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Dietmar Steverding - One of the best experts on this subject based on the ideXlab platform.

  • The significance of Transferrin Receptor variation in Trypanosoma brucei.
    Trends in parasitology, 2003
    Co-Authors: Dietmar Steverding
    Abstract:

    The Transferrin Receptor of Trypanosoma brucei is encoded by genes located in different expression sites. The various expression sites encode slightly different Transferrin Receptors, which differ substantially in their affinity for Transferrin of different host species. It was proposed that T. brucei has developed multiple expression sites encoding different Transferrin Receptors not only to cope with the diversity of mammalian Transferrins, but also to ensure sufficient iron uptake in the presence of anti-Transferrin Receptor antibodies. This article shows that calculations based on K(d) values argue against the first part of the hypothesis, but might support the second part.

  • The Transferrin Receptor of Trypanosoma brucei.
    Parasitology international, 2000
    Co-Authors: Dietmar Steverding
    Abstract:

    Bloodstream forms of Trypanosoma brucei, the causative agent of sleeping sickness in humans, require Transferrin for growth. Uptake of host Transferrin is mediated by a heterodimeric glycosylphosphatidylinositol-anchored Receptor. The trypanosomal Transferrin Receptor is homologous to the N-terminal domain of the variant surface glycoprotein (VSG) and bears no structural similarity with the human Transferrin Receptor. In this review, the structure, biochemical properties and function of the Transferrin Receptor of T. brucei are summarized and compared to the Transferrin Receptor of mammalian cells.

  • Iron-dependent regulation of Transferrin Receptor expression in Trypanosoma brucei.
    Biochemical Journal, 1999
    Co-Authors: Beate Fast, Katrin Kremp, Michael Boshart, Dietmar Steverding
    Abstract:

    Transferrin is an essential growth factor for African trypanosomes. Here we show that expression of the trypanosomal Transferrin Receptor, which bears no structural similarity with mammalian Transferrin Receptors, is regulated by iron availability. Iron depletion of bloodstream forms of Trypanosoma brucei with the iron chelator deferoxamine resulted in a 3-fold up-regulation of the Transferrin Receptor and a 3-fold increase of the Transferrin uptake rate. The abundance of expression site associated gene product 6 (ESAG6) mRNA, which encodes one of the two subunits of the trypanosome Transferrin Receptor, is regulated 5-fold by a post-transcriptional mechanism. In mammalian cells the stability of Transferrin Receptor mRNA is controlled by iron regulatory proteins (IRPs) binding to iron-responsive elements (IREs) in the 3'-untranslated region (UTR). Therefore, the role of a T. brucei cytoplasmic aconitase (TbACO) that is highly related to mammalian IRP-1 was investigated. Iron regulation of the Transferrin Receptor was found to be unaffected in Deltaaco::NEO/Deltaaco::HYG null mutants generated by targeted disruption of the TbACO gene. Thus, the mechanism of post-transcriptional Transferrin Receptor regulation in trypanosomes appears to be distinct from the IRE/IRP paradigm. The Transferrin uptake rate was also increased when trypanosomes were transferred from medium supplemented with foetal bovine serum to medium supplemented with sera from other vertebrates. Due to varying binding affinities of the trypanosomal Transferrin Receptor for Transferrins of different species, serum change can result in iron starvation. Thus, regulation of Transferrin Receptor expression may be a fast compensatory mechanism upon transmission of the parasite to a new host species.

Caroline A. Enns - One of the best experts on this subject based on the ideXlab platform.

  • Heterotypic interactions between Transferrin Receptor and Transferrin Receptor 2
    Blood, 2002
    Co-Authors: Todd M. Vogt, Aaron D. Blackwell, Anthony M. Giannetti, Pamela J. Bjorkman, Caroline A. Enns
    Abstract:

    Cellular iron uptake in most tissues occurs via endocytosis of diferric Transferrin (Tf) bound to the Transferrin Receptor (TfR). Recently, a second Transferrin Receptor, Transferrin Receptor 2 (TfR2), has been identified and shown to play a critical role in iron metabolism. TfR2 is capable of Tf-mediated iron uptake and mutations in this gene result in a rare form of hereditary hemochromatosis unrelated to the hereditary hemochromatosis protein, HFE. Unlike TfR, TfR2 expression is not controlled by cellular iron concentrations and little information is currently available regarding the role of TfR2 in cellular iron homeostasis. To investigate the relationship between TfR and TfR2, we performed a series of in vivo and in vitro experiments using antibodies generated to each Receptor. Western blots demonstrate that TfR2 protein is expressed strongest in erythroid/myeloid cell lines. Metabolic labeling studies indicate that TfR2 protein levels are approximately 20-fold lower than TfR in these cells. TfR and TfR2 have similar cellular localizations in K562 cells and coimmunoprecipitate to only a very limited extent. Western analysis of the Receptors under nonreducing conditions reveals that they can form heterodimers.

  • co trafficking of hfe a nonclassical major histocompatibility complex class i protein with the Transferrin Receptor implies a role in intracellular iron regulation
    Journal of Biological Chemistry, 1998
    Co-Authors: Cindy N Gross, Alivelu Irrinki, John N Feder, Caroline A. Enns
    Abstract:

    Abstract The mechanism by which a novel major histocompatibility complex class I protein, HFE, regulates iron uptake into the body is not known. HFE is the product of the gene that is mutated in >80% of hereditary hemochromatosis patients. It was recently found to coprecipitate with the Transferrin Receptor (Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., and Schatzman, R. C. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 1472–1477; Parkkila, S., Waheed, A., Britton, R. S., Bacon, B. R., Zhou, X. Y., Tomatsu, S., Fleming, R.E., and Sly, W. S. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 13198–13202) and to decrease the affinity of Transferrin for the Transferrin Receptor (Feder et al.). In this study, HeLa cells were transfected with HFE under the control of the tetracycline-repressible promoter. We demonstrate that HFE and the Transferrin Receptor are capable of associating with each other within 30 min of their synthesis with pulse-chase experiments. HFE and the Transferrin Receptor co-immunoprecipitate throughout the biosynthetic pathway. Excess HFE is rapidly degraded, whereas the HFE-Transferrin Receptor complex is stable. Immunofluorescence experiments indicate that they also endocytose into Transferrin-positive compartments. Combined, these results suggest a role for the Transferrin Receptor in HFE trafficking. Cells expressing HFE have modestly increased levels of Transferrin Receptor and drastically reduced levels of ferritin. These results implicate HFE further in the modulation of iron levels in the cell.

  • The Transferrin Receptor
    Biomembranes: A Multi-Volume Treatise, 1996
    Co-Authors: Caroline A. Enns, Elizabeth A. Rutledge, Anthony M. Williams
    Abstract:

    Publisher Summary This chapter discusses the structure and function of Transferrin Receptor (TfR). It also discusses the role of TfR in cell proliferation, TfR as a diagnostic marker of disease, and heterogeneity of the TfR and TfR in other organisms. The Transferrin Receptor (TfR) is an excellent model system to study ligand–Receptor interactions and Receptor-mediated endocytosis, as well as being important in the delivery of iron to cells. Iron is essential to many processes within the cell. Transferrin (Tf) is the major iron-transport protein in the blood of a wide variety of vertebrates and invertebrates. The uptake of Tf into cells that are rapidly proliferating or that have a specialized requirement for iron is mediated by a specific plasma membrane Receptor—the TfR. The TfR gene is 31 Kb and contains at least 19 introns. The mRNA is 4.9 Kb, 2.3 Kb of which codes for the TfR and the remaining 2.5 Kb is the 3' untranslated region. Chromosome mapping of the TfR revealed that it is located on human chromosome 3. More detailed mapping indicated that it is located on q26.2→qter. Two other iron proteins, Tf and p97, are also located on chromosome 3 in the same region.

  • Identification of the O-linked glycosylation site of the human Transferrin Receptor
    Glycobiology, 1992
    Co-Authors: Gary R Hayes, Caroline A. Enns, John J Lucas
    Abstract:

    : The human Transferrin Receptor is a glycoprotein containing three N-linked and one O-linked glycosylation sites. Tryptic digestion of the Receptor, followed by chromatography on BioGel P-2 and reverse-phase HPLC, yields a glycopeptide (amino acids 101-120) containing the O-linked site. Amino acid sequence analysis reveals that the site of O-glycosylation is Thr-104. Mass spectral analysis is consistent with the presence of a Gal-GalNAc core with predominantly two sialic acid residues.

  • a mutated Transferrin Receptor lacking asparagine linked glycosylation sites shows reduced functionality and an association with binding immunoglobulin protein
    Journal of Biological Chemistry, 1991
    Co-Authors: Anthony M. Williams, Caroline A. Enns
    Abstract:

    Abstract The function of the Transferrin Receptor is to transport iron-bound Transferrin into the cell. In order to function properly, this dimeric glycoprotein must be expressed on the cell surface and be able to bind Transferrin. Site-directed mutagenesis was performed to abolish the three asparagine-linked glycosylation consensus sequences of the human Transferrin Receptor. The DNA encoding the mutated Transferrin Receptor was stably transfected into mouse fibroblasts. This form of the human Transferrin Receptor shows reduced Transferrin binding, reduced intersubunit bond formation, and reduced cell surface expression, indicating that the Transferrin Receptor which lacks asparagine-linked glycosylation is not fully functional. In addition, the mutated form of the Receptor is not processed as quickly. It shows an association with an endoplasmic reticular chaperone protein, binding immunoglobulin protein, leading to the hypothesis that the mutated Transferrin Receptor experiences increased retention in the endoplasmic reticulum.

Marina Kvaternik - One of the best experts on this subject based on the ideXlab platform.

  • Soluble Transferrin Receptor and Transferrin Receptor-ferritin index in iron deficiency anemia and anemia in rheumatoid arthritis.
    Clinical chemistry and laboratory medicine, 2005
    Co-Authors: Sandra Margetić, Elizabeta Topić, Dragica Ferenec Ruzic, Marina Kvaternik
    Abstract:

    The aim of the study was to evaluate the clinical efficiency of soluble Transferrin Receptor and Transferrin Receptor-ferritin index (sTfR/IogF) in the diagnosis of iron deficiency anemia, as well as the differential diagnosis of iron deficiency anemia and anemia in rheumatoid arthritis. The study included 96 patients with anemia and 61 healthy volunteers as a control group. In healthy subjects there were no significant sex and age differences in the parameters tested. The study results showed these parameters to be reliable in the diagnosis of iron deficiency anemia, as well as in the differential diagnosis of iron deficiency anemia and anemia of chronic disease. The results indicate that sTfR/logF could be used to help differentiate coexisting iron deficiency in patients with anemia of chronic disease. Receiver operating characteristic analysis showed a higher discriminating power of Transferrin Receptor-ferritin index vs. soluble Transferrin Receptor in the diagnosis of iron deficiency anemia, as well as in the differential diagnosis between iron deficiency anemia and anemia of chronic disease. In patients with anemia in rheumatoid arthritis, the parameters tested showed no significant differences with respect to C-reactive protein concentration. These results suggested that the parameters tested are not affected by acute or chronic inflammatory disease.

Junji Kato - One of the best experts on this subject based on the ideXlab platform.

  • Transferrin Receptor in tissue and serum: updated clinical significance of soluble Receptor.
    International journal of hematology, 2002
    Co-Authors: Yutaka Kohgo, Yoshihiro Torimoto, Junji Kato
    Abstract:

    The Transferrin Receptor is an essential component of cellular uptake of iron, and it binds to serum Transferrin. Recently, 2 different types of Transferrin Receptors have been recognized: Transferrin Receptor (TfR or Transferrin Receptor 1) and Transferrin Receptor 2. Most cells possess a ubiquitous system controlling the biosynthesis of TfR at the posttranscriptional level to avoid excess iron influx into the cells through TfR. During the process of recycling of Transferrin Receptors, some are shed and appear as soluble or serum Transferrin Receptors. Measurement of serum Transferrin Receptor is a new marker of iron metabolism that reflects body iron stores and total erythropoiesis. It has been shown that serum Transferrin Receptor to ferritin ratios have significant predictive value for differentiating iron deficiency anemia from noniron deficiency anemia, such as anemia of chronic disorders, whereas serum ferritin is the only significant independent predictor of iron deficiency anemia.

  • Targeting cancer therapy by Transferrin Receptor mediated endocytosis.
    Drug Delivery System, 1993
    Co-Authors: Yutaka Kohgo, Junji Kato, Hiroshi Neda
    Abstract:

    The drug delivery system using Transferrin Receptor mediated endocytosis is described. Transferrin is a serum glycoprotein which carries iron to cells possessing its Receptor. The expression of Transferrin Receptor has been well known to be increased in cells with malignant transformation. Our aim is to utilize the Transferrin-Transferrin Receptor system for the specific delivery of anticancer drugs and foreign genes. Human Transferrin was conjugated with anticancer polypeptide, neocarzinostatin (NCS) by using (SPDP) and purified by ion exchange chromatography. The obtained Tf-NCS conjugate is capable binding to Transferrin Receptor and shows higher cytotoxicity. In vivo study using tumor inoculated mice also showed the significant growth suppression. The cytotoxicity of the conjugate was the sum of the Receptor binding and intracellular degradation. Similar strategy was adopted to foreign gene transfer to tumor cells and IL-2 activated lymphocytes both of which express Transferrin Receptors. Transferrin was conjugated with vector containing β-galactosidase by transamination. The conjugate was effectively transferred to cells by Receptor-mediated fashion and the transfected gene was expressed. This procedure would be useful for gene therapy.

Zev Sthoeger - One of the best experts on this subject based on the ideXlab platform.

  • diagnosis of iron deficiency anemia in the elderly by Transferrin Receptor ferritin index
    JAMA Internal Medicine, 2002
    Co-Authors: Ephraim Rimon, Shmuel Levy, Alexander Sapir, Gregorius Gelzer, Ronit Peled, David Ergas, Zev Sthoeger
    Abstract:

    Background: The diagnosis of iron deficiency anemia (IDA) in the elderly is difficult because of the prevalence of chronic diseases, which can cause anemia with high ferritin levels, even in the presence of iron deficiency. Therefore, we studied the sensitivity and specificity of a serum Transferrin Receptor assay, which is not affected by chronic diseases, in the diagnosis of IDA in elderly patients. Methods: We performed a prospective controlled study of 49 consecutive male and female patients older than 80 years who were admitted to an acute geriatric department. Bone marrow aspirate confirmed IDA in all 49 patients. Fourteen additional patients, also older than 80 years, with anemia but without evidence of iron deficiency on results of bone marrow examination, served as a control group. All patients underwent evaluation by means of a detailed medical history and results of complete physical examination, routine blood tests, and specific tests for diagnosis and evaluation of anemia. Examination of bone marrow aspirate was performed for all patients. Levels of Transferrin Receptor in serum were determined by means of a specific enzyme-linked immunosorbent assay. The Transferrin Receptor–ferritin index (TR-F index) was defined as the ratio of serum Transferrin Receptor level to log ferritin level. Results: Only 8 patients could be diagnosed as having IDA by means of routine blood test results (serum iron, ferritin, and Transferrin saturation levels). In contrast, the TR-F index disclosed IDA in 43 of the 49 patients, thus increasing the sensitivity from 16% to 88%. Conclusions: The diagnosis of IDA in the elderly by means of routine blood tests has a very low sensitivity. The TR-F index is much more sensitive, and when results are positive, the TR-F index can eliminate the need for bone marrow examination. Arch Intern Med. 2002;162:445-449