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)

Cancerous breast hyperthermia is seemingly associated with non-neurological vasodilation modulated by nitric oxide (NO). NO, associated with enhanced immune response, is produced autocatalytically involving ferritin as the supplier of Fe2+, which catalyses the formation of NO. NO, in turn, releases Fe2+ from ferritin. This mechanism implies: (1) dependence of hyperthermia on the ferritin content of the neoplastic tissue; (2) oscillatory behavior of the hyperperfusion; (3) hyperthermia that extends far beyond the boundaries of the neoplastic tissue; (4) diminished neurological control of the perfusion in the affected breast; (5) limitations on the observed asymmetry between the breasts. These five effects were previously observed in numerous independent studies. Monitoring the temporal behavior of the hyperthermia is expected to substantially increase both sensitivity and specificity of cancer detection.
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PMID:Hyperthermia of the cancerous breast: analysis of mechanism. 807 60

This study was undertaken to characterize the nitric oxide complexes of mammalian ferritin and their EPR properties to gain a better understanding of the interaction of NO with non-heme iron proteins within the cell. Measurements were made with horse spleen apo- and holoferritins, with chemically modified proteins, and with recombinant human H-chain apoferritin and its site-directed mutants. Three types of EPR signals (A, B, and C) have been identified and attributed to iron-nitrosyl complexes at imidazole groups of histidine, thiol groups of cysteine, and carboxylate groups of aspartate and glutamate, respectively. The C-type axial spectrum has features at g perpendicular' = 4 and g parallel' = 2 characteristic of a paramagnetic Fe(3+)-NO- complex with total spin S = 3/2 and probably arises from nonspecific binding to carboxylate groups on the protein. The S = 1/2 axial B-type signal g perpendicular' = 2.033 and g parallel' = 2.014) is formed at Cys-130 (human H-chain sequence numbering). His-128 and possibly His-118 are sites of formation of the rhombic S = 1/2 A-type complex (gx' = 2.055, gy' = 2.033, and gz' = 2.015); the former residue perhaps plays a role in the conformational stability of the protein as well as in iron binding. The data reveal that the residues Cys-130 and His-128 in the vicinity of 3-fold channels leading to the interior of the protein shell are important in iron-nitrosyl complex formation in mammalian ferritins.
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PMID:Identification of the EPR-active iron-nitrosyl complexes in mammalian ferritins. 814 66

Recent advances in the knowledge of iron metabolism underscore its complex relationship to overall cell metabolism. One of the key components of the iron uptake and storage pathway is ferritin, a protein that sequesters iron in a nontoxic form. Ferritin synthesis is translationally regulated by iron. Molecules such as nitric oxide and cytokines also affect transcriptional and/or posttranscriptional ferritin synthesis. Conversely, iron-containing molecules affect expression of mitochondrial aconitase, erythroid aminolevulinic acid synthase, and nitric oxide synthase. This observation indicates a complex linkage between iron metabolism and a variety of other important cell activities. The finding that the cytoplasmic iron-responsive protein (IRP) has two forms also raises intriguing questions about the relationship between the cytoplasmic aconitase and translational regulation of mRNAs such as ferritin. At least one of the IRPs can be phosphorylated. These recent discoveries open exciting new avenues for research that should lead to a better understanding of cellular iron metabolism.
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PMID:Regulation of iron metabolism: translational effects mediated by iron, heme, and cytokines. 852 20

Iron-regulatory proteins (IRP1 and IRP2) are RNA-binding proteins that bind to stem-loop structures known as iron-responsive elements (IREs). IREs are located in the 5'- or 3'-untranslated regions (UTRs) of specific mRNAs that encode proteins involved in iron homeostasis. The binding of IRPs to 5' IREs represses translation of the mRNA, whereas the binding of IRPs to 3' IREs stabilizes the mRNA. IRP1 and IRP2 binding activities are regulated by intracellular iron levels. In addition, nitric oxide (NO.) increases the affinity of IRP1 for IREs. The role of NO. in the regulation of IRP1 and IRP2 in rat hepatoma cells was investigated by using the NO.-generating compound S-nitroso-N-acetylpenicillamine (SNAP), or by stimulating cells with multiple cytokines and lipopolysaccharide (LPS) to induce NO. production. Mitochondrial and IRP1 aconitase activities were decreased in cells producing NO(.). NO. increased IRE binding activity of IRP1, but had no effect on IRE binding activity of IRP2. The increase in IRE binding activity of IRP1 was coincident with the translational repression of ferritin synthesis. Transferrin receptor (TfR) mRNA levels were increased in cells treated with NO.-generating compounds, but not in cytokine- and LPS-treated cells. Our data indicate that IRP1 and IRP2 are differentially regulated by NO. in rat hepatoma cells, suggesting a role for IRP1 in the regulation of iron homeostasis in vivo during hepatic inflammation.
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PMID:Differential regulation of IRP1 and IRP2 by nitric oxide in rat hepatoma cells. 863 20

The posttranscriptional control of iron uptake, storage, and utilization by iron-responsive elements (IREs) and iron regulatory proteins (IRPs) provides a molecular framework for the regulation of iron homeostasis in many animals. We have identified and characterized IREs in the mRNAs for two different mitochondrial citric acid cycle enzymes. Drosophila melanogaster IRP binds to an IRE in the 5' untranslated region of the mRNA encoding the iron-sulfur protein (Ip) subunit of succinate dehydrogenase (SDH). This interaction is developmentally regulated during Drosophila embryogenesis. In a cell-free translation system, recombinant IRP-1 imposes highly specific translational repression on a reporter mRNA bearing the SDH IRE, and the translation of SDH-Ip mRNA is iron regulated in D. melanogaster Schneider cells. In mammals, an IRE was identified in the 5' untranslated regions of mitochondrial aconitase mRNAs from two species. Recombinant IRP-1 represses aconitase synthesis with similar efficiency as ferritin IRE-controlled translation. The interaction between mammalian IRPs and the aconitase IRE is regulated by iron, nitric oxide, and oxidative stress (H2O2), indicating that these three signals can control the expression of mitochondrial aconitase mRNA. Our results identify a regulatory link between energy and iron metabolism in vertebrates and invertebrates, and suggest biological functions for the IRE/IRP regulatory system in addition to the maintenance of iron homeostasis.
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PMID:Translational regulation of mammalian and Drosophila citric acid cycle enzymes via iron-responsive elements. 864 5

Numerous laboratory and clinical investigations over the past few decades have observed that one of the dangers of iron is its ability to favour neoplastic cell growth. The metal is carcinogenic due to its catalytic effect on the formation of hydroxyl radicals, suppression of the activity of host defence cells and promotion of cancer cell multiplication. In both animals and humans, primary neoplasms develop at body sites of excessive iron deposits. The invaded host attempts to withhold iron from the cancer cells via sequestration of the metal in newly formed ferritin. The host also endeavours to withdraw the metal from cancer cells via macrophage synthesis of nitric oxide. Quantitative evaluation of body iron and of iron-withholding proteins has prognostic value in cancer patients. Procedures associated with lowering host iron intake and inducing host cell iron efflux can assist in prevention and management of neoplastic diseases. Pharmaceutical methods for depriving neoplastic cells of iron are being developed in experimental and clinical protocols.
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PMID:The role of iron in cancer. 866 5

Recent studies have indicated that nitric oxide may affect iron metabolism through disruption of the iron-sulfur complex of iron regulatory protein-1, a translational regulator. In the present study, we report that heterologous expression of murine macrophage nitric oxide synthase (NOS-2) in the human erythroleukemic K562 cell line results in constitutive production of nitric oxide associated with inhibition of hemoglobin expression. K562 cells were transfected with an episomally-maintained, hygromycin-selectable expression vector bearing the coding region of NOS-2. Constitutive NOS expression was detected by Western blotting of cell lysates and by the accumulation of nitrite in the culture media. Although NOS-transfected cells grew more slowly than control cells, they were able to maintain constitutive expression of NOS and production of nitric oxide for more than 1 month following transfection. The hemoglobin content of NOS-transfected K562 cells was less than one-fifth that of control cells, but increased markedly if NOS inhibitor was included in the culture media. The nitric oxide-mediated inhibition of hemoglobin expression was reversed by supplementing the culture media with 20 mumol/L hemin or 0.5 mmol/L 5-amino-levulinate, indicating that nitric oxide did not directly inhibit hemoglobin synthesis, but likely acted on a step in heme synthesis. mRNA levels for globin and erythroid aminolevulinic acid synthase (eALAS) were the same in both NOS-transfected and control cells. Our observations indicate that hemoglobin expression is inhibited by nitric oxide in NOS-transfected K562 cells by posttranscriptional repression of eALAS, the first enzyme of the heme biosynthetic pathway. The most likely mechanism is a nitric oxide-mediated translational repression of eALAS, as was recently demonstrated for ferritin synthesis. These observations further illustrate the potential for endogenously produced nitric oxide to regulate cellular posttranscriptional events. In particular, our observations may be relevant to the role of nitric oxide in anemia and lowered blood hemoglobin concentrations that are associated with chronic infections, such as tuberculosis or parasitic disease.
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PMID:Inhibition of hemoglobin expression by heterologous production of nitric oxide synthase in the K562 erythroleukemic cell line. 870 16

Cellular iron metabolism is altered during chronic inflammatory states, leading to reticuloendothelial iron sequestration and an associated anemia. To study the effects of nitric oxide (NO) on the expression of three genes involved in erythroid cell iron metabolism (gamma-globin, H-ferritin, and transferrin receptor [TfR]), we developed a series of human K562 erythroleukemic cell clones retrovirally transduced with inducible nitric oxide synthase (NOS-2) and producing different steady-state levels of NO. gamma-Globin and H-ferritin protein expression was reduced in NO-producing cells in relation to the amount of NO produced. Conversely, cell surface TfR expression increased in NO-producing clones. Both the inhibitory effects of NO on gamma-globin and H-ferritin expression and the stimulatory effect on TfR were reversed by the NOS inhibitor NG-methyl-L-arginine (NGMMA). gamma-Globin and H-ferritin mRNA levels were unaffected by NO production. In the case of TfR, NO appeared to stabilize mRNA in that the half life of TfR mRNA decreased from approximately 15 hours to less than 3 hours when NO production by NOS-transduced clones was inhibited. Thus, NO can regulate expression of these genes at the posttranscriptional level, an effect that is likely mediated by the known effect of NO on the RNA binding activity of iron regulatory protein-1 (Pantopoulos and Hentze, Proc Natl Acad Sci USA 92:1267, 1995). Furthermore, our findings suggest a mechanism for the observed relationship between NO production and the pathophysiology of the anemia of chronic disease.
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PMID:Nitric oxide alters the expression of gamma-globin, H-ferritin, and transferrin receptor in human K562 cells at the posttranscriptional level. 887 95

Primary intracellular targets for nitric oxide (NO) include nonheme iron-containing enzymes and protein-bound iron. Because NO is an important effector molecule in lung inflammation and endothelial cell-associated iron is critical to numerous forms of oxidant-mediated lung injury, we studied the effects of the NO donor S-nitrosoacetylpenicillamine (SNAP) on heme and iron metabolism in cultured sheep pulmonary artery endothelial cells. SNAP (300 microM) caused a transient increase in heme oxygenase-1 (HO-1) mRNA associated with a fivefold increase in HO activity that was completely blocked by the competitive HO inhibitor, tin protoporphyrin IX (SnPP). SNAP-induced activation of HO caused SnPP-sensitive reduction of activity of the hemoprotein catalase and decrease in heme iron. SNAP caused increases in iron-responsive gene products, ferritin and mitochondrial aconitase, secondary to the release of iron from heme stores via HO induction, since these changes were also sensitive to SNPP. The NO-induced increase in nonheme iron was apparent via electron paramagnetic resonance, where an enhanced SNAP-induced (300 microM for 4 h) g = 2.04 signal (e.g., dinitrosyl-iron-sulfur complex) was noted after exposure to a dose of SNAP (200 microM for 14 h) that in itself did not produce a detectable signal. These data show that exposure of pulmonary endothelial cells to NO results in profound changes in intracellular heme- and nonheme-iron homeostasis and that HO plays a central role in affecting this balance.
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PMID:Effect of nitric oxide on heme metabolism in pulmonary artery endothelial cells. 889 97

Ferritin protects endothelial cells from the damaging effects of iron-catalyzed oxidative injury. Regulation of ferritin occurs through the formation of an iron-sulfur cluster within a cytoplasmic protein, the iron regulatory protein (IRP) that controls ferritin mRNA translation. Nitric oxide has been shown to inhibit iron-sulfur proteins and is present at vascular sites of inflammation; therefore, we undertook a study to examine the influence of nitric oxide on changes in endothelial cell ferritin content in response to iron exposure, and the subsequent effects on susceptibility to oxidative injury. Iron-loaded endothelial cells (EC) exposed to nitric oxide donors synthesize markedly less ferritin. Treatment of EC with a nitric oxide donor increases IRP affinity for ferritin mRNA concomitant with a loss of cytoplasmic aconitase activity in iron-laden EC. Iron-treated EC exposed to NO donors were resistant to oxidative injury despite their low ferritin content when examined 1 h after the treatment period. In contrast, 24 h later, these same cells become sensitive to oxidants, whereas iron-treated EC that are ferritin-rich continue to be resistant. In conclusion, NO inhibits the increase of EC ferritin after exposure to iron but provides short-term protection against oxidants; ferritin, in turn, provides durable cytoprotection by inactivating reactive iron.
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PMID:Nitric oxide donors modulate ferritin and protect endothelium from oxidative injury. 890 80


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