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PubMed1985

The biosynthesis of rat transferrin. Evidence for rapid glycosylation, disulfide bond formation, and tertiary folding.

The transit time of newly synthesized transferrin in the liver is markedly longer than that of albumin. We sought to learn the basis of this difference by the use of labeled leucine and mannose in vivo and by isolation of newly formed transferrin from rough microsomes of rat liver. Albumin and alpha 1-antitrypsin, a second glycoprotein, were also studied for comparison. Minimal hepatic transit times were 17, 23, and 31 min for albumin, alpha 1-antitrypsin, and transferrin, respectively. The delay in the case of transferrin was found to occur chiefly in the rough endoplasmic reticulum and to be paralleled by an increase in the amount of transferrin relative to albumin in that organelle. Initial glycosylation of transferrin was as rapid as that of alpha 1-antitrypsin, and essentially all of the transferrin in the rough endoplasmic reticulum contained glycans which bound to concanavalin A and were removed by endoglycosidase H. Only 3% of the transferrin isolated from the rough microsomes came from the plasma by endocytosis or adsorption. Rapidity of disulfide bond formation in rough microsomes was evident from the presence of only 1.3 cysteine thiols/molecule of rough microsomal transferrin (total of 19 cystines) and the absence of mixed disulfides. Peptide patterns upon mild proteolysis were consistent with a native configuration of disulfide bond pairing. The ability of rough microsomal transferrin to bind and deliver iron through interaction with transferrin receptors on reticulocytes suggests that considerable tertiary structure is present. Thus, initial glycosylation, disulfide bridging, and tertiary folding are all rapid processes. The cause for the slow release of transferrin from the rough endoplasmic reticulum may lie with a rate-limiting transfer mechanism.

Animals↗
PubMed1982

Transferrin in the rat prostate Dunning tumor.

A major protein of the rat Dunning prostate tumor has been purified. It has physicochemical properties and an amino acid composition similar to that of transferrin. Furthermore, the isolated tumor protein reacts with antiserum to authentic rat transferrin. Immunoperoxidase staining with rabbit anti-rat transferrin localizes transferrin within tumor acinar glands. Rocket immunoelectrophoresis indicates that transferrin constitutes 30 to 40% of tumor fluid protein, but accounts for only approximately 9% of total serum protein. In normal rat prostate cytosols, the level of transferrin is at least 200 times lower than in tumor cytosol. Nevertheless, dorsal and lateral prostate show variable peroxidase staining indicating the presence of immunoreactive transferrin within acinar glands of these normal tissues. While intense staining for transferrin was found in the interstium of all regions of the normal prostate, transferrin was not detected within acinar glands of coagulating gland, ventral prostate, or seminal vesicle. Immunocytochemical localization of albumin indicates a distribution similar to that of transferrin in normal and neoplastic rat prostate. However, unlike transferrin, the albumin content was lower in tumor fluid than in serum. It is suggested that the high level of transferrin in tumor fluid may be due to selective uptake by the tumor from serum.

Albumins↗
PubMed1981

Comparison of derived and actual transferrin: a potential source of error in clinical nutritional assessment.

A prospective study was undertaken to evaluate the utility of calculating transferrin from total iron-binding capacity in the nutritional assessment of burned patients. Regression analysis was used to compare total iron-binding capacity with radial immunodiffusion transferrin determinations. The method used for calculating transferrin (0.8 TIBC - 43) is a frequently published conversion formula for deriving transferrin. One hundred twenty-five data sets were obtained from 45 burned patients. Values for derived transferrin ranged from 39 to 235 mg/dl, averaging 121 mg/dl. Actual transferrin averaged 162 mg/dl, ranging from 41 to 320 mg/dl. Forty-eight actual serum transferrin samples were normal (greater than 172 mg/dl) whereas only 17 derived transferrin values were normal. While there is a correlation between total iron-binding capacity and serum transferrin (r = 0.85), to calculate transferrin according to the formula above would have resulted in significant error in the clinical assessment of the patients' nutritional status (p less than 0.001). From our studies, the formula for conversion of total iron-binding capacity to transferrin was found to be (0.68 TIBC + 21). These results suggest that the development of a universal conversion factor is not feasible. Modification of the formula may be necessary at each institution for clinically useful evaluations of serum transferrins are to be derived from iron-binding capacity for use in nutritional assessment.

Adolescent↗
PubMed1993

Binding of lactoferrin and transferrin to the human promonocytic cell line U937. Effect on iron uptake and release.

We have compared the ability of lactoferrin and transferrin to interact with and donate iron to the monocytic cell line U937. About 10 times more lactoferrin was bound than transferrin, but most lactoferrin bound nonspecifically, and the degree of specific binding was similar for both proteins (2-3 x 10(6) sites/cell). The binding affinity for lactoferrin (83 nM) was about 4-fold lower than for transferrin (21 nM). Lactoferrin did not inhibit binding of transferrin, or vice versa. Binding of lactoferrin was not inhibited by 30 mM glucose or fucose nor by incubating the cells with heparinase. Transferrin, but not lactoferrin, was internalized, and 3 mM primaquine caused intracellular accumulation of transferrin but not lactoferrin. The cells rapidly acquired iron from transferrin, but uptake from lactoferrin was 10-fold slower and probably resulted from transfer of 59Fe from lactoferrin to unlabeled transferrin during culture. Lactoferrin, but not transferrin, released iron to the extracellular medium when bound to U937 cells. Lactoferrin inhibited cellular uptake of iron from Fe-nitrilotriacetate but not from transferrin. It is concluded that transferrin, but not lactoferrin, acts as an iron donor to U937 cells. Lactoferrin may regulate uptake of potentially toxic non-transferrin-bound iron.

Binding Sites↗
PubMed1987

NADH diferric transferrin reductase in liver plasma membrane.

Evidence is presented that rat liver plasma membranes contain a distinct NADH diferric transferrin reductase. Three different assay procedures for demonstration of the activity are described. The enzyme activity is highest in isolated plasma membrane, and activity in other internal membranes is one-eighth or less than in plasma membrane. The activity is inhibited by apotransferrin and antitransferrin antibodies. Trypsin treatment of the membranes leads to rapid loss of the transferrin reductase activity as compared with NADH ferricyanide reductase activity. Erythrocyte plasma membranes, which lack transferrin receptors, show no diferric transferrin reductase activity, although NADH ferricyanide reductase is present. The transferrin reductase is inhibited by agents that inhibit diferric transferrin reduction by intact cells and is activated by CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfate) detergent. Inhibitors of mitochondrial electron transport have no effect on the activity. We propose that the NADH diferric transferrin reductase in plasma membranes measures the activity of the enzyme that causes the reduction of diferric transferrin by intact cells. This transmembrane electron transport system requires the transferrin receptor for diferric transferrin reduction. Because the transmembrane electron transport has been shown to stimulate cell growth, the reduction of diferric transferrin at the cell surface may be an important function for diferric transferrin in stimulation of cell growth, in addition to its role in iron transport.

Animals↗
PubMed1981

Demonstration of the transferrin receptor in human breast cancer tissue. Potential marker for identifying dividing cells.

A transferrin receptor was demonstrated in tumor tissue from 10 patients with breast carcinoma and one patient with breast sarcoma. Binding studies were conducted by measuring the amont of 1251-transferrin binding to microsomal preparations of the tumor tissue. Elevated levels of specific transferrin binding were found in the tumors with a range of 11-35% of bound transferrin, whereas microsomes prepared from non-neoplastic breast tissue samples bound only 2.3% and 2.4% of the transferrin. Scatchard analysis of binding studies conducted with tissues from a breast cancer and from a breast sarcoma indicate that the receptor has a Ka = 9.0 x 10(8)M. The binding site is specific for transferrin, as studies show that non-radioactive transferrin displaced labelled transferrin, while human IgG and human albumin did not. The receptor-transferrin complex was precipitated from a detergent extract of the breast sarcoma with antiserum to human transferrin. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis of the immunoprecipitate gave a polypeptide of M 90,000 daltons, which is of similar molecular weight found for the putative transferrin receptor in all of a series of human cultured cell lines previously examined.

Breast Neoplasms↗
PubMed1993

The interaction of primate transferrins with receptors on bacteria pathogenic to humans.

The binding of primate transferrins by receptors in the human pathogens Neisseria meningitidis, Moraxella (Branhamella) catarrhalis, and Haemophilus influenzae was assessed and compared with the binding of anti-human transferrin monoclonal antibodies by primate transferrins. In competitive binding assays the three pathogens showed identical specificity for primate transferrins. Only human, gorilla, chimpanzee and orangutan sera were capable of blocking binding of labelled human transferrin. Direct binding assays and affinity isolation of receptor proteins confirmed that chimpanzee transferrin, but not rhesus monkey transferrin, was capable of effectively binding to the bacterial receptors. Five distinct patterns of binding were seen when five anti-human transferrin monoclonal antibodies were reacted with the primate transferrins and these patterns reflected phylogenetic relatedness of these species to humans. A monoclonal antibody which showed transferrin-binding specificity identical to that seen with the bacterial receptors was found to block binding of human transferrin by receptors in the three bacterial species.

Animals↗
PubMed1994

The endocytosis of transferrin by rat intestinal epithelial cells.

BACKGROUND/AIMS: The transferrin receptor is a prominent protein on the basal and lateral membranes of intestinal epithelial cells, yet little is known of the function of the receptor in the intestine. The aim of the present study was to determine whether intestinal transferrin receptors were capable of facilitating transferrin internalization. METHODS: Using the rat as an experimental model, the uptake of radiolabeled transferrin by cells isolated from different regions along the crypt-villus axis of the proximal small intestine was studied. RESULTS: An intestinal epithelial cell fraction highly enriched in crypt cells bound most radiolabeled transferrin. Cells in this fraction were able to internalize transferrin and recycle it back to the cell surface. A high affinity, saturable pathway of transferrin uptake by these cells predominated at transferrin concentrations below 0.3 mumol/L, whereas at higher concentrations, most uptake was via a nonsaturable process. Intravenously injected radiolabeled transferrin could be detected within intestinal crypt cells, indicating that these cells are able to internalize transferrin in vivo. CONCLUSIONS: These data suggest that intestinal crypt cells have an active transferrin/transferrin receptor system. Transferrin may play an important role in iron delivery to and/or as a growth factor for the rapidly proliferating intestinal epithelium.

Animals↗
PubMed1992

Ligand-receptor interactions in affinity cell partitioning. Studies with transferrin covalently linked to monomethoxypoly(ethylene glycol) and rat reticulocytes.

The partitioning of rat reticulocytes in poly(ethylene glycol) (PEG)-dextran two-phase systems increases into the PEG-rich top phase when the cells are incubated with transferrin covalently modified with monomethoxy-PEG (MPEG-transferrin) prior to partitioning. Two observations support the suggestion that such an increase in top-phase partitioning is due to the specific interaction of the MPEG-transferrin conjugate with the transferrin receptor on the surface of the reticulocyte: first, the MPEG-transferrin conjugate competes with [125I]transferrin for the transferrin receptor on reticulocytes (Ka = 6.28 x 10(6) l mol-1); and second, the MPEG-modified transferrin is unable to change the partitioning of rat erythrocytes, cells lacking the transferrin receptor. This example illustrates the feasibility of manipulating the partitioning of a selected cell population when ligand-receptor interactions are exploited. The increase in the partitioning of the reticulocytes takes place within a narrow range of MPEG-transferrin bound per cell, viz., 10.2-11.3 fg per cell. The latter range corresponds to ca. 80,000-89,000 molecules of MPEG-transferrin bound per cell.

Animals↗
PubMed1994

Lymphocyte lines under iron-depriving conditions: transferrin receptor expression related to various growth responses.

The relation of expression of cell surface transferrin receptors to growth responses under defined iron-depriving conditions was studied in mouse B-cell line PLV-01, human T-cell line Jurkat, and human B-cell line Raji. Iron chelator deferoxamine at a concentration of 150 microM, which inhibited completely growth of the cell lines cultured in a serum-free transferrin-containing (5 micrograms/ml) medium, stimulated the surface transferrin receptor number to increase to 150-250% within a 24-h incubation period. The increased number (300%) of transferrin receptors on PLV-01 cells was associated with complete growth inhibition of these cells in counterpart serum-free transferrin-free medium. Only a slight increase in transferrin receptor number on Raji cells corresponded with unaffected growth of these cells in the transferrin-free medium. Jurkat cells increased the number of transferrin receptors to 150-200% and decreased the number of cells grown in the transferrin-free medium to about 60%. The data show that, under limited availability of iron, a significant increase of transferrin receptor expression on lymphoid cells was found only when the growth of the cells was inhibited. However, complete inhibition of growth achieved under different iron-depriving conditions is accompanied by different degrees of increase in transferrin receptor number.

Animals↗
PubMed2003

Identification and characterization of the hepatic stellate cell transferrin receptor.

Activated hepatic stellate cells have been implicated in the fibrogenic process associated with iron overload, both in animal models and in human hemochromatosis. Previous studies have evaluated the role of ferritin/ferritin receptor interactions in the activation of stellate cells and subsequent fibrogenesis; however, the role of transferrin in hepatic stellate cell biology is unknown. This study was designed to identify and characterize the stellate cell transferrin receptor and to evaluate the influence of transferrin on stellate cell activation. Identification and characterization of the stellate cell transferrin receptor was determined by competitive displacement assays. The effect of transferrin on stellate cell activation was assessed using western blot analysis for alpha-smooth muscle actin expression, [(3)H]Thymidine incorporation, and real-time RT-PCR for procollagen alpha1(I) mRNA expression. A specific receptor for rat transferrin was observed on activated but not quiescent stellate cells. Transferrin significantly increased the expression of alpha-smooth muscle actin, but caused a decrease in proliferation. Transferrin induced a significant increase in procollagen alpha1(I) mRNA expression. In conclusion, this study has demonstrated for the first time a specific, high affinity receptor for rat transferrin on activated hepatic stellate cells, which via interaction with transferrin regulates stellate cell activation. This suggests that transferrin may be an important factor in the activation of hepatic stellate cells in conditions of iron overload.

Animals↗
PubMed2000

Overexpression of hemochromatosis protein, HFE, alters transferrin recycling process in human hepatoma cells.

HFE is a MHC class 1-like protein that is mutated in hereditary hemochromatosis. In order to elucidate the role of HFE protein on cellular iron metabolism, functional studies were carried out in human hepatoma cells (HLF) overexpressing a fusion gene of HFE and green fluorescent protein (GFP). The expression of HFE-GFP was found to be localized on cell membrane and perinuclear compartment by fluorescent microscopy. By co-immunoprecipitation and Western blotting, HFE-GFP protein formed a complex with endogenous transferrin receptor and beta(2)-microglobulin, suggesting that this fusion protein has the function of HFE reported previously. We then examined the (59)Fe uptake and release, and internalization and recycling of (125)I-labeled transferrin in order to elucidate the functional roles of HFE in the cell system. In the transfectants, HFE protein decreased the rate of transferrin receptor-dependent iron ((59)Fe) uptake by the cells, but did not change the rate of iron release, indicating that HFE protein decreased the rate of iron influx. Scatchard analysis of transferrin binding to HFE-transfected cells showed an elevation of the dissociation constant from 1.9 to 4. 3 nM transferrin, indicating that HFE protein decreased the affinity of transferrin receptor for transferrin, while the number of transferrin receptors decreased from 1.5x10(5)/cell to 1. 2x10(5)/cell. In addition, the rate of transferrin recycling, especially return from endosome to surface, was decreased in the HFE-transfected cells by pulse-chase study with (125)I-labeled transferrin. Our results strongly suggest an additional role of HFE on transferrin receptor recycling in addition to the decrease of receptor affinity, resulting in the reduced cellular iron.

Carcinoma, Hepatocellular↗
PubMed1991

Receptor-modulated iron release from transferrin: differential effects on N- and C-terminal sites.

Iron release to PPi from N- and C-terminal monoferric transferrins and their complexes with transferrin receptor has been studied at pH 7.4 and 5.6 in 0.05 M HEPES or MES/0.1 M NaCl/0.01 M CHAPS at 25 degrees C. The two sites exhibit kinetic heterogeneity in releasing iron. The N-terminal form is slightly less labile than its C-terminal counterpart at pH 7.4, but much more facile in releasing iron at pH 5.6. At pH 7.4, iron removal by 0.05 M pyrophosphate from each form of monoferric transferrin complexed to the receptor is considerably slower than from the corresponding free monoferric transferrin. However, at pH 5.6, complexation of transferrin to its receptor affects the two forms differently. The rate of iron release to 0.005 M pyrophosphate by the N-terminal species is substantially the same whether transferrin is free or bound to the receptor. In contrast, the C-terminal form releases iron much faster when complexed to the receptor than when free. Urea/PAGE analysis of iron removal from free and receptor-complexed diferric transferrin at pH 5.6 reveals that its C-terminal site is also more labile in the complex, but its N-terminal site is more labile in free diferric transferrin. Thus, the newly discovered role of transferrin receptor in modulating iron release from transferrin predominantly involves the C-terminal site. This observation helps explain the prevalence of circulating N-terminal monoferric transferrin in the human circulation.

Amino Acid Sequence↗
PubMed1985

Transferrin receptors in rat brain: neuropeptide-like pattern and relationship to iron distribution.

We have characterized and visualized the binding of 125I-labeled transferrin to sections of rat brain. This saturable, reversible, high-affinity (Kd = 1 X 10(-9) M) binding site appears indistinguishable from transferrin receptors previously characterized in other tissues. Moreover, a monoclonal antibody raised to rat lymphocyte transferrin receptors could immunoprecipitate recovered intact transferrin solubilized from labeled brain slices, indicating that labeling was to the same molecular entity previously characterized as the transferrin receptor. The pattern of transferrin receptor distribution visualized in brain with both 125I-labeled transferrin and an anti-transferrin receptor monoclonal antibody are almost indistinguishable but differ from the pattern of iron distribution. Iron-rich brain areas generally receive neuronal projections from areas with abundant transferrin receptors, suggesting that iron may be transported neuronally. However, many brain areas with a high density of transferrin receptors appear unrelated to iron uptake and neuronal transport and form a receptor distribution pattern similar to that of other known neuropeptides. This "neuropeptide-like" distribution pattern suggests that transferrin may have neuromodulatory, perhaps behavioral, function in brain.

Animals↗
PubMed1985

Phylogenetically more conservative epitopes among monoclonal antibody-defined antigenic sites of human transferrin are involved in receptor binding.

Of eight monoclonal antibodies raised against human transferrin, one (H.TF-14) cross reacted with pig and rabbit transferrins and one (H.TF-1) showed cross-reactivity with horse and dog transferrins. While rabbit and pig transferrins exhibited the same patterns of binding to MOLT-3 cell receptors as human and horse transferrins, binding of mouse and dog transferrins was weaker and bovine and carp transferrins gave entirely negative results. The results of these competitive binding experiments were confirmed by a biological test in which bovine transferrin had no effect on the growth of MOLT-3 cells when added to a serum-free medium. The observed correlation between cross-reactivity of anti-transferrin monoclonal antibodies and the binding abilities of transferrins to the MOLT-3 cell receptors may be associated with the conservatism of the part of the transferrin molecule recognized by the cell receptor.

Animals↗
PubMed1992

In vivo behaviour of rat transferrin bearing a hybrid glycan and its interaction with macrophages.

Production of rat transferrin containing a single hybrid glycan was induced by treating rats with swainsonine, an inhibitor of alpha-mannosidase II. The principal component of this variant transferrin containing one sialic acid residue per mole of protein was separated from other forms of transferrin by anion-exchange chromatography, followed by lectin affinity chromatography. Transferrin bearing the hybrid glycan was degraded in vivo with a half-life of 14 h as compared with 40 h for transferrin containing a standard diantennary glycan. By using 125I-labelled tyramine-cellobiose, a label whose discharge from lysosomes is strongly retarded, organs rich in reticuloendothelial elements (liver, bone marrow, lungs, and spleen) were identified as the major sites of catabolism of the transferrin variant. The liver took up more 59Fe from the variant (26% of the dose in 90 min) than from control rat transferrin (12%). The excess iron uptake was reduced by the intravenous injection of either human transferrin or ovalbumin, and it was abolished by administering both. Macrophages from bone marrow and lungs degraded the transferrin variant in vitro. The degradation was significantly enhanced when transferrin receptors were blocked by human transferrin, and it was significantly reduced by ovalbumin and methyl glucopyranoside.

Animals↗
PubMed1989

Uptake and distribution of transferrin and iron in perfused, iron-deficient rat liver.

Uptake of transferrin and iron by the rat liver was investigated by perfusion in vitro with 125I-59Fe-labeled rat transferrin and subcellular fractionation on sucrose density gradients. Most of the 125I-transferrin was located in a low-density vesicle fraction. The 59Fe was in three peaks, of lower, the same, and higher densities than the transferrin peak. Iron deficiency resulted in a large increase in transferrin and iron uptake into all subcellular fractions. When livers were perfused with increasing concentrations of transferrin the uptake into the different peaks of transferrin and iron increased in a curvilinear fashion, which indicated that uptake occurred by saturable and nonsaturable processes, both of which increased in iron deficiency. In contrast, the uptake of 131I-labeled rat serum albumin increased linearly with concentration, and there was no difference between control and iron-deficient livers. It is concluded that iron deficiency leads to an increase in the number of high-affinity transferrin receptors and receptor-mediated endocytosis of transferrin. It also increases a nonsaturable transferrin uptake process that is probably due to adsorptive, but selective, endocytosis of transferrin.

Animals↗
PubMed1989

[Detection of transferrin in the digestive juices of rat and its possible role in iron absorption from the small intestine].

Presence of transferrin in digestive juices and its possible role in iron absorption of rats were examined. Transferrin concentrations in saliva, bile, pancreas juice and intestinal fluid obtained from adult rats of the Wistar strain were measured by Rocket immunoelectrophoretic assay. Transferrin concentration in pancreas juice was the highest (approximately 0.28 mg/ml) in the collected digestive juices and the concentration in iron deficient rats was 4 times higher than that of normal rats. The iron saturation rate of transferrin in pancreas juice was approximately 40%. The participation of transferrin in iron absorption was investigated by the absorption through the intestinal segment of rats, into which 59Fe labeled diferric transferrin was injected. The rate of iron absorption was more efficient in duodenal and proximal segments compared to the distal segment of the small intestine. The value was approximately 20% in the duodenal segment but less than 2% in the ileal segment. Iron absorption from diferric transferrin in the duodenal segment was inhibited by 1 mM monodansylcadaverine, the inhibitor of endocytosis, or addition of 20 times the normal amounts of nonradioactive transferrin in the test material. These data indicated that the process of iron absorption through diferric transferrin was not a passive phenomenon. Furthermore, one hour after the absorption of diferric 125I-labeled transferrin in the proximal segment of the small intestine, 125I-labeled transferrin was detected from the mucosal tissue of the segment, the luminal surface of which had been treated by 0.25% pronase E before the mucosal scraping.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗