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PubMedDate not supplied

Transferrin secretion in response to different modes of FSH stimulation and cycloheximide in superfused Sertoli cell cultures.

The influence of different modes of FSH stimulation and cycloheximide on transferrin secretion by rat Sertoli cells was investigated using a superfusion culture system. Sertoli cells from 18-day-old rats were cultured in serum-free medium on Matrigel-covered slides first in static conditions for 19 hours, and then superfused at a flow rate of 2.5 ml/hour. After an equilibration period of 48 hours to establish the basal rate of transferrin secretion, the cultures were exposed to various modes of FSH stimulation. Sertoli cells stimulated intermittently (20 min/2 hours) up to 22 hours responded to each consecutive FSH pulse with a rapid increase of transferrin secretion followed by a decline toward basal values. Continuous 22-hour exposure to FSH elicited an immediate increase followed by irregular fluctuations and a transient decline towards the baseline. With either mode of FSH stimulation, there was a secondary prolonged increase in transferrin secretion. Although cultures stimulated intermittently or continuously during the entire experimental period (22 hours) secreted similar cumulative amounts of transferrin (10.8 +/- 0.5 micrograms and 11.1 +/- 0.8 micrograms, respectively), there was a direct correlation between the secreted amount of transferrin and the duration of FSH exposure up to 8 hours. Addition of cycloheximide decreased both basal and FSH-stimulated transferrin secretion. However, even when cycloheximide was added 1 hour before FSH, an early secretory peak in response to FSH was still observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of epidermal growth factor on transferrin receptor phosphorylation and surface expression in malignant epithelial cells.

The transferrin (Tf) receptor is a major transmembrane protein which provides iron for normal and malignant cell growth. Epidermal growth factor (EGF) has been reported to rapidly and transiently alter the number of surface Tf receptors in normal and transformed epithelial cells. To investigate mechanisms of EGF-induced changes in surface Tf display, EGF effects on surface Tf receptors were compared in two cell lines which differ in their number of EGF receptors and growth responses to EGF. In cloned A431 cells with high receptor numbers which are growth-inhibited by EGF, EGF caused a 50% decrease in Tf receptor expression after 30 min. In contrast, EGF induced a rapid, transitory increase (within 5 min) in the number of surface Tf receptors on KB carcinoma cells which returned to basal levels by 15 min. The observed changes in Tf receptor display were due to altered receptor distribution and not changes in ligand affinity or total cellular transferrin receptor pools. Anti-EGF receptor monoclonal antibody blocked effects of EGF on transferrin receptor expression. Since the antibody is internalized and causes EGF receptor down-regulation, effects on transferrin receptor expression were independent of these events. EGF-induced alterations in Tf receptor display occurred even when cells were pretreated with colchicine, suggesting that changes in surface Tf binding were not mediated by cytoskeletal components. Na orthovanadate, which mimics some early cellular effects of EGF, duplicated EGF's effects on A431 Tf receptors, but had no effect on KB cells, suggesting these responses occur by differing mechanisms. To determine whether EGF caused changes in Tf receptor phosphorylation, 32P-labelled Tf receptors were immunoprecipitated after EGF treatment. After exposure to EGF, A431 cells showed no change in Tf phosphorylation, but KB cells showed a transient, 6-fold increase in transferrin receptor phosphorylation on serine residues. In both A431 and KB cells, phorbol ester (PMA) also increased phosphorylation on transferrin receptors, but had little effect on surface Tf receptor expression. In malignant cell lines, EGE induces rapid, variable changes in transferrin receptor expression and phosphorylation which differ from the effects of PMA. These early responses to EGF appear to differ with the cell type and correlate poorly with alterations in Tf receptor phosphorylation. These results suggest Tf receptor phosphorylation does not regulate Tf receptor display in all cells.

Animals↗
PubMed2005

Mouse HFE inhibits Tf-uptake and iron accumulation but induces non-transferrin bound iron (NTBI)-uptake in transformed mouse fibroblasts.

Iron-uptake and storage are tightly regulated to guarantee sufficient iron for essential cellular processes and to prevent the production of damaging free radicals. A non-classical class I MHC molecule, the hemochromatosis factor (HFE), has been shown to regulate iron metabolism, potentially via its interaction with the transferrin receptor. Whereas, the effect of human HFE (hHFE) on transferrin/transferrin receptor association, as well as on transferrin receptor recycling and the level of cellular iron pools in various cell lines was analyzed, very little is known about the mouse HFE (mHFE) protein. In the following study, our aim was to analyze in more detail the function of mHFE. Surprisingly, we observed that over-expression of mHFE, but not of hHFE, in a mouse transformed cell line, results in a most significant inhibition of transferrin-uptake which correlated with apoptotic cell death. mHFE inhibited transferrin-uptake immediately following transfection and this inhibition persisted in the surviving stable transfectants. Concomitantly, cellular iron derived from transferrin-iron uptake was dramatically limited. The activation of a non-transferrin bound iron-uptake pathway that functions in the stable mHFE-transfected clones could explain their normal growth curves and survival. The hypothesis that iron starvation can induce iron-uptake by a novel transferrin-independent pathway is discussed.

Animals↗
PubMed1984

"Trophic" effect of transferrin on amphibian limb regeneration blastemas.

In light of the recent demonstration that one "neurotrophic factor" of peripheral nerves is the iron-transport glycoprotein transferrin, we tested the effects of heterologous transferrin on cellular events in cultured newt forelimb blastemas. Addition of transferrin to medium containing 1% fetal bovine serum resulted in DNA labeling and mitotic activity approximately twice as high as that of blastemas cultured in medium with 1% serum alone. Blastemas maintained for 24 hr in medium with 1% serum were stimulated to increased levels of DNA synthesis by the addition of transferrin, and this response was dose-dependent. Varying the concentrations of iron and transferrin in the medium gave results indicating that the glycoprotein's trophic effect is due to its ability to furnish iron to the cells in an appropriate manner. Results of the study are consistent with the hypothesis that blastema cell proliferation is promoted by transferrin or transferrin-like factors released from nerves.

Animals↗
PubMed1991

Proliferation of chick embryo neuroblasts grown in the presence of horse serum requires exogenous transferrin.

We have previously shown that neuroblasts from cerebral hemispheres of 6-day-old chick embryos are able to proliferate when grown in the presence of fetal calf serum. We report here that in the presence of horse serum alone the proliferative rate of neuroblasts is strongly reduced. A high proliferative rate is restored upon the addition of bovine transferrin and to a lesser extent with added FeSO4 or hemin. These findings suggest that the transferrin of horse serum cannot be used by chick neuroblasts in vitro, while bovine transferrin exogenously added is active in promoting cell proliferation. We propose that the stimulatory activity of the fetal calf serum is due to bovine transferrin, since when this serum is fractionated by gel filtration, the fractions that stimulate the proliferation of neuroblasts grown in the presence of horse serum are located in the molecular weight area of transferrin, and they do contain transferrin as seen by immunoblotting with a specific anti-transferrin antibody.

Animals↗
PubMed1995

Carbohydrate composition of serum transferrin isoforms from patients with high alcohol consumption.

Normal human serum transferrin is present in several isoforms, due to differences in glycosylation. Transferrin has two potential glycosylation sites, both normally occupied by oligosaccharide chains. Two of the transferrin isoforms, called carbohydrate deficient transferrin, are specifically increased in patients with high alcohol consumption. In this study, five isoforms of transferrin were isolated from patients with high alcohol consumption. N-linked glycans were released by N-glycosidase digestion and were radioactively labeled by NaB3H4 reduction. The purified oligosaccharides were analyzed by high-pH anion-exchange chromatography, and the carbohydrate composition of each individual transferrin isoform was determined. The carbohydrate deficient transferrin isoforms were found to lack one or both of their entire carbohydrate chains.

Alcohol Drinking↗
PubMedDate not supplied

Polymorphisms in the transferrin 5' flanking region associated with differences in total iron binding capacity: possible implications in iron homeostasis.

We have identified five single nucleotide polymorphisms (SNPs) upstream (5') of the transferrin coding region. One polymorphism is in the 5' UTR at nt +49, and four are in the promoter region at nt -34, -551, -617, and -739, numbering from the start of transcription. The -34 and -617 SNPs are tightly but not completely linked. The -34 polymorphism lies between a conserved Sp1 site and the TATA box. The -617 polymorphism is within the DRII enhancer region. Five haplotypes have been defined from these SNPs by the identification of at least one homozygous individual, and two other haplotypes were deduced from heterozygous individuals. The total iron-binding capacity associated with each transferrin haplotype was haplotype 2 > 1 > 4 > 3. Transferrin promoter haplotype 2 had a significantly higher mean TIBC and haplotype 3 had a significantly lower mean TIBC than the more common haplotype 1. Persons with haplotype 4, which includes the -34T and -617A minor alleles, have a lower mean TIBC but the difference was not statistically significant. In normal individuals, the differences in the haplotypes were not found to be associated with differences in transferrin saturation and ferritin levels. There was no difference in the extent of increase in the mean TIBC levels in individuals with iron deficiency anemia in regard to their haplotype. Furthermore, there was no difference in the relative frequencies of the transferrin haplotypes in the iron-deficient population. In hemochromatosis patients who were homozygous for the C282Y HFE mutation, no particular haplotype was associated with a significant difference in transferrin saturation or ferritin levels. In White patients with Parkinson's disease, a disorder in which there is abnormal iron deposition in the brain, the presence of transferrin haplotype 3 was in slight excess over the normal White population.

Alleles↗
PubMed2000

Iron regulation of transferrin synthesis in the human hepatoma cell line HepG2.

In human beings, serum transferrin levels increase during iron deficiency and decrease with iron overload. Yet, whether or not iron levels actually affect the synthesis of transferrin in human liver cells is not known. In previous studies, iron was shown to suppress the expression of chimeric human transferrin genes in livers of transgenic mice. The goal of this study was to determine if iron suppresses intact endogenous human transferrin synthesis by testing the effects of changes in iron levels on synthesis of transferrin in a human hepatoma cell line HepG2. In HepG2 cells, normalized(35)S-metabolically labeled transferrin synthesis was consistently less following iron treatment with hemin or ferric citrate, than following treatment with an iron-chelator deferroxamine. Thus, this study provides new evidence that iron can regulate synthesis of intact endogenous human transferrin.

Carcinoma, Hepatocellular↗
PubMed1995

An in vitro study on the binding of Al(III) to human serum transferrin with the isoelectric focusing technique.

Transferrin saturated with Al3+ subjected to isoelectric focusing (IEF) in a pH gradient can be separated into four fractions, representing the apotransferrin, transferrin with aluminum at the metal binding site in the C- or N-terminal lobe, or both. The electrophoretic mobilities of these four fractions are identical to those of the iron-transferrin counterparts. Simultaneous binding of aluminum and iron to transferrin can also be demonstrated. The decreased saturation after IEF indicates that the affinity of transferrin for aluminum is low compared with its affinity for iron. This effect is particularly evident when bicarbonate is used as the synergistic anion in the loading procedure. In contrast, loading of transferrin with aluminum in the presence of oxalate produces a di-aluminum-transferrin complex that is stable during IEF.

Aluminum↗
PubMed1986

Independence of in vitro iron absorption from mucosal transferrin content in rat jejunal and ileal segments.

Isolated non blood-perfused intestinal segments from normal and iron-deficient rats were used in vitro. A modification of the luminal perfusion method according to Fisher and Parsons allowed the comparison of iron and transferrin quantities in the serosal fluid at 15 min intervals. Iron transfer in jejunal and ileal segments was directly proportional to the luminal iron concentration within a dose range of 1 to 100 mumol/l, did not show saturation characteristics and was linear over time. Jejunal segments from iron-deficient rats transferred about twice as much iron as the jejunal controls. In ileal segments there was no difference in iron transfer between iron-deficient and control rats; in both cases transfer amounted to approx. 10% of jejunal controls. An exponential correlation was found, when the decreasing transferrin content of the tissue was plotted against the cumulative water transport. Transferrin and albumin release from jejunal and ileal segments into the absorbate cumulated asymptotically, which is typical for wash-out phenomena. As iron transfer cumulated linearly while transferrin release cumulated in an asymptotic manner, the capacity of transferrin to bind iron ions is exceeded roughly 100 times by molar equivalents of iron in the last absorbate fractions. Independence of iron transfer from mucosal transferrin quantities is concluded. As the molar transferrin/albumin ratios do not show significant differences between plasma and the sequence of absorbate samples, a wash-out from the gut's interstitial space is assumed, which makes plasma the most likely origin of transferrin in the mucosa.

Absorption↗
PubMed1988

On the origin of intestinal transferrin.

The incorporation of 35S-L-methionine (35S-Met) into TCA-precipitable protein is used to measure protein synthesis in isolated non-vascular perfused jejunal segments and in isolated liver cells under steady-state conditions in rats. 10(5) X g supernatants of homogenates from jejunal segments and from liver cells as well as the jejunal absorbate were processed immuno-electrophoretically. Incorporation of 35S-Met radioactivity into precipitin lines with sera against transferrin, IgG and plasma proteins were autoradiographed and compared semiquantitatively with each other. Calculated on a wet-weight basis this system is sensitive enough to detect transferrin synthesis down to a level of 1% of that in the liver. Still, no transferrin synthesis was found in the jejunal mucosa, while 35S-Met incorporation into TCA precipitates and into IgG continued in isolated jejunal segments for over 2 h. A good correlation was found (r = 0.88, P less than 0.01) between mucosal and plasma transferrin in normal as well as in iron deficient rats. A complete immunologic cross-reactivity could be demonstrated between different plasma transferrins and the transferrin in three different preparations of the intestinal mucosa. Immunoblots of electropherograms after isoelectric focussing showed no distinct differences between transferrin in the plasma, bile, and in the mucosal epithelium.

Animals↗
PubMed2006

Transferrin localizes in Bunina bodies in amyotrophic lateral sclerosis.

Transferrin, an iron-binding protein, plays an important role in the transport and delivery of circulating ferric iron to the tissues. Amyotrophic lateral sclerosis (ALS) is characterized by the presence of Bunina bodies, skein-like inclusions, Lewy body-like inclusions/round inclusions, and basophilic inclusions in the remaining anterior horn cells in the spinal cord. We examined transverse paraffin sections of lumbar spinal cords from 12 ALS cases including two ALS with dementia and two ALS with basophilic inclusions, using antibodies to human transferrin. The results demonstrated that transferrin localized in Bunina bodies and some of the basophilic inclusions. In contrast, skein-like inclusions and Lewy body-like inclusions or round inclusions did not show obviously detectable transferrin immunoreactivities. Our findings suggest that although the mechanisms underlying transferrin accumulation in Bunina bodies and basophilic inclusions are unknown, transferrin could be involved in forming these inclusions. Furthermore, following cystatin C, transferrin is the second protein that localizes in the Bunina bodies.

Adult↗
PubMed1982

Biphasic uptake of iron-transferrin complex by L1210 murine leukemia cells and rat reticulocytes.

The kinetics of the cellular uptake of iron-transferrin complex was studied in L1210 murine leukemia cells and rat reticulocytes using 125I-transferrin. Saturation of transferrin with iron was necessary for optimal uptake. Following the incubation of cells with the radiolabeled complex a biphasic pattern of uptake was observed. The initial phase was rapid and relatively temperature-independent and was not altered by ethylamine, an inhibitor of transglutaminase activity which is necessary for receptor-mediated endocytosis. This phase was considered to result from receptor-ligand interaction which could be reversed to a great degree by replacement with unlabeled transferrin. A plateau was then reached, indicating a saturation of receptors. After 30 min a second phase of uptake was indicated by the second rise in the curve. This phase was slow, relatively temperature-dependent and could be abolished by ethylamine. It was interpreted as evidence of internalization of the ligand. Analysis of the data from competition studies with unlabeled transferrin indicated that the first phase might itself comprise a reversible and an irreversible step with a ratio of 5 to 1.4 for bound transferrin. Thus, the cellular uptake of iron-transferrin complex may consist of a reversible ligand-receptor interaction. Conformational changes may render this interaction irreversible and the internalization of the ligand may then follow.

Animals↗
PubMed1989

Human platelets mediate iron release from transferrin by adenine nucleotide-dependent and -independent mechanisms.

We assessed the ability of platelet sonicates and mediators secreted by unstimulated and thrombin-stimulated platelets to facilitate the release of iron from transferrin. Platelet sonicates and platelet conditioned media potentiated the release of iron from transferrin. The rate of release of iron was dependent on the pH of the reaction and amount of platelet sample added. Conditioned media from thrombin-stimulated platelets was more effective in mediating the release of iron from transferrin than was conditioned media from unstimulated cells. The rate of iron released from transferrin following addition of ATP and ADP in amounts equivalent to that present in platelet conditioned media was significantly less than the rate of iron released following the addition of conditioned media from platelets. Depletion of ATP and ADP in platelet conditioned media by incubation with apyrase only partially inhibited their ability to enhance the rate of iron release from transferrin. These observations indicate that platelets enhance the release of iron from transferrin by adenine nucleotide-dependent and -independent mechanisms. These observations are consistent with the hypothesis that platelets promote oxidant-induced tissue injury at sights of inflammation secondary to their ability to enhance the local release of iron from transferrin.

Adenine Nucleotides↗
PubMed1994

Posttranslational acylation of the transferrin receptor in LSTRA cells with myristate, palmitate and stearate: evidence for distinct acyltransferases.

When incubated with [3H]myristate or [3H]palmitate, LSTRA cells, a murine T cell line, incorporated radiolabel into a protein of 95 kDa as analyzed by SDS-polyacrylamide gel electrophoresis. This dually acylated protein was identified as the transferrin receptor by immunoprecipitation with a monoclonal anti-transferrin receptor antibody. Acylation of the transferrin receptor was posttranslational and occurred via ester or thioester linkages. Analysis of radiolabeled transferrin receptor protein from [3H]myristate-labeled cells by acid hydrolysis followed by thin layer chromatography revealed the exclusive presence of [3H]myristate. Labeled transferrin receptor protein from [3H]palmitate-labeled cells contained predominantly [3H]stearate and smaller amounts of [3H]palmitate. This is in contrast to the protein-tyrosine kinase p56lck, which in [3H]palmitate-treated LSTRA cells, incorporated primarily [3H]palmitate. An analog of myristic acid, 5-nonanyloxyfuran-2-carboxylic acid, inhibited the incorporation of [3H]myristate, but not [3H]palmitate or [3H]stearate into transferrin receptor protein, suggesting that these acylation events are distinct. These studies indicate that the murine transferrin receptor is acylated posttranslationally with myristate, palmitate and stearate and suggest that more than one acyltransferase activity is responsible for its acylation.

Acylation↗
PubMed1987

Diferric transferrin reduction stimulates the Na+/H+ antiport of HeLa cells.

Proton release from HeLa cells is stimulated by external oxidants for the transplasmalemma electron transport enzymes. These oxidants, such as ferricyanide and diferric transferrin, also stimulate cell growth. We now present evidence that proton release associated with the reduction of ferricyanide and diferric transferrin is through the Na+/H+ antiport. The stoichiometry of H+/e- release with diferric transferrin is over 50 to 1, which is greater than expected for oxidation of a protonated transmembrane electron carrier. Diferric transferrin induced proton release depends on external sodium and is inhibited by amiloride. Proton release is also inhibited when diferric transferrin reduction is inhibited by apotransferrin. A tightly coupled association between the redox system and the antiport is shown by sodium dependence and amiloride inhibition of diferric transferrin reduction. The results indicate a new role for ferric transferrin in growth stimulation by activation of the sodium-proton antiport.

Carrier Proteins↗
PubMed1991

High affinity binding of transferrin in cultures of embryonic neurons from the chick retina.

Immunohistochemical and autoradiographic analysis of neuronal cultures from embryonic day 8 (E8) and day 11 (E11) chick retina indicate that transferrin receptors and binding sites are present on soma and neurites. Cultures maintained in the presence of transferrin expressed elevated transferrin binding due to an increase in the number of transferrin receptors. Cultures from E11 neural retina exhibited a decrease in transferrin binding when compared to E8 cultures. This appears to be due to a decrease in the number of binding sites. Neurons maintained in a transferrin-free medium supplemented with 0.4 microM of iron sulfate generally expressed slight increases in transferrin binding.

Animals↗
PubMed1992

Transferrin receptors of rat and human brain and cerebral microvessels and their status in Alzheimer's disease.

We studied the regional distribution of specific [125I]transferrin binding to transferrin receptors in the brains and cerebral microvessels of humans and rats. We also assessed transferrin receptors in subjects with Alzheimer's disease. Human diferric [125I]transferrin bound to regional brain and cerebral microvessels with high affinity (dissociation constants of 1-10 nM), and the maximal binding densities ranged from 30 to 90 pmol/mg protein in the brain and were several-fold higher in cerebral microvessels. In Alzheimer's disease, transferrin receptor densities were significantly reduced in the hippocampus and the temporal and occipital cortex but were unchanged in the frontal and parietal cortex and the cerebellum. Although [125I]transferrin binding was higher in cerebral microvessels from subjects with Alzheimer's disease than in those of age-matched controls, this difference did not attain statistical significance. These results suggest that transferrin receptor density was decreased in some cortical areas including the hippocampus in Alzheimer's disease but relatively unchanged in cerebral microvessels.

Alzheimer Disease↗