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At least 289 records · Page 16Linked to original sources
PubMed1997

Fluorescent recovery after photobleaching (FRAP) of a fluorescent transferrin internalized in the late transferrin endocytic compartment of living A431 cells: theory.

In previous works, other authors characterized a compartment (LCT) of A431 carcinoma cells in which markers of transferrin endocytose had accumulated during a long chase period. This compartment, was essentially formed by large stationary vacuoles. A few small vesicles budded from these vacuoles, rapidly saltated along microtubules and eventually fused with other vacuoles, causing an intracellular transport of the marker bound to the limiting membrane (M. De Brabander, R. Nuygens, H. Geerts, C.R. Hopkins, Cell. Mot. Cytoskel. 9 (1988) 30). In the present paper, we derived the fluorescence recovery after photobleaching (FRAP) of a fluorescent marker of LCT. We assumed that the rate of the intracellular transport of the marker was controlled by the fission-fusion process between vesicles and vacuoles. We showed that the concentration of a bleached fluorescent marker was a decreasing exponential function of the time elapsed from the beginning of the recovery phase. The rate constant of this exponential was equal to the product of the vesicle surface by the number of vesicles which fused with a unit of vacuole surface during one second. If a fraction of the marker spontaneously reactivated itself with a much higher rate constant of reaction than the rate constant of the transport process, the fractional FRAP of the marker was the sum of the fractional FRAP of both processes occurring separately. In a companion paper (F. Azizi, P. Wahl, Biochim. Biophys. Acta 1327 (1997) 75-88), our FRAP experiments will be described and analysed with the mathematical expressions derived in the present paper.

Biological Transport, Active↗
PubMed2001

Pro-apoptotic and anti-apoptotic effects of transferrin and transferrin-derived glycans on hematopoietic cells and lymphocytes.

The aim of this study was to test the hypothesis that transferrin (Tf) has anti-apoptotic properties and thereby exerts a cytoprotective effect against tissue damage induced by irradiation and other cytotoxic modalities. This hypothesis was tested in several models, including in vitro human short-term marrow cultures, subpopulations of marrow cells, particularly, CD56(+) natural killer cells (and natural killer cell lines), and in vivo radioprotection of murine marrow cells. Reverse transcriptase polymerase chain reaction analysis was used for determination of cytokine mRNA. Preincubation of human marrow with Tf protected cells (except for a CD56(+) subpopulation) against cell death induced by gamma-irradiation, tumor necrosis factor-alpha (TNF-alpha), and agonistic anti-Fas monoclonal antibody. Deglycosylation of Tf abrogated this action of Tf; conversely, Tf-derived glycans (Tf-Gly) (but not glycans isolated from other proteins) mimicked the effects of the intact Tf molecule on apoptosis. Antibodies specific for the Tf receptor (CD71) did not block the effects of Tf or Tf-Gly on apoptosis. Determination of cytokine mRNA in the course of Fas-mediated apoptosis in the presence of Tf or Tf-Gly showed upregulation of mRNA for Fas ligand and TNF-alpha in CD56(+) and downregulation of these transcripts along with upregulation of mRNA for interleukin-10 in CD3(+) marrow cells. Under these conditions, a distinct increase in Fas-associated phosphatase-1 message was observed in CD3(+) cells that were protected by Tf or Tf-Gly against apoptosis. The in vitro data were confirmed in a murine in vivo model in which pretreatment of mice with Tf protected marrow cells against gamma-irradiation-induced cell death. These data suggest a role for Tf and particularly Tf-Gly in the regulation of programmed cell death, apparently via alterations in cytokine expression, and provide a basis for additional studies on the use of Tf in cytoprotective protocols.

Animals↗
PubMed1987

Heterogeneity of the human transferrin receptor and use of anti-transferrin receptor antibodies to detect tumours in vivo.

The human transferrin receptor (TFR) which is present on dividing cells, many tumours and erythroid precursors is readily identified using specific monoclonal antibodies. A new anti-human TFR monoclonal antibody, HuLy-m9, is described and its distribution on cell lines, normal and tumour tissue was examined and compared with two other anti-TFR monoclonal antibodies, namely, OKT9 and 5E9. The three antibodies were shown to recognise different epitopes on the surface of the TFR and have different reactivities with in vitro cell lines. Peptide map analyses of the TFR recognised by each monoclonal antibody from the same cell line were identical; however, differences were observed between cell lines. 131I-radiolabelled HuLy-m9 was used to successfully localise a nasopharyngeal carcinoma in vivo.

Antibodies, Monoclonal↗
PubMed2000

Soluble transferrin receptor levels and soluble transferrin receptor/log ferritin index in the evaluation of erythropoietic status in childhood infections and malignancy.

UNLABELLED: Soluble transferrin receptor (sTfR) is a new diagnostic tool for determining iron status and erythropoietic activity. The increased concentrations of sTfR in patients with iron deficiency reflect the hyperplasia of erythroid precursors. The objective of this study was to evaluate sTfR and sTfR/log ferritin index (sTfR-F) values in healthy children (n = 64), full-term neonates (n = 18), children with iron deficiency (n = 16), hemolytic anemia (n = 7), beta-thalassemia traits (n = 18), respiratory infections (n = 41) and malignancies (n = 13), and to compare these parameters for the different subgroups with those of healthy children. The sTfR levels were increased in children with iron deficiency in the same way as in adults (p < 0.0001) and in cases of increased erythropoietic activity, such as during the neonatal period (p < 0.0001), and of hemolytic anemias (p = 0.006). The index was significantly increased in iron deficiency (p < 0.0001) and decreased in neonates (p = 0.011). Children carriers of beta-thalassemia were found to have increased sTfR values (p = 0.015), but not sTfR/log ferritin index (p = 0.491), a finding suggesting that use of both parameters is necessary for distinguishing between those with and those without iron deficiency. In children with upper respiratory infection, the sTfR levels were close to normal, while the index was found to be low. In order to evaluate the iron status in infections, we further subdivided the children into two groups according to the value of ferritin, with the cut-off point at 35 microg/L. Children with ferritin level above 35 microg/L experienced normal sTfR levels but very low index, a finding which could enable the use of these two parameters for distinguishing patients with infection without concomitant iron deficiency. In the group of malignancies under chemotherapy both indices were low (p = 0.005, p < 0.0001) mainly due to myelosuppression. CONCLUSION: The interpretation of both sTfR and sTfR/log ferritin index is useful in the evaluation of iron status and erythropoietic activity, especially in children with heterozygous beta-thalassemia, infection and malignancies.

Adolescent↗
PubMed1994

Reduction site of transferrin-dependent and transferrin-independent iron in cultured human fibroblasts.

Mammalian cells internalize iron as diferric transferrin (Fe2Tf) iron via receptor-mediated endocytosis (RME) and a redox mechanism under physiological condition and as an iron salt through the Tf-independent iron uptake (Tf-IU) system under morbid conditions. We have previously shown that Tf iron is reduced at the Tf molecule through a redox system on the plasma membrane prior to uptake [Oshiro, S., Nakajima, H., Markello, T., Krasnewich, D., Bernadini, I., & Gahl, W. (1993) J. Biol. Chem. 268, 21586-21591]. In the present study, the reduction site for Tf iron uptake via RME and for Tf-independent iron uptake via the Tf-IU system were examined using specific iron sources and well-characterized ferric or ferrous iron chelators in cultured human fibroblasts. At 4 degrees C for 1 h, although [55Fe]2Tf was not internalized into the cells, 55Fe from [55Fe]2Tf-Sepharose was taken up. However, under the same conditions, EDTA or dipyridyl removed the radioactive iron as a ferric or ferrous iron-chelator complex from [55Fe]2Tf bound to the Tf receptor on the cell surface. Moreover, after 55Fe-citrate was loaded into the cells at 4 degrees C for 1 h, 55Fe was removed from the cell surface by dipyridyl just as observed for [55Fe]2Tf-Sepharose. In inhibition experiments, ferric citrate showed a dose-dependent inhibition of the iron uptake of both Tf iron and Tf-independent iron. Conversely, Fe2Tf dose-dependently inhibited the uptake of 55Fe-citrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Membrane↗
PubMed1999

Ehrlichia chaffeensis and E. sennetsu, but not the human granulocytic ehrlichiosis agent, colocalize with transferrin receptor and up-regulate transferrin receptor mRNA by activating iron-responsive protein 1.

Ehrlichia chaffeensis and E. sennetsu are genetically divergent obligatory intracellular bacteria of human monocytes and macrophages, and the human granulocytic ehrlichiosis (HGE) agent is an obligatory intracellular bacterium of granulocytes. Infection with both E. chaffeensis and E. sennetsu, but not HGE agent, in the acute monocytic leukemia cell line THP-1 almost completely inhibited by treatment with deferoxamine, a cell-permeable iron chelator. Transferrin receptors (TfRs) accumulated on both E. chaffeensis and E. sennetsu, but not HGE agent, inclusions in THP-1 cells or the cells of the promyelocytic leukemia cell line HL-60. Reverse transcription-PCR showed an increase in the level of TfR mRNA 6 h postinfection which peaked at 24 h postinfection with both E. chaffeensis and E. sennetsu infection in THP-1 or HL-60 cells. In contrast, HGE agent in THP-1 or HL-60 cells induced no increase in TfR mRNA levels. Heat treatment of E. chaffeensis or the addition of monodansylcadaverine, a transglutaminase inhibitor, 3 h prior to infection inhibited the up-regulation of TfR mRNA. The addition of oxytetracycline 6 h after E. chaffeensis infection caused a decrease in TfR mRNA which returned to the basal level by 24 h postinfection. These results indicate that both internalization and continuous proliferation of ehrlichial organisms or the production of ehrlichial proteins are required for the up-regulation of TfR mRNA. Results of electrophoretic mobility shift assays showed that both E. chaffeensis and E. sennetsu infection increased the binding activity of iron-responsive protein 1 (IRP-1) to the iron-responsive element at 6 h postinfection and remained elevated at 24 h postinfection. However, HGE agent infection had no effect on IRP-1 binding activity. This result suggests that activation of IRP-1 and subsequent stabilization of TfR mRNA comprise the mechanism of TfR mRNA up-regulation by E. chaffeensis and E. sennetsu infection.

Base Sequence↗
PubMed1987

A comparison of two procedures used for complexing Fe(III) with human apotransferrin. II. Uptake of Fe(III) by K-562 cells from 55Fe . transferrins and Fe . [3H]transferrins.

Samples of human apotransferrin (apo . HTr) were saturated with Fe(III) by two different techniques, a method employing excess trisodium citrate to chelate Fe(III) and a nonchelating approach which involves the ferroxidase activity of ceruloplasmin to convert Fe(II)----Fe(III). The samples were radiolabelled with either 55Fe or 3H. Using an initial molar Fe/apo . HTr ratio of 2.0-2.1, preparations of human transferrin with bound Fe (Fe . HTr) using the citrate method invariably contained 2.2-2.4 atoms Fe/molecule, whereas Fe . HTr (ceruloplasmin method) contained 2.0 atoms/molecule as shown by spectrophotometric and radioactivity measurements. Uptake of Fe from these Fe . HTr preparations by K-562 cells grown in a serum-free medium was marginally, but consistently, more rapid from 55Fe . HTr (citrate) than from 55Fe . HTr (ceruloplasmin). Taking account of the different Fe contents of the Fe . HTr preparations, the rate measured over a 2-h period amounted to approximately 12,700 and 16,100 Fe atoms/(cell . min) for Fe . HTr (ceruloplasmin) and Fe . HTr (citrate), respectively. However, cell binding by the two Fe . [3H]HTr preparations did not differ significantly over the 8-h incubation period. Furthermore, from the 3H distribution, the quantities of Fe . HTr bound reversibly at the cell surface and contained within the cell were similar for the two Fe . HTr preparations. The results indicate that apo . HTr may bind Fe in different ways depending on the method of Fe presentation and that the Fe . HTr product can donate Fe to K-562 cells at a rate which may reflect the method used for Fe-complex formation.

Apoproteins↗
PubMed2004

Regulation of transferrin receptor 2 protein levels by transferrin.

Transferrin receptor 2 (TfR2) plays a critical role in iron homeostasis because patients carrying disabling mutations in the TFR2 gene suffer from hemochromatosis. In this study, iron-responsive regulation of TfR2 at the protein level was examined in vitro and in vivo. HepG2 cell TfR2 protein levels were up-regulated after exposure to holotransferrin (holoTf) in a time- and dose-responsive manner. ApoTf or high-iron treatment with non-Tf-bound iron failed to elicit similar effects, suggesting that TfR2 regulation reflects interactions of the iron-bound ligand. Hepatic TfR2 protein levels also reflected an adaptive response to changing iron status in vivo. Liver TfR2 protein levels were down- and up-regulated in rats fed an iron-deficient and a high-iron diet, respectively. TfR2 was also up-regulated in Hfe(-/-) mice, an animal model that displays liver iron loading. In contrast, TfR2 levels were reduced in hypotransferrinemic mice despite liver iron overload, supporting the idea that regulation of the receptor is dependent on Tf. This idea is confirmed by up-regulation of TfR2 in beta-thalassemic mice, which, like hypotransferrinemic mice, are anemic and incur iron loading, but have functional Tf. Based on these combined results, we hypothesize that TfR2 acts as a sensor of iron status such that receptor levels reflect Tf saturation.

Animals↗
PubMed1995

Follicle stimulating hormone (FSH) stimulates transferrin gene transcription in rat Sertoli cells: cis and trans-acting elements involved in FSH action via cyclic adenosine 3',5'-monophosphate on the transferrin gene.

FSH is a major regulator of transferrin (Tf) production in the testis. FSH effects on Sertoli cell Tf production are believed to be mediated, at least in part, via cAMP second messenger system. Previously, it has been shown that FSH and (Bu)2cAMP stimulate Tf mRNA levels. This study examines the effect of cAMP and FSH on Tf gene transcription using run-on assays. These data demonstrate rapid induction of Tf gene by (Bu)2cAMP (2.3-fold) and FSH (2.8-fold) within 30 min and 2 h, respectively. Furthermore, the ability of (Bu)2cAMP and FSH to drive the transcription of chimeric constructs containing a 0.6-kilobase segment of the 5'-regulatory region of the human Tf gene coupled to a chloramphenicol acetyltransferase (CAT) was examined. Deletion analysis indicated that the sequence -100/-52 base pairs is required for the cAMP-dependent transcription. This sequence shows no homology to that of the consensus cAMP-regulatory element (CRE). However, cotransfection experiments with a CRE-binding protein (CREB) expression vector revealed a basal induction of the Tf transcriptional activity as well as a synergistic activation of CREB and (Bu)2cAMP. Expression of KCREB, a dominant negative mutant form of CREB, completely blocked the cAMP induction of the -100+39Tf-CAT construct. This region contains two functional regions PRI and PRII. Gel shift assay with nuclear proteins from Sertoli cells using the PRII and PRI probes showed that the band shifts formed by PRII were competitive complexes with CRE, and a CREB antiserum retarded the migration of nuclear Sertoli cells proteins. We conclude that CREB is implicated in the FSH regulation on the Tf gene in Sertoli cells.

Animals↗
PubMedDate not supplied

[Effect of alpha-lipoic acid preparations on bilirubin and transferrin levels and ferritin iron and transferrin iron content].

The influence of ethylendiamine salt of alpha-lipoic acid on the indices of iron metabolism in patients with occupational pathologies has been studied using quantitative electron spin resonance spectroscopy. In the cases of treatment in the patients suffering from hyperferremia the decrease in transferrin iron concentration in the whole blood and plasma occurs correlating with the enhancement of iron excretion from urine and decline of bilirubin level in serum. We have found that the preparation chelates iron from iron (III)-citrate complex and form stable iron (III) complexes. The conclusion is that the positive effects of lipoic acid preparation in the patients with hyperferremia at least partially could be associated with normalization of iron exchange and reduction in the labile iron pool.

Bilirubin↗
PubMed1991

The role of diferric transferrin in iron absorption and transferrin concentration in rat pancreatic juice and milk.

Transferrin (Tf) was found immunologically in pancreatic juice of normal rats at a concentration of 0.28 +/- 0.10 mg/ml but was found to be approximately 4-times higher in iron-deficient rats. Iron saturation of pancreatic Tf of normal rats was 40% and similar to that of serum Tf. Approximately 27% of a dose of iron from 59Fe-diferric Tf was absorbed through the ligated segments of proximal intestine in normal rats. The iron absorption ratio of 59Fe-diferric Tf was higher from the duodenal and jejunal segments than the ileum and significantly inhibited by monodansylcadaverine (MDC) or 20-times excess of unlabeled diferric Tf. The presence of Tf receptors was demonstrated by specific binding of 125I-diferric Tf to the brush border membrane vesicles of the small intestine in normal rats. The binding was not inhibited by the presence of albumin or IgG. The association constant (Ka) was 1.03 +/- 0.50 x 10(8) M-1 and number of binding sites was 5.10 +/- 0.96 x 10(12) sites/mg protein in the proximal intestine. The number of binding sites for Tf was higher in the proximal intestine than in the distal one. These results suggested that some iron was absorbed as diferric Tf into enterocytes through receptor-mediated endocytosis.

Animals↗
PubMed1991

Shedding of transferrin receptor from rat reticulocytes during maturation in vitro: soluble transferrin receptor is derived from receptor shed in vesicles.

Measurements of circulating transferrin (Tf) receptor are useful in assessing erythropoiesis; however, steps involved in the generation of soluble Tf receptor from cellular receptor are incompletely understood. To obtain a better understanding of this process, we investigated the loss of Tf receptor during terminal maturation of rat reticulocytes in vitro. Previous studies have identified Tf receptor-containing vesicles in the culture medium of maturing reticulocytes. In the present study, vesicle-free reticulocyte culture medium was found to contain functional and immunoreactive soluble Tf receptor, which increased over time. During a 44-hour incubation, Tf receptor on reticulocytes decreased by approximately 69%, while, of the Tf receptor shed to the medium, 65% was present in vesicles and 35% was in a soluble form. Isolated vesicles reincubated in fresh medium released soluble Tf receptor to the medium. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), the isolated soluble receptor protein was mainly 190 Kd and 95 Kd under nonreducing and reducing conditions, respectively, similar in size to the vesicular and cellular receptor. Our studies show that loss of Tf receptor from rat reticulocytes during maturation in vitro involves shedding of cellular Tf receptor in vesicles and release of soluble receptor from these vesicles.

Animals↗
PubMed1991

Some molecular properties of human seminal transferrin (HSmT) in comparison with human serum transferrin (HSrT).

In this paper we report some structural features of human seminal transferrin (HSmT) in comparison with the homologous protein purified from human serum (HSrT). In particular, the sequence of the first 13 N-terminal amino acids of HSmT shows 12/13 of identity with the first 13 N-terminal amino acids of HSrT, the ninth residue of the former protein being not definitely determined. Moreover, HSrT and HSmT analysed under the same conditions, by means of reversed phase HPLC, thiol groups determination and second derivative spectroscopy, show a different content of amino acids. In particular, HSmT exhibits mainly: i) a lower Asx/Glx ratio; ii) a reduction of about 50% in Cys residues; iii) a decrease of Tyr and Trp residues. Eventually oligosaccharide parallel analyses of HSmT and HSrT show the same glycosidic bond and almost the same sugar content (around 5.5% w/w); conversely, HSmT lacks of sialic acid residues and probably it contains fucose. These results, taken all together, could be sound of interest to a better understanding of the possible physiological roles of HSmT.

Amino Acid Sequence↗
PubMed1986

Purified human transferrin and "transferrin" released from sorted T8+ lymphocytes suppress release of granulocyte-macrophage colony-stimulating factors from sorted T4+ lymphocytes stimulated by phytohemagglutinin.

Nonadherent, low-density E-rosette-positive human peripheral blood cells were separated into T4+ and T8+ lymphocytes by immuno-fluorescence-activated cell sorting (FACS) with monoclonal antibodies OKT4 and OKT8. Both T4+ and T8+ lymphocytes released granulocyte-macrophage colony-stimulating factors (GM-CSF) in response to phytohemagglutinin (PHA). Purified iron-saturated human transferrin (TF) suppressed release of GM-CSF only from the T4+ subset of lymphocytes. A TF-type inhibitory activity was released from the T8+ subset of lymphocytes alone, and this inhibitory activity, as well as that in purified TF, was inactivated by preincubation with antihuman TF monoclonal antibody (HT/1). These studies suggest that, at least in vitro, subsets of T-lymphocytes and TF may be involved in the regulation of myelopoiesis.

Cell Separation↗
PubMed1998

Serum transferrin receptor and transferrin receptor-ferritin index identify healthy subjects with subclinical iron deficits.

Despite the established utility of serum transferrin receptor (sTfR), serum ferritin, and the sTfR/log ferritin ratio (TfR-F Index) in the diagnosis of iron deficiency (ID) anemia, the numeric values of these parameters, which are indicative of subclinical ID, remain to be clearly defined. In this study, 65 apparently healthy nonanemic adults (22 men and 43 women) were treated with 3 months of oral iron supplementation to evaluate its effect on parameters reflecting iron status and to determine the prevalence of subclinical iron deficiency in apparently healthy adults. Significant supplementation-induced changes were observed in sTfR, ferritin, and TfR-F Index values in women, whereas in men, none of the studied parameters showed any significant change. Iron-deficient erythropoiesis (IDE) was not observed in men, but was found in 17 women (40%). Although individuals with a compromised iron status may be represented in substantial numbers in conventional reference populations, they can be readily identified using sTfR, ferritin, and TfR-F Index determinations.

Administration, Oral↗