Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A total of fifty-two foetal sheep between 49 and 126 days gestation were injected with polymeric and monomeric flagellin, dinitrophenylated monomeric flagellin, chicken red blood cells, ovalbumin, ferritin, chicken gamma-globulin and the somatic antigens of Salmonella typhimurium in a variety of combinations. Immune responses were followed in these animals by taking serial blood samples from them through indwelling vascular cannulae and measuring the circulating titres of antibody. Of the antigens tested, ferritin induced immune responses in the youngest foetuses. A short time later in gestation, the majority of foetuses responded to chicken red blood cells, polymeric flagellin, monomeric flagellin and dinitrophenylated monomeric flagellin. Only older foetuses responded regularly to chicken gamma-globulin and ovalbumin. However, antibodies to all these antigens were first detected over the relatively short period of development between 64 and 82 days gestation and this made it difficult to define any precise order in the development of immune responsiveness. Of the antigens tested only the somatic antigens of S. typhimurium failed to induce a primary antibody response during foetal life. The character and magnitude of the antibody responses in foetuses changed throughout in utero development. Both the total amount of antibody produced and the duration of the response increased with foetal age. Foetuses younger than 87 days gestation did not synthesize 2-mercaptoethanol resistant antibodies or IgG1 immunoglobulin to any of the antigens tested, whereas most foetuses older than this regularly did so.
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PMID:Humoral immune responses in foetal sheep. 71 Dec 49

The nature and some biological properties of the natural antitumor cytotoxins previously found in normal C3Hf serum, have been investigated. By immunoelectronmicroscopy study, employing rabbit hybrid antibodies with specificity for mouse Ig and ferritin, the C3Hf cytotoxins were shown to belong to immunoglobulins. By gel filtration, by inhibition experiments of the cytotoxic serum activity with monospecific anti-IgG and anti-IgM sera, and by 2-mercaptoethanol treatment of the C3Hf serum, the cytotoxic immunoglobulins were demonstrated to belong to the IgM class. They were not inactivated by heating until 60 degrees C and were able to activate guinea pig, rabbit, and human complement. The highest cytotoxic activity of the normal C3Hf serum was found when cells and serum were incubated at the low temperature, suggesting a low binding affinity of the cytotoxic IgM.
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PMID:Nature and properties of C3Hf natural antitumor cytotoxins directed against murine lymphosarcoma cells. 103 63

The mRNA-binding protein, iron-regulatory factor (IRF) has a central role in iron metabolism. It coordinately increases transferrin-receptor mRNA stability and inhibits translation of ferritin and erythroid delta-aminolevulinate synthase mRNA by binding to specific mRNA structures, the iron-responsive elements (IRE). In gel-retardation assays, IRF had a broad tissue distribution, showing activity in cytosolic extracts from 12 mouse organs tested. In all these extracts, IRF could be further activated in vitro by 2-mercaptoethanol. In cultured mouse 3T6 fibroblasts, growth stimulation after low serum arrest increased IRF activity 10-fold, mainly through activation of existing inactive IRF. No change was observed during progression of 3T6 cells through the cell cycle. IRF activation by iron chelators has been postulated to result in the reduction of an intramolecular sulfhydryl group. In a search for redox conditions that regulate IRE binding of IRF, we studied several compounds in vitro or in vivo. Hemin, known to inactivate IRF in vivo, showed a similar, reversible effect in vitro, presumably by oxidizing IRF. However, this did not appear to be relevant for the mode of IRF regulation in vivo. Addition of protoporphyrin IX to intact cells induced IRF activity almost to the same extent as desferrioxamine. This effect was inhibited by iron salts, indicating that IRF is activated in vivo through depletion of a chelatable iron pool. In vitro activation by reductants other than 2-mercaptoethanol suggested some selectivity in their access to relevant sulfhydryl groups, but did not reveal which natural redox-sensitive compound might regulate IRF in vivo. However, in cultured cells, inactivation of free IRF by the sulfhydryl-specific oxidizing agent diamide was much more rapidly reversed than inactivation by iron salts. This indicates the direct involvement of a cellular reductant in setting IRF activity and suggests a rate-limiting IRF conformation that is reached only in the presence of iron, but not after diamide oxidation.
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PMID:In vivo and in vitro modulation of the mRNA-binding activity of iron-regulatory factor. Tissue distribution and effects of cell proliferation, iron levels and redox state. 139 66

A fluorescein- and lactoperoxidase-conjugated ferritin-anti-ferritin immune complex has been prepared for cell surface labeling experiments on immune recognition and effector function. Lactoperoxidase (LPO) has been covalently coupled to affinity-purified anti-ferritin antibodies with p-benzoquinone by a modified version of the method of Ternynck and Avrameas [Ternynck, T., & Avrameas, S. (1976) Ann. Immunol. (Paris) 127C, 197]. The conjugate is a heterodimer of Mr230 000 with linkages to either or both of the heavy and light chains of the antibody, as judged by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in the absence and presence of 2-mercaptoethanol. The conjugate retains antibody-binding activity as measured by a quantitative precipitin assay. When incorporated into immune complexes, the modified antibody also retains Fc receptor recognition ability as determined by erythrocyte-antibody rosette inhibition assays. Electron microscopy demonstrated that the antigen, ferritin, was monodisperse with complete apoprotein sheaths surrounding the core. Ferritin-anti-ferritin-LPO complexes were formed in 4-fold antigen excess. Complexes were verified by fluorescence and electron microscopy. Immune complexes were masked with "cold" iodine by use of the endogenous LPO activity. The complexes bound to cells at 4 degrees C as shown by electron microscopy and fluorescence video/intensification microscopy. The LPO delivered to the cell surface in this fashion can be utilized to iodinate the surface with 125I. Under saturation conditions, the labeling with local LPO delivery followed by SDS-PAGE and autoradiography is identical with labeling with free LPO. Labeling has also been conducted under conditions of substrate deficit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Macrophage recognition of immune complexes: development and application of novel cell surface labeling procedures. 405 86

The control of cellular iron homeostasis involves the coordinate post-transcriptional regulation of ferritin mRNA translation and transferring receptor mRNA stability. These regulatory events are mediated by a soluble cytoplasmic protein, iron regulatory factor (IRF), which binds specifically to mRNA hairpin structures, termed iron-responsive elements (IREs), in the respective mRNAs. IRF is modulated by variations of cellular iron levels and exists as either an apo-protein or a [4Fe-4S]-cluster protein. The two conformations show distinct, mutually exclusive functions. High-affinity IRE binding is observed with the apo-form induced by iron deprivation, but is lost under high iron conditions when IRF is converted to the [4Fe-4S]-cluster form which shows cytoplasmic aconitase activity. Moreover, IRE binding is inactivated by the sulfhydryl-oxidizing agent diamide and fully activated in vitro by 2% 2-mercapto-ethanol, whereas alkylation of IRF inhibits IRE binding. In the present study, we analyzed each of the above features using site-directed mutants of recombinant human IRF. The results support the bifunctional nature of IRF. We conclude that cysteines 437, 503 and 506 anchor the [4Fe-4S]-cluster, and are essential to the aconitase activity. Mutagenesis changing any of the cysteines to serine leads to constitutive RNA binding in 0.02% 2-mercaptoethanol. Cysteine 437 is particularly critical to the RNA-protein interaction. The spontaneous or diamide-induced formation of disulfide bonds between cysteines 437 and 503 or 437 and 506, in apo-IRF, as well as its alkylation by N-ethylmaleimide, inhibit binding to the IRE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mutational analysis of the [4Fe-4S]-cluster converting iron regulatory factor from its RNA-binding form to cytoplasmic aconitase. 750 61

Cellular iron homeostasis is regulated by the cytoplasmic iron regulatory protein (IRP), which binds to iron-responsive elements (IRE) of mRNAs, modulating iron uptake and sequestration, respectively. When iron is scarce, IRP binds to IRE and coordinately increases the synthesis of transferrin receptor and decreases that of ferritin, thus providing the cell with readily available free iron. When iron is in excess, IRP does not bind and iron sequestration prevails over iron uptake. We have found that incubation of rat liver lysates with xanthine oxidase (XO), which generates superoxide (O2-.) and hydrogen peroxide (H2O2), caused a remarkable but reversible inhibition of IRP activity, as the formation of IRE-IRP decreased by 70-80% but returned to baseline values upon exposure to a reducing agent like 2-mercaptoethanol. IRP inhibition was prevented by separate or simultaneous addition of superoxide dismutase and catalase, showing that both O2-. and H2O2 were involved. By contrast, iron chelators and hydroxyl radical scavengers did not impede the inhibition of IRP, suggesting that O2-. and H2O2 acted independently of free iron sources. Ferritin enhanced IRP inhibition, but this process involved tightly bound iron centers that shunted reducing equivalents from XO and returned them to oxygen, thus increasing the formation of O2-. In agreement with the exclusive role of O2-. and H2O2, XO also inhibited recombinant human IRP in the absence of iron. These results demonstrate that O2-. and H2O2 can directly but reversibly down-regulate the RNA-binding activity of IRP, causing transient decrease of free iron that otherwise would convert them into more potent oxidants such as hydroxyl radicals or equally aggressive iron-peroxo complexes. This establishes a novel protective stratagem against oxidative injury under pathophysiologic conditions characterized by the excessive generation of O2-. and H2O2.
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PMID:Superoxide and hydrogen peroxide-dependent inhibition of iron regulatory protein activity: a protective stratagem against oxidative injury. 914 4

Ferritin was purified from iron-fed Drosophila melanogaster extracts by centrifugation in a gradient of potassium bromide. On polyacrylamide gel electrophoresis, the product showed two protein bands corresponding to the ferritin monomer and dimer. Electrophoresis following dissociation with SDS and 2-mercaptoethanol revealed three strong bands of approximately 25, 26, and 28 kDa. N-terminal amino acid sequences were identical for the 25-kDa and 26-kDa subunits, but different for the 28-kDa subunit. Conserved ferritin PCR primers were used to amplify a 360-bp cDNA product, which was used to isolate a clone from a D. melanogaster cDNA library that contained the complete coding sequence for a ferritin subunit. Additional 5' sequence obtained by the RACE method revealed the presence of a putative iron regulatory element. The PCR product was also used to locate the position of the ferritin subunit gene at region 99F on the right arm of the third chromosome. The deduced amino acid sequence of the D. melanogaster ferritin subunit contained a signal sequence and resembled most closely ferritin of the mosquito Aedes aegypti. The evolution of ferritin sequences is discussed.
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PMID:Isolation and properties of Drosophila melanogaster ferritin--molecular cloning of a cDNA that encodes one subunit, and localization of the gene on the third chromosome. 926 86

The fetal lamb in utero is able to form large amounts of specific antibody in response to antigenic stimulus as early as the 66th to 70th day of the 150 day gestation period. Among the several antigens employed, the fetal lamb responded earliest, and with the highest titers, to bacteriophage varphiX. Slightly less effective as an antigen was horse ferritin, while ovalbumin proved to be a weak antigen, especially in younger fetuses. Ineffective in stimulating an antibody response at any time during fetal or early neonatal life were diphtheria toxoid, Salmonella typhosa, and BCG. Thus, it may not be feasible to fix precisely the time of onset of immunologic responsiveness in a species, inasmuch as it appears to differ so greatly from one antigen to another. The quantity of antibody found 10 days after varphiX immunization was not significantly different in fetuses injected at 60 to 120 days of gestation. The earliest anti-phage antibody produced by the lamb fetus is a macroglobulin sensitive to the action of 2-mercaptoethanol. Only in older fetuses with longer lasting stimuli were appreciable amounts of 7S gamma-globulin antibodies formed. The conformity of these observations to theories on the ontogenesis of the immune response is discussed.
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PMID:Fetal response to antigenic stimulus. II. Antibody production by the fetal lamb. 1399 61

Iron regulatory protein-1 (IRP-1) is a bifunctional [4Fe-4S] protein that functions as a cytosolic aconitase or as a trans-regulatory factor controlling iron homeostasis at a post-transcriptional level. Because IRP-1 is a sensitive target protein for nitric oxide (NO), we investigated whether this protein is nitrated in inflammatory macrophages and whether this post-transcriptional modification changes its activities. RAW 264.7 macrophages were first stimulated with interferon-gamma and lipopolysaccharide (IFN-gamma/LPS) and then triggered by phorbol 12-myristate 13-acetate (PMA) in order to promote co-generation of NO* and O*2-.. IRP-1 was isolated by immunoprecipitation and analyzed for protein-bound nitrotyrosine by Western blotting. We show that nitration of endogenous IRP-1 in NO-producing macrophages boosted to produce O*2- was accompanied by aconitase inhibition and impairment of its capacity to bind the iron-responsive element (IRE) of ferritin mRNA. Lost IRE-binding activity was not recovered by exposure of IRP-1 to 2% 2-mercaptoethanol and was not due to protein degradation. Inclusion of cis-aconitate with cell extract to stabilize the [4Fe-4S] cluster of holo-IRP-1 rendered protein insensitive to nitration by peroxynitrite, suggesting that loss of [Fe-S] cluster and subsequent change of conformation are prerequisites for tyrosine nitration. IRP-1 nitration was strongly reduced when IFN-gamma/LPS/PMA-stimulated cells were incubated with myeloperoxidase inhibitors, which points to the contribution of the nitrite/H2O2/peroxidase pathway to IRP-1 nitration in vivo. Interestingly, under these conditions, IRP-1 recovered full IRE binding as assessed by treatment with 2% 2-mercaptoethanol. Peroxidase-mediated nitration of critical tyrosine residues, by holding IRP-1 in an inactive state, may constitute, in activated macrophages, a self-protecting mechanism against iron-induced toxicity.
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PMID:Endogenous nitration of iron regulatory protein-1 (IRP-1) in nitric oxide-producing murine macrophages: further insight into the mechanism of nitration in vivo and its impact on IRP-1 functions. 1525 60