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PubMed1995

Influence of cellular trafficking on protein synthesis inhibition of immunotoxins directed against the transferrin receptor.

Previously, a quantitative analysis that related protein synthesis inhibition of transferrin-toxin conjugates to the cellular trafficking of transferrin was proposed (P.T. Yazdi and R. M. Murphy, Cancer Res., 54: 6387-6394, 1994). Here, this work is extended to evaluate cellular trafficking of anti-transferrin receptor antibodies and protein synthesis inhibition kinetics of immunotoxins constructed from the same antibodies and the toxin gelonin. Cellular trafficking models for two monoclonal anti-transferrin receptor antibodies (5E9 and OKT9) in HeLa cells were developed. The two mAbs had similar trafficking parameters, which differed significantly from those for transferrin. Protein synthesis inhibition kinetics for immunotoxins constructed from 5E9 or OKT9 and gelonin were measured. Analysis of the data using our previously proposed relationship between protein synthesis and cellular trafficking indicated that the relationship is also valid for these new systems. The protein synthesis inhibition constants for 5E9-gelonin and OKT9-gelonin conjugates were similar to those for the transferrin-gelonin conjugate. These results suggest that it may be possible to predict the efficacy of gelonin immunotoxins from knowledge of the trafficking of the corresponding targeting agent. A sensitivity analysis showed which cellular trafficking parameters have the greatest influence on immunotoxin efficacy and are, therefore, the most likely to be profitably manipulated.

Antibodies, Monoclonal↗
PubMed1996

Effects of dietary iron loading with carbonyl iron and of iron depletion on intestinal growth, morphology, and expression of transferrin receptor in the rat.

BACKGROUND: The intestine has one of the highest cell turnovers of the body, which is characterised by cell proliferation and differentiation occurring at specified locations along the crypt to the villus axis. These processes require iron for the synthesis of iron-dependent proteins, the supply of which is mediated through the transferrin receptor. In this study, we varied dietary iron intake to determine whether this affected the pattern of transferrin receptor expression and activity on intestinal cell turnover and cell differentiation. METHODS: Variations in iron stores were produced by feeding a control diet and diets high (2% carbonyl iron) or low in iron for 8-10 weeks. Total tissue DNA and the incorporation of thymidine into DNA, and RNA and protein were used as indices of hyperplasia and hypertrophy, respectively. Transferrin receptor expression and activity in the intestinal mucosa were assessed by using in situ hybridisation and the uptake of transferrin-bound 55Fe. RESULTS: Iron loading caused mucosal hypertrophy in the small and large intestines. With all levels of dietary iron transferrin- receptor expression and activity were present within the progenitor and differentiating regions of the mucosa but ceased upon cellular maturation. CONCLUSIONS: Feeding carbonyl iron leads to mucosal hypertrophy. Expression of transferrin receptor mRNA and activity is dependent upon proliferation and differentiation of the mucosal epithelium, regardless of the cellular iron stores within these cells.

Animals↗
PubMed2002

Mapping of stereoselective recognition sites on human serum transferrin by capillary electrophoresis and molecular modelling.

Stereoselective recognition of chiral compounds can be used for mapping of surface interaction sites on proteins. Iron-free human serum transferrin is a suitable chiral selector in capillary electrophoresis used in native form in solution. Separation of optical isomers of tryptophan-methylester, tryptophan-ethylester and tryptophan-butylester and various drugs were studied in capillary zone electrophoresis applying a distinct transferrin zone prior to sample injection. Changes in the electrophoretic patterns (i.e., in the migration properties) of the molecules reflected the possible interactions with the protein. The tryptophan derivatives and eight drugs possessed stereoselective interactions, seven drugs showed interactions without appreciable chiral separation, and the others did not present any direct complexation with the protein molecules. Molecular modelling was performed to characterize the binding areas at the iron binding site of iron-free transferrin. The docking of tryptophan derivatives on transferrin showed that the R-enantiomers possess a stronger complexation with transferrin, whereas the S-enantiomers are bound by weaker interactions, which is in excellent agreement with the capillary electrophoresis results, where the R-enantiomers were always retarded stronger by transferrin. A ranking of drugs by the lipo score parameter of the docking shows an accordance with the stereoselective interactions by the protein.

Binding Sites↗
PubMed1984

Transferrin receptors on human reticulocytes: variation in site number in hematologic disorders.

Assays of binding of 125iodine-labeled (125I) human transferrin were used to study transferrin receptor sites on reticulocytes from 15 normal subjects and from 66 patients with various hematologic disorders. In normal subjects, few or no transferrin receptors were detected whereas the average number of receptors per reticulocyte varied greatly from patient to patient, ranging from 0 to 67,700 in samples, from 35 patients, on which Scatchard analysis of binding of [125I]-transferrin was done. Marked heterogeneity in the number of reticulocyte transferrin receptors in different hematologic disorders was also found in assays with [125I]-OKT9 (monoclonal antibody to the human transferrin receptor). The number of receptors was not correlated with either the reticulocyte count or the hemoglobin.

Anemia, Hypochromic↗
PubMed1986

Role of transferrin in iron transport between maternal and fetal circulations of a perfused lobule of human placenta.

The transfer of iron between the maternal and fetal circulations of an isolated perfused lobule of term human placenta was investigated using 125I-labelled or 59Fe-labelled diferric transferrin. There was negligible transplacental transfer of intact transferrin whereas nearly 4 per cent of the added 59Fe was transferred into the fetal circulation after 2 h, where it became associated with fetal transferrin. Over 20 per cent of the added 59Fe radioactivity was sequestered within the placental tissue during this period, associated with transferrin, ferritin and other uncharacterized molecules. This suggests an important role for an intracellular pool in regulating transfer. The presence of 10 mM chloroquine in the maternal circulation substantially reduced tissue accumulation of 59Fe and totally inhibited transfer to the fetus. It is concluded that the initial stages of iron transfer to the fetus involve the internalization of maternal iron-saturated transferrin bound to membrane receptors by receptor-mediated endocytosis, which can be inhibited by the drug chloroquine. Subsequently, the transplacental transfer of iron to the fetus does not involve the concomitant movement of transferrin.

Female↗
PubMed1997

Intestinal absorption and enterohepatic cycling of biliary iron originating from plasma non-transferrin-bound iron in rats.

In iron overload, non-transferrin-bound iron (NTBI) is found in plasma and is rapidly removed by hepatocytes. Some of this NTBI is excreted into bile. Biliary excretion of NTBI, in the form of an iron-deferiprone chelate, is greatly increased by deferiprone, an iron chelator. The aim of this study was to test whether biliary iron as such or as an iron-deferiprone chelate (both originating from plasma NTBI) is absorbed from the intestine and re-secreted into bile. In healthy biliary fistula (donor) rats, biliary 55Fe originating from plasma NTBI was obtained by injecting Fe citrate (to saturate transferrin) followed by 55Fe. This biliary 55Fe was infused into the duodenum of (recipient) rats whose transferrin was saturated or unsaturated. Similar experiments were performed using iron-overloaded (donor) rats given deferiprone, followed by infusion of the biliary 55Fe-deferiprone chelate into iron-overloaded (recipient) rats. The results show that in healthy (recipient) rats, duodenal infusion of 55Fe from NTBI was followed by increased plasma 55Fe when transferrin was unsaturated, or by biliary excretion of 55Fe when transferrin was saturated, indicating intestinal absorption of 55Fe. In iron-overloaded rats, neither plasma nor bile became radioactive, indicating no intestinal absorption of iron from the deferiprone chelate. We conclude that biliary iron, originating from NTBI, is absorbed from the intestine, and undergoes enterohepatic circulation if transferrin is saturated. In iron-overloaded rats, biliary iron originating from plasma NTBI and present as an iron-deferiprone chelate in bile is not absorbed.

Animals↗
PubMed1989

Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3' untranslated region of the mRNA.

Post-transcriptional regulation of transferrin receptor mRNA levels by iron is mediated by a portion of the 3' untranslated region (UTR) of the mRNA. We have previously shown that a 678 nucleotide fragment of the 3'UTR contains the regulatory element(s). Within this region are five RNA structures which resemble the iron-responsive element (IRE) in the 5' untranslated region of the ferritin mRNA which is regulated translationally by iron. The IREs from the ferritin and transferrin receptor mRNAs compete in an in vitro assay for interaction with a cytoplasmic protein; the activity of this IRE-binding protein is dependent upon the iron status of the cells. Based on further deletion analysis reported here, the sequence required for iron regulation of the transferrin receptor have been limited to 250 nucleotides which we have produced synthetically and cloned. This sequence, which contains three IREs, is capable of producing iron-dependent regulation of transferrin receptor levels. Removal of the three IREs from the synthetic element results in loss of iron regulation. Moreover, deletion of a single cytosine residue from each of the three IREs in the synthetic regulatory element eliminates high-affinity binding to the IRE-binding protein in vitro and results in low levels of iron-independent transferrin receptor expression, consistent with production of a constitutively unstable mRNA. These data indicate that the ability of the mRNA to interact with the IRE-binding protein is required for regulation of transferrin receptor mRNA levels by iron.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Chicken serum transferrin duplicates the myotrophic effects of sciatin on cultured muscle cells.

Sciatin, a glycoprotein purified from chicken sciatic nerves, has been shown to have trophic effects on chicken skeletal muscle cells in culture. Since we recently observed pronounced structural similarities between sciatin and chicken serum transferrin [Markelonis et al, 1982a], we decided to investigate the muscle growth-promoting activity of transferrin on cultured muscle cells. Serum transferrin was isolated by the same protocol used to purify sciatin, viz., affinity chromatography on concanavalin A-agarose followed by ion-exchange chromatography on DEAE cellulose. The serum protein recovered by this purification scheme was indistinguishable immunologically from sciatin as evidenced by a positive precipitin reaction against goat anti-sciatin serum on double immunodiffusion in agar. Purified serum transferrin had myotrophic effects identical to those of sciatin when added to skeletal muscle cells in vitro. For example, even when chicken embryo extract--a constituent normally required for chicken muscle cell differentiation in vitro--was omitted from culture medium, either serum transferrin or sciatin promoted myogenesis in culture as measured by a stimulation of the fusion index. Furthermore, both proteins caused a significant increase in the level of protein synthesis, the number of acetylcholine receptors and the activity of acetylcholinesterase in treated muscle cultures. By contrast, commercially obtained ovotransferrin (conalbumin) or FeSO4 (100 microM) were unable to fully support myogenesis of skeletal muscle in vitro if embryo extract was omitted from the culture medium. From these data, we conclude that the neuronal myotrophic protein sciatin is both structurally and biologically related to serum transferrin. Furthermore, we suggest that sciatin may represent a neuronal form of this iron-transport protein.

Animals↗
PubMed1978

Molecular characteristics of the transferrin-receptor complex of the rabbit reticulocyte.

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.

Animals↗
PubMed1995

Effect of separation conditions on automated isoelectric focusing of carbohydrate-deficient transferrin and other human isotransferrins using the PhastSystem.

To investigate the effect of automated isoelectric focusing conditions in the PhastSystem, e.g., the point of sample application, prerun and separation times, and minimized gels on isotransferrin band pattern, human sera were analyzed with native transferrin iron load, after iron saturation or iron depletion in vitro. Varying the focusing conditions we found (i) Point of sample application (anode, middle of the gel, cathode) strongly affected transferrin iron loss. It was greatest at the anode and least at the cathode. (ii) Without prerun, distinct transferrin iron loss also occurred. A short prerun time prevented iron loss, but increasing it did not improve transferrin iron load stability as stated by others. (iii) An inappropriately long separation time inevitably yielded iron loss. In conclusion, inappropriate isoelectric focusing conditions strongly affect iron load stability of isotransferrins (obviously via low pH within the gel), resulting in transferrin iron release and cofocusing of isotransferrins with different sialic acid or iron contents. For determination of carbohydrate-deficient transferrin, such conditions resulted in overestimation of the marker of chronic alcohol abuse. Our findings may be of guiding importance for isoelectric focusing of protein-ligand complexes. We recommend the procedure described for development of isoelectric focusing of protein-ligand complexes.

Carbohydrates↗
PubMed2000

Rab11b is essential for recycling of transferrin to the plasma membrane.

Members of the Rab family of small GTPases play important roles in membrane trafficking along the exocytic and endocytic pathways. The Rab11 subfamily consists of two highly conserved members, Rab11a and Rab11b. Rab11a has been localized both to the pericentriolar recycling endosome and to the trans-Golgi network and functions in recycling of transferrin. However, the localization and function of Rab11b are completely unknown. In this study green fluorescent protein (GFP)-tagged Rab11b was used to determine its subcellular localization. GFP-Rab11b colocalized with internalized transferrin, and using different mutants of Rab11b, the role of this protein in transferrin uptake and recycling was examined. Two of these mutants, Rab11b-Q/L (constitutively active) and Rab11b-S/N (constitutively inactive), strongly inhibited the recycling of transferrin. Interestingly, both of them had no effect on transferrin uptake. In contrast, the C-terminally altered mutant Rab11b-DeltaC, which cannot be prenylated and therefore cannot interact with membranes, did not interfere with wild-type Rab11b function. From these data we concluded that functional Rab11b is essential for the transport of internalized transferrin from the recycling compartment to the plasma membrane.

Animals↗
PubMed1994

Transferrin, one of the major vitreous proteins, is produced within the eye.

Transferrin occurs in the vitreous at a higher relative concentration than found in the plasma or in the aqueous humor. This has been related to a possible local synthesis of transferrin by some component of the eye, although convincing evidence for this has not been available. Recently, the intraocular synthesis of several vitreous glycoproteins, possibly by the ciliary body, was demonstrated by our group. This paper reports experiments that characterize vitreous transferrin as one of these glycoproteins. Vitreous of rabbits injected intravitreally either with 3H-fucose or 3H-tyrosine and killed 40 hr after the injection was processed for 1D and 2D-electrophoresis, followed by immunoblot techniques or fluorography. It was possible to detect a labeled polypeptide with the same molecular weight and pI of rabbit plasma transferrin. Furthermore, this labeled polypeptide could be specifically eluted from columns of Sepharose conjugated with antibody against rabbit plasma transferrin. Thus, these results demonstrate that at least part of the transferrin of the vitreous is synthesized within the eye.

Animals↗
PubMed1988

Experimental candidiasis associated with liver injury. Role of transferrin.

In an attempt to perform a further investigation on the proposal that an increasing susceptibility to Candida infection in liver injury may be related to unsaturated transferrin level (UIBC) and/or to a total amount of transferrin represented by TIBC, we conducted experimental candidiasis using mice with galactosamine-induced liver injury and investigated the effect of preadministration of transferrin prior to inoculation of Candida albicans. Final mortality was 10% in the mice without liver injury and without transferrin (Group 1) and ones with liver injury and with transferrin (Group 3). By contrast a 50% mortality was given in one only with liver injury (Group 2). The TIBCs in Groups 1 and 3 were significantly higher than that in Group 2. The UIBCs in Groups 2 and 3, although there was no significant difference between them, were significantly lower than that in Group 1. This study confirmed that transferrin (TIBC) may have a direct deterring effect on systemic Candida infection and the decreased TIBC in the liver injury enhances the growth of C. albicans.

Animals↗
PubMed1980

Electrophoretic mobility of N- and C-terminal monoferric fragments of bovine transferrin phenotypes AA, D1D1, D2D2, and EE, and N-terminal amino acid sequences.

Iron-saturated bovine transferrins A, D1, D2 and E were cleaved by trypsin yielding monoferric fragments. The N-terminal fragments (F) of transferrins A and D2 had identical mobility in cellulose acetate electrophoresis, that of transferrin D1 a slower mobility, and that of E a still slower mobility. The C-terminal fragments (S) gave multiple bands which were essentially identical in the case of transferrins A, D1, and E, but of slower mobility in the case of transferrin D2. All four variants had identical N-terminal amino acid sequences. The electrophoretic mobility of the C-terminal fragments was reduced by neuraminidase treatment, but the N-terminal fragments were unaffected. The four transferrin variants therefore appear to be made up from three electrophoretically distinguishable N-terminal halves and two C-terminal halves. The feature responsible for the electrophoretic double banding of homozygous bovine asialotransferrins is consistently associated with the C-terminal half of the molecule.

Amino Acid Sequence↗
PubMed1996

The identification of abnormal glycoforms of serum transferrin in carbohydrate deficient glycoprotein syndrome type I by capillary zone electrophoresis.

One of the biochemical characteristics of carbohydrate deficient glycoprotein syndromes is the presence of abnormal glycoforms in serum transferrin. Both glycoform heterogeneity and variable site occupancy may, in principle, lead to the generation of a range of glycoforms which contain different numbers of sialic acid residues, and therefore variable amounts of negative charge. Capillary zone electrophoresis was used to resolve the glycoforms of normal human serum transferrin and also of a set of glycoforms which were prepared by digesting the sugars on the intact glycoprotein with sialidase. The sugars on the intact glycoprotein were also modified by a series of exoglycosidase enzymes to produce a series of neutral glycoforms which were-also analysed by capillary zone electrophoresis. The oligosaccharide population of human serum transferrin was analysed by a series of mixed exoglycosidase digests on the released glycan pool and quantified using a novel HPLC strategy. Transferrin was isolated from carbohydrate deficient glycoprotein syndromes type I serum and both the intact glycoforms and released sugars were resolved and quantified. The data presented here confirm the presence of a hexa-, penta- and tetra-sialoforms of human serum transferrin in both normal and carbohydrate deficient glycoprotein syndrome type I serum samples. Consistent with previous reports carbohydrate deficient glycoprotein syndrome type I transferrin also contained a di-sialoform, representing a glycoform in which one of the two N-glycosylation sites is unoccupied, and a non-glycosylated form where both remain unoccupied. This study demonstrates that capillary zone electrophoresis can be used to resolve quantitatively both sialylated and neutral complex type glycoforms, suggesting a rapid diagnostic test for the carbohydrate deficient glycoprotein syndromes group of diseases.

Carbohydrates↗
PubMedDate not supplied

Comparative binding study of aluminum and chromium to human transferrin. Effect of iron.

The characteristics of aluminum and chromium binding to apo-transferrin (apo-tf) have been investigated and compared. Both metal ions were taken up by human transferrin forming complexes with the maximum absorbances at 405 nm for chromium-transferrin (cr-tf) and 240 nm for aluminum-transferrin (Al-tf). In the presence of citric acid, chromium binding to transferrin is five times more than aluminum. The binding of aluminum or chromium to apo-transferrin was reduced by 18 and 22% in the presence of 200 ng/mL of iron. The binding of both metals to apo-tf appears to be pH dependent. In acidic pHs, less chromium and more aluminum binding occurred.

Aluminum↗
PubMed1994

[Transferrin concentration in seminal plasma in testicular varicocele with various sperm concentrations and various forms of azoospermia].

Seminal plasma transferrin concentrations were measured in semen samples from 424 men attending a fertility unit. There was a clear positive correlation between seminal plasma transferrin concentration and sperm density: transferrin concentrations decrease with decreasing sperm density and are lowest in patients with azoospermia and those who have undergone vasectomy. The differences between the various groups in sperm density are highly significant, but individual data counts also vary widely. Furthermore, it was demonstrated that in polyzoospermia the seminal plasma transferrin concentration is increased, suggesting primary tubular hyperactivity. No correlations with other seminal parameters or hormonal values were found. Seminal plasma transferrin concentrations in normozoospermia and in varicocele testis or in cases with increased numbers of immature germ cells in the ejaculate were not significantly different. This may be interpreted as indicative of intact secretory activity of Sertoli cells in both varicocele and increased desquamation of immature germ cells. The absence of correlation with any of several important spermatological parameters and our inability to differentiate between azoospermia caused by obstruction and by tubular impairment indicate that seminal plasma transferrin is not a useful marker for Sertoli cell function or for seminiferous tubular dysfunction.

Adolescent↗
PubMed1999

Serum transferrin receptors in detection of iron deficiency in pregnancy.

A prospective hospital-based study was conducted to evaluate the efficacy of serum transferrin receptors in the detection of iron deficiency in pregnant women. The iron status of 100 pregnant women with single uncomplicated term pregnancies in the first stage of labor was established using standard laboratory measures. These included complete hemogram, red cell indices, serum iron, percent transferrin saturation, and serum ferritin. In addition, serum transferrin receptor (STFR) was estimated. The results of 81 women with complete laboratory profiles were analyzed. Thirty-five (43.2%) women were anemic (hemoglobin <11 g/dl). Hemoglobin (Hb) showed a significant correlation with MCH, MCHC, serum iron, and percent transferrin saturation, suggesting that the anemia was likely to be due to iron deficiency. The mean STFR level was 18.05+/-9.9 mg/l in the anemic women and was significantly raised (p<0.001) compared with that of the nonanemic women. STFR correlated significantly with Hb (p<0.001), MCH (p<0.05), MCHC (p<0.01), serum iron (p<0.01), and percent transferrin saturation (p<0.01) and also showed a highly significant correlation with the degree of anemia. Serum ferritin in these women did not correlate with Hb, and only 54.4% of the women had levels <12 ng/ml, which does not reflect the true prevalence of iron deficiency. Serum transferrin receptor estimation is thus a useful measure for detecting iron deficiency in pregnancy.

Adult↗