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)

Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant disorder characterized by bilateral cataracts and increased serum L-ferritin, in the absence of iron overload. Under physiological conditions, ferritin synthesis is finely regulated at the translational level by iron availability. This regulation is achieved by the high-affinity interaction between cytoplasmic mRNA-binding proteins (iron regulatory proteins, IRPs), and mRNA stem-loop structures, known as iron responsive elements (IREs), located in the untranslated regions (UTRs) of the mRNAs. A single IRE is located on the 5' UTR of a series of genes involved in iron metabolism, like L-ferritin, and the binding IRE-IRPs represses these genes translation. The deregulation of ferritin production responsible of HHCS is caused by heterogeneous mutations in the iron regulatory element (IRE) of L-ferritin that interfere with the binding of iron regulatory proteins, disrupting the negative control of L-ferritin synthesis and causing the constitutive up-regulation of ferritin L-chains. The HHCS families originate from different countries of Europe and North America, suggesting that HHCS may be distributed widely throughout the world and not sporadic, whereas its prevalence remains to be established. The lens seems to be particularly sensitive to the increased amount of L-ferritin and the alteration of the proteic equilibrium in this tissue can be responsible of the cataract. In spite of the elucidation of the genetic basis, the genotype phenotype correlation is not clear. Recently, a study based on the thermo-denaturation profile and dissociation constant of the IRE-IRP complex performed for several mutated IREs has provided evidence for a possible correlation between heterogeneous IRE mutations and serum ferritin levels. On the other hand, the in vivo relevance of these conclusions has not been determined completely. A clinical variability among subjects sharing the same mutation, whether they belonged to the same family or not, has also been demonstrated. These findings suggest that, besides the L-ferritin IRE genotype, additional factors are likely to modulate the lens involvement and the rate of progression to severe cataract in HHCS patients.
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PMID:Pathogenesis of hyperferritinemia cataract syndrome. 1254 47

Genetic ablation of iron regulatory protein 2 (IRP-2), a protein responsible for post-transcriptional regulation of expression of several iron metabolism proteins, predisposes IRP-2 -/- mice to develop adult onset neurodegenerative disease. Ferric iron reproducibly accumulates within axonal tracts and neuronal cell bodies in discrete regions of the brain, and areas of iron accumulation colocalize with areas of high ferritin expression. To better evaluate the onset and progression of neurodegeneration in IRP-2 -/- mice, we performed a high-resolution magnetic resonance imaging study comparing live, age-matched wild-type and IRP-2 -/- mice, using an 11.7-Tesla magnet and a custom-designed head coil. The mice were perfused after imaging, and iron stains and immunohistochemical studies were performed. We detected increases in the number of pixels with low T(2) values expected from accumulations of iron in IRP-2 -/- mice. Moreover, in several areas of the brain, including the substantia nigra and the superior colliculus, we detected areas with unusually high T(2) values that likely represented accumulation of water. On histopathological examination we discovered relatively small vacuoles in these brain regions of IRP-2 -/- mice. Our ability to gather T(2) data within regions of interest enabled us to define a bimodal T(2) intensity pattern that likely represents both ferritin iron accumulation and its associated pathological consequences within the brain. Our discoveries may have significant applications for the diagnosis and treatment of human diseases if such high-resolution techniques can be adapted for use in human subjects.
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PMID:MRI detection of ferritin iron overload and associated neuronal pathology in iron regulatory protein-2 knockout mice. 1269 42

Iron regulatory proteins (IRP1 and IRP2) are RNA-binding proteins that affect the translation and stabilization of specific mRNAs by binding to stem-loop structures known as iron responsive elements (IREs). IREs are found in the 5'-untranslated region (UTR) of ferritin (Ft) and mitochondrial aconitase (m-Aco) mRNAs, and in the 3'-UTR of transferrin receptor (TfR) and divalent metal transporter-1 (DMT1) mRNAs. Our previous studies show that besides iron, IRPs are regulated by hypoxia. Here we describe the consequences of IRP regulation and show that iron homeostasis is regulated in 2 phases during hypoxia: an early phase where IRP1 RNA-binding activity decreases and iron uptake and Ft synthesis increase, and a late phase where IRP2 RNA-binding activity increases and iron uptake and Ft synthesis decrease. The increase in iron uptake is independent of DMT1 and TfR, suggesting an unknown transporter. Unlike Ft, m-Aco is not regulated during hypoxia. During the late phase of hypoxia, IRP2 RNA-binding activity increases, becoming the dominant regulator responsible for decreasing Ft synthesis. During reoxygenation (ReO2), Ft protein increases concomitant with a decrease in IRP2 RNA-binding activity. The data suggest that the differential regulation of IRPs during hypoxia may be important for cellular adaptation to low oxygen tension.
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PMID:Effects of iron regulatory protein regulation on iron homeostasis during hypoxia. 1285 87

Inhalation of airborne pollution particles that contain iron can result in a variety of detrimental changes to lung cells and tissues. The lung iron burden can be substantially increased by exposure to cigarette smoke, and cigarette smoke contains iron particulates, as well as several environmental toxins, that could influence intracellular iron status. We are interested in the effects of environmental contaminants on intracellular iron metabolism. We initiated our studies using lung A549 type II epithelial cells as a model, and we evaluated the effects of iron dose and smoke treatment on several parameters of intracellular iron metabolism. We show that iron at a physiological dose stimulates ferritin synthesis without altering the transferrin receptor (TfR) mRNA levels of these cells. This is mediated primarily by a reduction of iron regulatory protein 2. Higher doses of iron reduce iron regulatory protein-1 binding activity and are accompanied by a reduction in TfR mRNA. Thus, for A549 cells, different mechanisms influencing IRP-IRE interaction allow ferritin translation in the presence of TfR mRNA to provide for iron needs and yet prevent excessive iron uptake. More importantly, we report that smoke treatment diminishes ferritin levels and increases TfR mRNA of A549 cells. Ferritin serves as a cytoprotective agent against oxidative stress. These data suggest that exposure of lung cells to low levels of smoke as are present in environmental pollutants could result in reduced cytoprotection by ferritin at a time when iron uptake is sustained, thus enhancing the possibility of lung damage by iron-mediated oxidative stress.
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PMID:Effects of sham air and cigarette smoke on A549 lung cells: implications for iron-mediated oxidative damage. 1500 39

Cellular iron homeostasis is accomplished by the coordinated regulated expression of the transferrin receptor and ferritin, which mediate iron uptake and storage, respectively. The mechanism is posttranscriptional and involves two cytoplasmic iron regulatory proteins, IRP1 and IRP2. Under conditions of iron starvation, IRPs stabilize the transferrin receptor and inhibit the translation of ferritin mRNAs by binding to "iron responsive elements" (IREs) within their untranslated regions. The IRE/IRP system also controls the expression of additional IRE-containing mRNAs, encoding proteins of iron and energy metabolism. The activities of IRP1 and IRP2 are regulated by distinct posttranslational mechanisms in response to cellular iron levels. Thus, in iron-replete cells, IRP1 assembles a cubane iron-sulfur cluster, which prevents IRE binding, while IRP2 undergoes proteasomal degradation. IRP1 and IRP2 also respond, albeit differentially, to iron-independent signals, such as hydrogen peroxide, hypoxia, or nitric oxide. Basic principles of the IRE/IRP system and recent advances in understanding the regulation and the function of IRP1 and IRP2 are discussed.
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PMID:Iron metabolism and the IRE/IRP regulatory system: an update. 1510 51

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

We have previously shown that hepcidin transgenic embryos are severely anemic and die around birth. Here, we report that embryonic hepcidin transgene expression decreases transferrin receptor 1 (TfR1) mRNA level in placenta, as shown by cDNA microarray analysis and quantitative RT-PCR, by a mechanism which is independent of placenta iron content and iron responsive element/iron regulatory protein (IRE/IRP) activity. On the contrary, iron injections into pregnant mothers result in increased placenta iron and ferritin content, and reduced IRE binding activity of IRP1 leading to decreased TfR1 mRNA level. Taken together, these results suggest that hepcidin action on placenta is mostly through transcriptional downregulation of the iron uptake machinery.
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PMID:Transferrin receptor 1 mRNA is downregulated in placenta of hepcidin transgenic embryos. 1535 63

Small inhibitory RNAs (siRNAs) are produced from longer RNA duplexes by the RNAse III family member Dicer. The siRNAs function as sequence-specific guides for RNA cleavage or translational inhibition. The precise mechanism by which siRNAs direct the RNA-induced silencing complex (RISC) to find the complementary target mRNA remains a mystery. Some biochemical evidence connects RNAi with translation making attractive the hypothesis that RISC is coupled with the translational apparatus for scanning mRNAs. Such coupling would facilitate rapid alignment of the siRNA antisense with the complementary target sequence. To test this hypothesis we took advantage of a well-characterized translational switch afforded by the ferritin IRE-IRP to analyze RNAi mediated cleavage of a target mRNA in the presence and absence of translation. Our results demonstrate that neither active translation nor unidirectional scanning is required for siRNA mediated target degradation. Our findings demonstrate that nontranslated mRNAs are highly susceptible to RNAi, and blocking scanning from both the 5' and 3' ends of an mRNA does not impede RNAi. Interestingly, RNAi is about threefold more active in the absence of translation.
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PMID:Uncoupling of RNAi from active translation in mammalian cells. 1557 16

Previous studies have shown that IRP1(+/-) IRP2(-/-) knockout mice develop progressive neurodegenerative symptoms similar to those observed in human movement disorders such as Parkinson's disease. Histological investigations using optical microscopy show that these IRP knockout mice display accumulation of ferritin in axonal tracts in the brain, suggesting a possible role for excess ferritin in mediating axonal degeneration. Direct observation of the 3D distribution of ferritin by electron tomography indicates that ferritin amounts are increased by 3- to 4-fold in selected regions of the brain, and structural damage is observed within the axon as evidenced by the loss of the internal network of filaments, and the invaginations of neighboring oligodendrocyte membranes into the axonal medium. While optical microscopic investigations suggest that there is a large increase in ferritin in the presumptive axonal regions of the IRP knockout mice, electron tomographic studies reveal that most of the excess ferritin is localized to double-walled vesicular compartments which are present in the interior of the axon and appear to represent invaginations of the oligodendrocyte cells into the axon. The amount of ferritin observed in the axonal space of the knockout mice is at least 10-fold less than the amount of ferritin observed in wild-type mouse axons. The surprising conclusion from our analysis, therefore, is that despite the overall increase in ferritin levels in the knockout mouse brain, ferritin is absent from axons of degenerating neurons, suggesting that trafficking is compromised in early stages of this type of neuronal degeneration.
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PMID:Electron tomography of degenerating neurons in mice with abnormal regulation of iron metabolism. 1586 37

Ferritin, the main iron storage protein, exerts a cytoprotective effect against the iron-catalyzed production of reactive oxygen species, but its role in brain injury caused by hypoxia/reoxygenation is unclear. Ferritin expression is regulated mainly at post-transcriptional level by iron regulatory proteins (IRP1 and IRP2) that bind specific RNA sequences (IREs) in the 5'untranslated region of ferritin mRNA. Here, we show that hypoxia decreases IRP1 binding activity in glial cells and enhances it in cortical neurons. These effects were reversed by reoxygenation in both cell types. In glial cells there was an early increase of ferritin synthesis during hypoxia and reoxygenation. Conversely, in cortical neurons, ferritin synthesis increased during the late phase of reoxygenation. Steady-state analysis of ferritin mRNA levels suggested that ferritin synthesis is regulated mainly post-transcriptionally by IRPs in glioma cells, both transcriptionally and post-transcriptionally in type-1 astrocytes, and mainly at transcriptional level in an IRP-independent way in neurons. The different regulation of ferritin expression may account for the different vulnerability of neurons and glial cells to the injury elicited by oxygen and glucose deprivation (OGD)/reoxygenation. The greater vulnerability of cortical neurons to hypoxia-reoxygenation was strongly attenuated by the exogenous administration of ferritin during OGD/reoxygenation, suggesting the possible cytoprotective role exerted by this iron-segregating protein.
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PMID:Divergent modulation of iron regulatory proteins and ferritin biosynthesis by hypoxia/reoxygenation in neurones and glial cells. 1613 72


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