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PubMed2003

Isolation and characterization of a termite transferrin gene up-regulated on infection.

PCR-based subtractive hybridization was used to isolate genes preferentially expressed in a termite (Mastotermes darwiniensis) following exposure to an entomopathogenic fungus. The subtraction procedure yielded a cDNA clone encoding a putative transferrin that, when sequenced to its ends, is the largest (728 amino acids) for any insect transferrin characterized to date. Cysteines and residues comprising putative iron-binding sites are conserved in both N- and C-terminal lobes, suggesting structural and functional similarity to diferric vertebrate transferrins. A quantitative PCR assay confirmed a significant increase in transferrin expression following infection, suggesting its up-regulation is part of the innate immune response. However, codon-based tests for selection among known insect transferrins revealed only a small proportion of codon-sites positively selected. Thus, unlike certain vertebrate transferrin lineages, no widespread evidence for pathogen-mediated positive selection was detected at this locus.

Amino Acid Sequence↗
PubMed2000

Effects of natural selection on patterns of DNA sequence variation at the transferrin, somatolactin, and p53 genes within and among chinook salmon (Oncorhynchus tshawytscha) populations.

This paper describes DNA sequence variation within and among four populations of chinook salmon (Oncorhynchus tshawytscha) at the transferrin, somatolactin and p53 genes. Patterns of variation among salmon species at the transferrin gene have been hypothesized to be shaped by positive natural selection for new alleles because the rate of nonsynonymous substitution is significantly greater than the rate of synonymous substitution. The twin goals of this study were to determine if the history of selection among salmon species at the transferrin gene is also reflected in patterns of intraspecific variation in chinook salmon, and to look for evidence of local adaptation at the transferrin gene by comparing patterns of nonsynonymous and synonymous variation among chinook salmon populations. The analyses presented here show that unlike patterns of variation between species, there is no evidence of greater differentiation among chinook salmon populations at nonsynonymous compared to synonymous sites. There is also no evidence of a reduction of within-species variation due to the hitchhiking effect at the transferrin gene, although in some populations nonsynonymous and synonymous derived mutations are both at higher frequencies than expected under a simple neutral model. Population size weighted selection coefficients (4Ns) that are consistent with both the inter and intraspecific data range from approximately 10 to approximately 235, and imply that between 1 and 40% of new nonsynonymous mutations at the transferrin gene have been beneficial.

Alleles↗
PubMed2004

Soluble transferrin receptor in Aboriginal children with a high prevalence of iron deficiency and infection.

OBJECTIVES: Aboriginal children in tropical Australia have a high prevalence of both iron deficiency and acute infections, making it difficult to differentiate their relative contributions to anaemia. The aims of this study were to compare soluble transferrin receptor with ferritin in iron deficiency anaemia (IDA), and to examine how best to distinguish the effect of iron deficiency from infection on anaemia. METHODS: We conducted a prospective study of 228 admissions to Royal Darwin Hospital in children from 6 to 60 months of age. Transferrin receptor concentrations were measured by a particle-enhanced immunoturbidimetric assay and ferritin by a microparticle enzyme immunoassay. RESULTS: On multiple regression, the best explanatory variables for haemoglobin differences (r2=33.7%, P<0.001) were mean corpuscular volume (MCV), red cell distribution width (RDW) and C-reactive protein (CRP); whereas transferrin receptor and ferritin were not significant (P>0.4). Using > or =2 abnormal indices (MCV, RDW, blood film)+haemoglobin <110 g/l as the reference standard for IDA, transferrin receptor produced a higher area under the curve on receiver operating characteristic curve analysis than ferritin (0.79 vs. 0.64, P<0.001) or the transferrin receptor-ferritin index (0.77). On logistic regression, the effect of acute infection (CRP) on haemoglobin was significant (P<0.001) at cut-offs of 105 and 110 g/l, but not at 100 g/l when only iron deficiency indicators (MCV, RDW, blood film) were significant. CONCLUSIONS: Transferrin receptor does not significantly improve the diagnosis of anaemia (iron deficiency vs. infection) over full blood count and CRP, but in settings with a high burden of infectious diseases and iron deficiency, it is a more reliable adjunctive measure of iron status than ferritin.

Anemia, Iron-Deficiency↗
PubMed2000

Studies on the recycling of the transferrin receptor in Trypanosoma brucei using an inducible gene expression system.

Uptake of host transferrin in bloodstream forms of Trypanosoma brucei is mediated by a heterodimeric, glycosylphosphatidylinositol-anchored receptor. After endocytosis, transferrin is delivered to lysosomes where it is proteolytically degraded. Whether the heterodimeric transferrin receptor is returned to mediate several cycles in ligand uptake is undefined. By using an inducible gene expression system we provide evidence for recycling of the transferrin receptor in bloodstream forms of T. brucei. The metabolic half-life of the transferrin receptor in bloodstream-form trypanosomes is determined to be 7 h which is comparable to the half-lives of recycling receptors in mammalian cells. The cycling time of the trypanosomal transferrin receptor is calculated to be 11 min. By means of the half-life and the cycling time, we calculated that each receptor is recycled 60 times before being degraded on average.

Animals↗
PubMed1985

Transferrin and HLA: spontaneous abortion, neural tube defects, and natural selection.

We report evidence that transferrin C3, a gene present in 9 to 10 per cent of whites, is associated with recurrent spontaneous abortion (P = 0.001) and that maternal transferrin genotype has an effect on the transmission ratio of the common transferrin genes (C1, C2, and C3) from heterozygous fathers to normal offspring (P less than 0.002). The effect of maternal genotype on paternal gene transmission is an unusual example of the operation of selection in the human reproductive process. This effect, together with the separate evidence for association of the transferrin C3 allele with spontaneous abortion, indicates that transferrin is a second marker (in addition to HLA) of genes important in reproduction. On the basis of comparison of the frequencies of transferrin (chromosome 3) and HLA (chromosome 6) mating types in 348 control couples and in 81 couples who had had a child with a neural tube defect, we hypothesize that some combinations of maternal and fetal genes on these two chromosomes may be associated with neural tube defects.

Abortion, Habitual↗
PubMed1983

Competitive advantage of diferric transferrin in delivering iron to reticulocytes.

Radioiron- and radioiodine-labeled forms of human diferric and monoferric transferrin and apotransferrin, isolated by preparative isoelectric focusing, were used to define transferrin-iron uptake by human reticulocytes. In mixtures of human diferric and monoferric transferrin, the diferric molecule had a constant 7-fold advantage in delivering iron to reticulocytes, as compared with the 2-fold advantage when single solutions of mono- and diferric transferrins were compared. This was shown to be due to competitive interaction in iron delivery, probably at a common membrane-receptor binding site for transferrin. Apotransferrin did not interfere with the iron-donating process and its limited cellular uptake was inhibited in noncompetitive fashion by diferric transferrin.

Apoproteins↗
PubMed1990

Transferrin-polycation conjugates as carriers for DNA uptake into cells.

We have developed a high-efficiency nucleic acid delivery system that uses receptor-mediated endocytosis to carry DNA macromolecules into cells. We accomplished this by conjugating the iron-transport protein transferrin to polycations that bind nucleic acids. Human transferrin, as well as the chicken homologue conalbumin, has been covalently linked to the small DNA-binding protein protamine or to polylysines of various sizes through a disulfide linkage. These modified transferrin molecules maintain their ability to bind their cognate receptor and to mediate efficient iron transport into the cell. The transferrin-polycation molecules form electrophoretically stable complexes with double-stranded DNA, single-stranded DNA, and modified RNA molecules independent of nucleic acid size (from short oligonucleotides to DNA of 21 kilobase pairs). When complexes of transferrin-polycation and a bacterial plasmid DNA containing the gene for Photinus pyralis luciferase are supplied to eukaryotic cells, high-level expression of the luciferase gene occurs, demonstrating transferrin receptor-mediated endocytosis and expression of the imported DNA. We refer to this delivery system as "transferrinfection."

Animals↗
PubMed1994

Molecular cloning of bullfrog saxiphilin: a unique relative of the transferrin family that binds saxitoxin.

Plasma and tissue of certain vertebrates contain a protein called saxiphilin that specifically binds the neurotoxin saxitoxin with nanomolar affinity. We describe the isolation of a cDNA clone of saxiphilin from liver of the North American bullfrog (Rana catesbeiana). The cDNA sequence encodes a protein that is evolutionarily related to members of the transferrin family of Fe(3+)-binding proteins. Pairwise sequence alignment of saxiphilin with various transferrins reveals amino acid identity as high as 51% and predicts 14 disulfide bonds that are highly conserved. The larger size of saxiphilin (91 kDa) versus serum transferrin (approximately 78 kDa) is primarily due to a unique insertion of 144 residues. This insertion contains a 49-residue domain classified as a type 1 repetitive element of thyroglobulin, which is shared by a variety of membrane, secreted, and extracellular matrix proteins. Saxiphilin also differs from transferrins in 9 of 10 highly conserved amino acids in the two homologous Fe3+/HCO3-binding sites of transferrin. Identification of saxiphilin implies that transferrin-like proteins comprise a diverse superfamily with functions other than iron binding.

Amino Acid Sequence↗
PubMed2000

Competitive binding of bismuth to transferrin and albumin in aqueous solution and in blood plasma.

Several bismuth compounds are currently used as antiulcer drugs, but their mechanism of action is not well established. Proteins are thought to be target sites. In this work we establish that the competitive binding of Bi(3+) to the blood serum proteins albumin and transferrin, as isolated proteins and in blood plasma, can be monitored via observation of (1)H and (13)C NMR resonances of isotopically labeled [epsilon-(13)C]Met transferrin. We show that Met(132) in the I132M recombinant N-lobe transferrin mutant is a sensitive indicator of N-lobe metal binding. Bi(3+) binds to the specific Fe(3+) sites of transferrin and the observed shifts of Met resonances suggest that Bi(3+) induces similar conformational changes in the N-lobe of transferrin in aqueous solution and plasma. Bi(3+) binding to albumin is nonspecific and Cys(34) is not a major binding site, which is surprising because Bi(3+) has a high affinity for thiolate sulfur. This illustrates that the potential target sites for metals (in this case Bi(3+)) in proteins depend not only on their presence but also on their accessibility. Bi(3+) binds to transferrin in preference to albumin both in aqueous solution and in blood plasma.

Albumins↗
PubMed1980

The effect of iron-deficiency anaemia on two indices of nutritional status, prealbumin and transferrin.

1. Serum prealbumin, transferrin and iron concentrations were measured in ninety-two north Cameroonian children under 5 years of age. The results were grouped according to the blood haemoglobin concentration range in order to show the interactions of anaemia with prealbumin and transferrin concentrations. 2. Transferrin concentration showed a significant negative correlation with serum Fe and percentage saturation of transferrin values. Prealbumin concentration showed a significant direct correlation with haemoglobin but did not correlate with either serum Fe or percentage saturation of transferrin. 3. It is concluded that in regions where Fe-deficiency anaemia is endemic transferrin concentration may be of little value in determining nutritional status. On the contrary, prealbumin seems to be more useful.

Anemia, Hypochromic↗
PubMed1989

Changes in serum transferrin and iron concentrations in humans suffering from malaria with parasitaemia.

Sera from non-malarial (control) and Plasmodium falciparum-infected (malaria) subjects were assayed for transferrin and iron. The mean serum transferrin concentration in the malaria sera was found to be elevated by 44% above the control value. The mean serum iron was also raised in the malaria sera, but the increase (19%) was found to be well below that of transferrin. The mean saturation of serum transferrin with iron fell from 42 +/- 17% in the control group to 37 +/- 9% in the malaria group. It is suggested that the increase in transferrin concentration in the sera of malaria subjects probably resulted from an increase in the rate of transferrin synthesis, perhaps in response to the raised serum iron and/or the hypoxia which is known to be associated with malaria infection.

Adolescent↗
PubMed1979

Antifungal activity of transferrin.

Inhibitory effects of transferrin on fungal growth were successfully estimated by measuring fungal ATP content. By this method, it was demonstrated that both human and rabbit transferrin possessed the inhibitory effect in the absence of any other factor on yeast-like and filamentous fungi. However, rabbit stimulation factor enhanced the inhibitory effect. The inhibitory effect of transferrin was nonspecific and correlated with unsaturated iron binding capacity (UIBC) of transferrin. Human transferrin was more inhibitory than rabbit transferrin.

Animals↗
PubMed1999

Serum amyloid A and transferrin in chicken. A preliminary investigation of using acute-phase variables to assess diseases in chickens.

The concentrations of serum amyloid A protein (SAA) and transferrin in blood samples from broilers in various stages of natural Staphylococcus aureus infection, from healthy counterparts, and from turpentine- or saline-injected pullets were measured using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting, and densitometry. SAA was not detected in healthy chickens but was detected in turpentine-injected pullets and in S. aureus-infected broilers. Relative percentages of transferrin in turpentine- and saline-injected pullets were not different. Broilers with a S. aureus infection had a two-fold higher transferrin level than did their unaffected counterparts. There was also a difference between the transferrin levels of healthy broilers and healthy pullets, which indicates that other variables, such as breed or breeding conditions, may influence the transferrin level. This preliminary study showed that SAA is an acute-phase protein and a more reliable variable for diagnosing lesions in chickens than transferrin.

Animals↗
PubMed2005

Transferrin coupled liposomes as drug delivery carriers for brain targeting of 5-florouracil.

Diseases and disorders of the brain are extremely difficult to treat pharmacologically because most drugs are unable to pass across the blood--brain barriers. Complex multi-strand tight junctions between adjacent cerebral endothelial cells and between choroid plexus epithelial cells form a physical barrier and prevent the passage of water soluble drugs from the blood into the brain, whereas the inward passage of lipid soluble drugs is restricted by drug efflux pumps which act as a functional barrier. In the present work, a transferrin-coupled liposomal system for brain delivery of 5-florouracil has been investigated.5-florouracil and (99m)Tc-DTPA bearing non-coupled liposomes were prepared by cast film method, which were coupled with the transferrin by incubating these liposomes with transferrin in the presence of the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in saline phosphate buffer (pH 7.4). These liposomal systems were characterized for vesicle size, percent drug entrapment, and in vitro drug release. The size of the liposomes was increased on coupling with transferrin while percent drug entrapment reduced. The results of the in vitro release profile demonstrated that non-coupled liposomal formulation releases a comparatively higher percent (i.e. 74.8+/-3.21%) of drug than coupled liposomes. Results of in vivo study suggested a selective uptake of the transferrin-coupled liposomes from the brain capillary endothelial cells. In case of coupled liposomes, the level of radioactivity was 17-fold more as compared to the free radioactive agent and 13 times more with the non-coupled liposomes. Therefore, it could be concluded that using transferrin coupled liposomes the brain uptake of the drug could be enhanced.

Animals↗
PubMed1989

Localization of transferrin receptors and insulin-like growth factor II receptors in vesicles from 3T3-L1 adipocytes that contain intracellular glucose transporters.

Transferrin receptors in detergent extracts of subcellular membrane fractions prepared from 3T3-L1 adipocytes were measured by a binding assay. There was a small but significant increase (1.2-fold) in the amount of receptor in a crude plasma membrane fraction and a 40% decrease in the number of transferrin receptors in microsomal membranes prepared from insulin-treated cells, when compared with corresponding fractions from control cells. Intracellular vesicles containing insulin-responsive glucose transporters (GT) have been isolated by immunoadsorption from the microsomal fraction (Biber, J. W., and G. E. Lienhard. 1986. J. Biol. Chem. 261:16180-16184). All of the transferrin receptors in this fraction were localized in these vesicles; however, because the GT vesicles contain approximately 30-fold fewer transferrin receptors than GT, on the average only one vesicle in three contains a transferrin receptor. The binding of 125I-pentamannose 6-phosphate BSA to 3T3-L1 adipocytes at 4 degrees C was used to monitor surface insulin-like growth factor II (IGF-II)/mannose 6-phosphate receptors. Exposure of cells to insulin at 37 degrees C for 5 min resulted in a 2.5-4.5-fold increase in surface receptors. There was a corresponding 20% decrease in the amount of IGF-II receptors in the microsomal membranes prepared from insulin-treated cells, as assayed by immunoblotting. Moreover, the IGF-II receptors and GT were located in the same intracellular vesicles, since antibodies to the carboxyterminal peptide of either protein immunoadsorbed vesicles containing 70-95% of both proteins initially present in the microsomal fraction. In conjunction with other studies, these results indicate that in 3T3-L1 adipocytes, three membrane proteins (the GT, the transferrin receptor, and the IGF-II receptor) respond similarly to insulin, by redistributing to the surface from intracellular compartment(s) in which they are colocalized.

Adipose Tissue↗
PubMed1990

Role of the human transferrin receptor cytoplasmic domain in endocytosis: localization of a specific signal sequence for internalization.

Wild-type and mutant human transferrin receptors have been expressed in chicken embryo fibroblasts using a helper-independent retroviral vector. The internalization of mutant human transferrin receptors, in which all but four of the 61 amino acids of the cytoplasmic domain had been deleted, was greatly impaired. However, when expressed at high levels, such "tailless" mutant receptors could provide chicken embryo fibroblasts with sufficient iron from diferric human transferrin to support a normal rate of growth. As the rate of recycling of the mutant receptors was not significantly different from wild-type receptors, an estimate of relative internalization rates could be obtained from the distribution of receptors inside the cell and on the cell surface under steady-state conditions. This analysis and the results of iron uptake studies both indicate that the efficiency of internalization of tailless mutant receptors is approximately 10% that of wild-type receptors. Further studies of a series of mutant receptors with different regions of the cytoplasmic domain deleted suggested that residues within a 10-amino acid region (amino acids 19-28) of the human transferrin receptor cytoplasmic domain are required for efficient endocytosis. Insertion of this region into the cytoplasmic domain of the tailless mutant receptors restored high efficiency endocytosis. The only tyrosine residue (Tyr 20) in the cytoplasmic domain of the human transferrin receptor is found within this 10-amino acid region. A mutant receptor containing glycine instead of tyrosine at position 20 was estimated to be approximately 20% as active as the wild-type receptor. We conclude that the cytoplasmic domain of the transferrin receptor contains a specific signal sequence located within amino acid residues 19-28 that determines high efficiency endocytosis. Further, Tyr 20 is an important element of that sequence.

Amino Acid Sequence↗
PubMed1984

A lipophilic iron chelator can replace transferrin as a stimulator of cell proliferation and differentiation.

Of the different growth supplements used in chemically defined media, only transferrin is required for differentiation of tubules in the embryonic mouse metanephros. Since transferrin is an iron-carrying protein, we asked whether iron is crucial for tubulogenesis. Differentiation of metanephric tubules both in whole embryonic kidneys and in a transfilter system was studied. The tissues were grown in chemically defined media containing transferrin, apotransferrin, the metal-chelator complex ferric pyridoxal isonicotinoyl hydrazone (FePIH), and excesses of ferric ion. Although we found that apotransferrin was not as effective as iron-loaded transferrin in promoting proliferation in the differentiating kidneys, excess ferric ion at up to 100 microM, five times the normal serum concentration, could not promote differentiation or proliferation. However, iron coupled to the nonphysiological, lipophilic iron chelator, pyridoxal isonicotinoyl hydrazone, to form FePIH, could sustain levels of cell proliferation and tubulogenesis similar to those attained by transferrin. Thus, the role of transferrin in cell proliferation during tubulogenesis is solely to provide iron. Since FePIH apparently bypasses the receptor-mediated route of iron intake, the use of FePIH as a tool for investigating cell proliferation and its regulation is suggested.

Animals↗
PubMed1996

The Mycobacterium tuberculosis phagosome interacts with early endosomes and is accessible to exogenously administered transferrin.

Previous studies have demonstrated that the Mycobacterium tuberculosis phagosome in human monocyte-derived macrophages acquires markers of early and late endosomes, but direct evidence of interaction of the M. tuberculosis phagosome with the endosomal compartment has been lacking. Using the cryosection immunogold technique, we have found that the M. tuberculosis phagosome acquires exogenously added transferrin in a time-dependent fashion. Near-maximal acquisition of transferrin occurs within 15 min, kinetics of acquisition consistent with interaction of the M. tuberculosis phagosome with early endosomes. Transferrin is chased out of the M. tuberculosis phagosome by incubation of the infected macrophages in culture medium lacking human transferrin. Phagosomes containing latex beads or heat-killed M. tuberculosis, on the other hand, do not acquire staining for transferrin. These and other findings demonstrate that M. tuberculosis arrests the maturation of its phagosome at a stage at which the phagosome interacts with early and late endosomes, but not with lysosomes. The transferrin endocytic pathway potentially provides a novel route for targeting antimicrobials to the M. tuberculosis phagosome.

Biological Transport↗