SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
The transferrin receptor has been isolated from human placenta using immunochromatography and affinity chromatography. The receptor is a glycoprotein and has a Mr = 90,000 on sodium dodecyl sulfate-gel electrophoresis in the presence of 2-mercaptoethanol. The isolated receptor is immunologically related to the transferrin receptor on the reticulocyte cell surface.
Transferrin and specific transferrin receptors are demonstrated on the microvillous surface of syncytiotrophoblast in human immature and term placentae by immuno histological techniques with the use of light and electron microscopy. That the distribution of transferrin is limited to the materno-foetal interface supports the hypothesis that binding of maternal transferrin to trophoblast receptors is involved in the process of iron transport to the foetus. Parallel studies with baboon placentae demonstrate the presence of trophoblast receptors which bind both baboon and human transferrin, thereby putting forward an experimental model which might be used to test the biological significance of placental transferrin receptors in primates. In addition, investigation of a large number of human cell lines shows that many transformed cells, but no normal cells (such as blood lymphocytes) or cells from primary culture (such as neonatal foreskin fibroblasts), possess the ability to bind transferrin to their membranes. These findings suggest that transferrin receptors may play important biological roles in addition to that of iron transport from mother to foetus. One such role could be the limitation of iron in intervillous spaces, thus depriving iron-requiring microorganisms of iron, hence serving as a non-specific factor of resistance for placentae. Another role for foetal transferrin receptors on trophoblasts could be to bind maternal transferrin at the materno-foetal interface, thus frustrating maternal immunosurveillance. This is similar to a mechahism used by schistosomes in the host-parasite relation where host proteins are bound by the parasite to escape immunological recognition. The presence of transferrin receptors on transformed cells suggests that this mechanism might also be employed by tumour cells. Finally, in view of previous studies which show that transferrin is required by stimulated lymphocytes to pass from the G1 to the S phase of cellular replication, it is proposed that trophoblast transferrin receptors could limit the amount of transferrin in intervillous spaces and thus impede the proliferation and possible cytotoxicity of maternal activated lymphocytes at the materno-foetal interface.
The hypothesis that modulation of transferrin receptors during haematopoiesis is mediated by changes in the lipid fluidity of the cell membranes was tested in this study with bone marrow cells. Binding conditions were first established, under which internalization of fluorescently-labelled transferrin was reduced to a minimum during the binding assays. Cholesterol depletion, which was achieved by a mild physiological treatment, and which increased the membrane-lipid fluidity, resulted in a substantial increase in the average number of the available transferrin receptors per bone marrow cell. Cholesterol enrichment mediated a converse effect. These findings correlate well with the changes observed in the availability of transferrin receptors and membrane microviscosity during differentiation of erythroid cells. In line with the notion of passive modulation, it is proposed that the transferrin receptor is a cross-membrane protein with a substantial portion facing the cytoplasm.
Experiments were performed to examine the fate of transferrin receptors in reticulocytes as these cells mature in vivo to erythrocytes. Reticulocytosis, synchronized by administration of actinomycin D, was induced in adult rabbits. Simultaneous measurements were made of haematological parameters and the interaction between transferrin and reticulocytes while the cells matured in vivo to erythrocytes. As the reticulocytes matured there was a parallel decline in their ability to take up transferrin and transferrin iron. At the same time, there was a proportionate decrease in the density of receptors for transferrin on the reticulocyte surface. The affinity of the receptors for transferrin remained unaltered during the maturation process. It was concluded that the inability of erythrocytes to take up transferrin or its iron is due primarily to the loss of transferrin receptors from the maturing reticulocyte surface.
PURPOSE: Many advanced-stage pancreatic cancers are fatal, highlighting the need for solid prognostic indicators. This study evaluates transferrin receptor-1 (TfR1) expression in pancreatic cancer tissues and cell lines for clinical and therapeutic potential. METHOD: The GuangRe database, which integrates mRNA data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project, was used to assess TFRC gene expression in pancreatic cancer and normal tissues. ROC curves and Kaplan-Meier and Log-rank tests were used to evaluate TFRC gene expression's diagnostic and survival efficacy. In vitro Western blotting and immunofluorescence experiments on pancreatic cancer cell lines assessed TfR1 expression. IHC staining was done on tissue samples from 90 patients to determine TfR1's clinical importance. RESULTS: The study found that TFRC mRNA levels were significantly higher in pancreatic cancer tissues compared to nearby normal tissues (P < 0.05), with an AUC of 0.936. We found higher TfR1 protein levels in pancreatic cancer cell lines (P < 0.01) using western blot and immunofluorescence studies. Immunohistochemistry showed that pancreatic cancer tissues expressed 30.1% TfR1 compared to paracancer (11.1%) (P = 0.003). In COX regression analysis, increased TfR1 expression was related with lower overall survival (OS) and progression-free survival (PFS), making it an independent prognostic factor. CONCLUSION: Higher TfR1 expression is associated with poor pancreatic cancer outcomes, suggesting its potential as a prognostic biomarker and therapeutic target.
This report describes investigations of plasma membrane transferring receptors on a variety of lymphoid cell lines and normal peripheral blood lymphocytes during activation and cell growth cycles. Transformed lymphoid cell lines have as many as 1,000 times the number of receptors found on normal resting lymphocytes. The number of iron transferrin receptors on continuous cell lines as well as normal human fibroblasts is down-regulated during the transition from log-phase growth to stationary plateau growth. When normal lymphocytes are transformed by mixed lymphocyte culture or mitogens, they rapidly express a 50-fold increase in the number of transferrin binding sites. This appearance of iron transferrin receptors anticipates nuclear changes during cell activation and subsequent mitosis of normal cells.
We have examined the binding of human transferrin to cultured human choriocarcinoma cell lines and to detergent extracts of such cells. The results indicate the presence of a high-affinity saturable binding site (Ka = 4.25 x 10(8) M-1) that is specific for transferrin. This receptor has also been detected on three other human cell lines of different phenotypic origin, including Wil-2 (splenic lymphocytes of B-cell origin), RPMI-2650 (a quasi-diploid nasopharyngeal carcinoma), and WI-38 (embryonic lung fibroblasts). By using anti-human transferrin antiserum to immunoprecipitate the receptor-transferrin complex from detergent extracts of cells containing saturating levels of transferrin followed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis, a single polypeptide of 90,000 daltons has been identified as a subunit of the putative transferrin receptor. The protein shows immunochemical identity and coelectrophoreses in sodium dodecyl sulfate gels with a cell surface glycoprotein subunit, previously identified in placental brush border membrane preparations, on all human cultured cell lines examined. These results suggest that the recent demonstration of transferrin dependence of maximal cell growth in culture [e.g., Hutchings, S.E. & Sato, G.H. (1978) Proc. Natl. Acad. Sci. USA 75, 901-904] is mediated through expression of this glycoprotein receptor.
A Triton X-100 solubilized macromolecular complex of transferrin and a membrane constituent can be isolated by gel chromatography from rabbit reticulocytes previously incubated with 125I-labeled transferrin. The apparent molecular weight of this complex is close to that of ferritin, or about 445 000. On sodium dodecyl sulfate gel electrophoresis the complex displays two glycoprotein subunits, of molecular weights 176 000 and 95 000 in addition to transferrin. A transferrin-binding fraction with a molecular weight near 400 000, containing these subunits, can also be identified in membranes of nonincubated reticulocytes. The corresponding membrane fraction from mature erythrocytes, which have lost transferrin-binding activity, displays both protein subunits, but the 176 000 molecular weight component fails to give a PAS stain for carbohydrate. Treatment of reticulocytes with Pronase, which destroys the ability of the cells to form specific complexes with transferrin, degrades both components. We believe these results are consistent with the hypothesis that the primary transferrin receptor of the rabbit reticulocyte is a glycoprotein of molecular weight in the range 350 000-400 000, comprised of a combination of two subunits with molecular weights 176 000 and 95 000, respectively. Transferrin-binding activity appears to depend on the carbohydrate moiety of the 176 000 subunit.
Experiments demonstrating the existence of receptors for iron-saturated transferrin on both B and T lymphoblastoid cell lines of human origin are described. Binding of 125I-labeled transferrin is rapid, saturable and reversible. It can be specifically inhibited by unlabeled transferrin but not by other proteins. The number of receptors on T cell lines determined by Scatchard analysis is almost double the number on B cell lines but the binding affinities are equal. The putative transferrin receptor can be removed from the cell by the proteolytic enzymes papain and trypsin, and is re-expressed during overnight incubation at 37 degrees C. Resynthesis is inhibited by puromycin. The receptor can be solubilized by deoxycholate, and retains transferrin binding capacity when non-covalently attached to an amphipathic matrix consisting of deoxycholate-coupled poly(L-lysyl) Agarose.
A macromolecular complex of transferrin and a membrane component was isolated by gel filtration chromatography from Triton X-100-solubilized ghosts of reticulocytes previously incubated with 125I-labeled transferrin. This complex is believed to be transferrin specifically associated with its primary receptors. Following the procedures of Clark [14], the complex in Triton X-100 was found to behave as an asymmetric molecule with a molecular weight of approximately 250,000 and an axial ratio of 9:1. On SDS-poly-acrylamide gel electrophoresis the complex displays, in addition to transferrin, components of molecular weights 176,000 and 95,000, respectively. The larger component may be a dimer of the smaller. Each appears to crosslink, with dimethyl suberimidate, to transferrin. These results are compatible with the hypothesis that the transferrin receptor itself has a molecular weight near 175,000 and may be a dimer of two smaller components each of molecular weight near 95,000.
Reticulocytes were separated on the basis of density by isopycnic centrifugation in dextran gradients. This parameter was shown to correlate with the degree of maturity of the cells. Lactoperoxidase iodination of cells of different densities followed by sodium dodecyl sulfate (NaDodSO4) electrophoresis revealed a 190 000 molecular weight protein which was well labeled in early reticulocyte membranes. Efficiency of labeling decreased as the cells increased in density, and high specific activity iodination of mature erythrocytes did not result in the labeling of any species near this molecular weight. Inclusion of rabbit transferrin prior to the iodination procedure resulted in a specific loss of labeling of this 190 000 molecular weight species. When steps were taken to clear endogenous transferrin from the membranes, the labeling of this species was enhanced. These observations are consistent with the concept that transferrin can block the lactoperoxidase catalyzed iodination of this membrane protein by specifically associating with it. Coomassie blue and periodic acid-Schiff staining of NaDodSO4 gels of these membranes revealed that a glycoprotein present at this molecular weight is lost during the course of reticulocyte maturation. It is concluded from these studies that a glycoprotein of molecular weight 190 000 constitutes the transferrin receptor in the reticulocyte membrane.
The ability of Friend erythroleukemic cells to bind transferrin and take up its iron increases substantially as a result of dimethyl sulfoxide-stimulated differentiation. Although transferrin-binding activity is also demonstrable in another mouse cell line of hematopoietic origin, the lymphoma cell, it does not increase on exposure to dimethyl sulfoxide. Gel filtration studies corroborate that the binding of transferrin to the erythroleukemic cells is due to the formation of a specific complex of transferrin and a membrane receptor. Thus, the specific interaction of transferrin with its receptor is another expression of dimethyl sulfoxide-induced differentiation in the Friend cell.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
1. In the process of iron uptake by precursors of the erythrocytes probably more than one membrane component is involved; besides the specific transferrin receptor, another membrane component with a high iron activity after incubation with 59Fe can be isolated. 2. A striking resemblance exists between rat and human reticulocyte components which are involved in the process of iron uptake. 3. Incubation of reticulocytes with Fab fragments of an antibody against the membrane receptor for transferrin causes a concentration-dependent decrease in transferrin binding and iron uptake. 4. The membrane receptor complex isolated is still heterogeneous; analytical ultracentrifugation studies suggest a molecular weight lower than 230,000. 5. Intact immature red cells are necessary for specific binding of transferrin with the receptor followed by iron uptake. This is the only mechanism for iron uptake. 6. Immunofluorescence studies showed that the receptor for transferrin is localized at the outside of the cell membrane.
In hepatocytes, transferrin receptor 1 (Tfr1) plays a limited role in iron acquisition but negatively regulates signaling to the iron hormone hepcidin (Hamp) through its interaction with the hemochromatosis protein Hfe. Its homolog, transferrin receptor 2 (Tfr2), operates as an iron sensor and direct positive regulator of hepcidin expression. We generated TfrcAlb-Cre;Tfr2Alb-Cre mice with hepatocyte-specific ablation of both Tfr1 and Tfr2 to study their effects on iron homeostasis. These animals are viable and develop systemic iron overload, recapitulating a key feature of Tfr2Alb-Cre mice, albeit with milder hepatic iron accumulation and relatively higher residual hepcidin expression, presumably driven by liberated Hfe. Only Tfr1-expressing primary hepatocytes from Tfrcfl/fl;Tfr2fl/fl and Tfr2Alb-Cre mice internalized fluorescent holo-transferrin (AF647-Tf), arguing against a significant contribution of Tfr2 or other receptors in transferrin-bound iron uptake. Under dietary iron restriction, Hamp mRNA suppression and hepatic iron depletion were comparable in Tfr2-deficient livers from TfrcAlb-Cre;Tfr2Alb-Cre and Tfr2Alb-Cre mice despite compensatory Tfr1 upregulation in the latter, which likely sequesters Hfe. Conversely, Tfr1-deficient but Tfr2-expressing livers from TfrcAlb-Cre mice displayed relatively elevated Hamp mRNA, as expected. Following an acute dietary iron challenge, Hamp mRNA induction and Smad1,5,9 phosphorylation occurred only in the liver of Tfr2-expressing TfrcAlb-Cre but not in TfrcAlb-Cre;Tfr2Alb-Cre mice, indicating that "liberated" Hfe requires Tfr2 to become functionally active. Collectively, these findings demonstrate that transferrin receptors are dispensable for hepatocellular iron supply, and Tfr2 and Hfe exhibit nonredundant functions under chronic iron loading but act cooperatively to induce hepcidin in response to an acute iron challenge.