg, M., Vennström, B. EMBO J. (1990) [Pubmed]
  13. Transferrin receptor hyperexpression in primary erythroblasts is lost on transformation by avian erythroblastosis virus. Lobmayr, L., Sauer, T., Killisch, I., Schranzhofer, M., Wilson, R.B., Ponka, P., Beug, H., Müllner, E.W. Blood (2002) [Pubmed]
  14. Multiple mechanisms of chicken ovalbumin upstream promoter transcription factor-dependent repression of transactivation by the vitamin D, thyroid hormone, and retinoic acid receptors. Cooney, A.J., Leng, X., Tsai, S.Y., O'Malley, B.W., Tsai, M.J. J. Biol. Chem. (1993) [Pubmed]
  15. Physiological levels of binding and iron donation by complementary half-molecules of ovotransferrin to transferrin receptors of chick reticulocytes. Brown-Mason, A., Woodworth, R.C. J. Biol. Chem. (1984) [Pubmed]
  16. Casein kinase II activity is required for transferrin receptor endocytosis. Cotlin, L.F., Siddiqui, M.A., Simpson, F., Collawn, J.F. J. Biol. Chem. (1999) [Pubmed]
  17. Chick ciliary neurotrophic factor is secreted via a nonclassical pathway. Reiness, C.G., Seppa, M.J., Dion, D.M., Sweeney, S., Foster, D.N., Nishi, R. Mol. Cell. Neurosci. (2001) [Pubmed]
  18. Characterization of early and late endocytic compartments of the transferrin cycle. Transferrin receptor antibody blocks erythroid differentiation by trapping the receptor in the early endosome. Killisch, I., Steinlein, P., Römisch, K., Hollinshead, R., Beug, H., Griffiths, G. J. Cell. Sci. (1992) [Pubmed]
  19. Localization of transferrin binding protein in relation to iron, ferritin, and transferrin receptors in the chicken cerebellum. Cho, S.S., Shin, D.H., Lee, K.H., Hwang, D.H., Chang, K.Y. Brain Res. (1998) [Pubmed]
  20. Identification and characterization of the chicken transferrin receptor. Schmidt, J.A., Marshall, J., Hayman, M.J. Biochem. J. (1985) [Pubmed]
  21. 1,25-Dihydroxyvitamin D3 inhibits thyroid hormone-induced osteocalcin expression in mouse osteoblast-like cells via a thyroid hormone response element. Varga, F., Spitzer, S., Rumpler, M., Klaushofer, K. J. Mol. Endocrinol. (2003) [Pubmed]
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