Gene/Protein Disease Symptom Drug Enzyme Compound
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1. Autism is a severe neurodevelopmental disorder with potential genetic and environmental etiologies. Recent genetic linkage reports and biochemical analysis of postmortem autistic cerebellum point to Reelin, an important secretory extracellular protein, as being involved in the pathology of autism. 2. We hypothesized that blood levels of Reelin and its isoforms would be altered in autistic twins, and their first degree relatives versus normal controls. 3. We measured blood levels of unprocessed Reelin (410 kDa) and its proteolytic cleavage products (Reelins 330 and 180 kDa) as well as albumin and ceruloplasmin in 28 autistic individuals, their parents (13 fathers, 13 mothers), 6 normal siblings, and 8 normal controls using SDS-PAGE and western blotting. 4. Results indicated significant reductions in 410 kDa Reelin species in autistic twins (-70%, p < 0.01), their fathers (-62%, p < 0.01), their mothers (-72%, p < 0.01), and their phenotypically normal siblings (-70%, p < 0.01) versus controls. Reelin 330 kDa values did not vary significantly from controls. Reelin 180 kDa values for parents (fathers -32% p < 0.05 vs. controls, mothers -34%) declined when compared to controls. In contrast autistic Reelin 180 kDa increased, albeit nonsignificantly versus controls. Albumin and ceruloplasmin values for autistics and their first degree relatives did not vary significantly from controls. There were no significant meaningful correlations between Reelin, albumin and ceruloplasmin levels, age, sex, ADI scores, or age of onset. 5. These results suggest that Reelin 410 deficiency may be a vulnerability factor in the pathology of autism.
Cell Mol Neurobiol 2002 Apr
PMID:Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder. 1236 96

Genes encoding ferritins were isolated and cloned from cDNA libraries of hard tick Ixodes ricinus and soft tick Ornithodoros moubata. Both tick ferritins are composed of 172 amino-acid residues and their calculated mass is 19,667.2 Da and 19,974.5 Da for I. ricinus and O. moubata, respectively. The sequences of both proteins are closely related to each other as well as to the ferritin from another tick species Dermacentor variabilis (>84% similarity). The proteins contain the conserved motifs for ferroxidase center typical for heavy chains of vertebrate ferritins. The stem-loop structure of a putative iron responsive element was found in the 5' untranslated region of ferritin mRNA of both ticks. Antibodies against fusion ferritin from O. moubata were raised in a rabbit and used to monitor the purification of a small amount of ferritins from both tick species. The authenticity of ferritin purified from O. moubata was confirmed by mass-fingerprinting analysis. In the native state, the tick ferritins are apparently larger (~500 kDa) than horse spleen ferritin (440 kDa). On SDS-PAGE tick ferritins migrate as a single band of about 21 kDa. These results suggest that tick ferritins are homo-oligomers of 24 identical subunits of heavy-chain type. The Northern blot analysis revealed that O. moubata ferritin mRNA level is likely not up-regulated after ingestion of a blood meal.
Insect Biochem Mol Biol 2003 Jan
PMID:Molecular cloning, expression and isolation of ferritins from two tick species--Ornithodoros moubata and Ixodes ricinus. 1245 5

Alveolar lining fluid normally contains proteins of important physiological, antioxidant, and mucosal defense functions [such as albumin, immunoglobulin G (IgG), secretory IgA, transferrin, and ceruloplasmin]. Because concentrations of plasma proteins in alveolar fluid can increase in injured lungs (such as with permeability edema and inflammation), understanding how alveolar epithelium handles protein transport is needed to develop therapeutic measures to restore alveolar homeostasis. This review provides an update on recent findings on protein transport across the alveolar epithelial barrier. The use of primary cultured rat alveolar epithelial cell monolayers (that exhibit phenotypic and morphological traits of in vivo alveolar epithelial type I cells) has shown that albumin and IgG are absorbed via saturable processes at rates greater than those predicted by passive diffusional mechanisms. In contrast, secretory component, the extracellular portion of the polymeric immunoglobulin receptor, is secreted into alveolar fluid. Transcytosis involving caveolae and clathrin-coated pits is likely the main route of alveolar epithelial protein transport, although relative contributions of these internalization steps to overall protein handling of alveolar epithelium remain to be determined. The specific pathways and regulatory mechanisms responsible for translocation of proteins across lung alveolar epithelium and regulation of the cognate receptors (e.g., 60-kDa albumin binding protein and IgG binding FcRn) expressed in alveolar epithelium need to be elucidated.
Am J Physiol Lung Cell Mol Physiol 2003 Feb
PMID:Protein transport across the lung epithelial barrier. 1253 9

Mitochondrial ferritin (MtF) is a novel H-type ferritin encoded by an intronless gene on chromosome 5q23.1. The protein is synthesized as a precursor of about 30 kDa that is targeted to mitochondria by a leader sequence of 60 amino acids. This leader is proteolytically removed inside the mitochondria and the resulting 22 kDa subunit forms typical ferritin shells. These shells have ferroxidase activity and are therefore likely to sequester potentially harmful free iron. However, this may be a limited function since MtF has a very restricted tissue expression. High amounts are found in testis but only very low levels are found in iron storage organs. The levels of MtF appear to correlate more with mitochondrial abundance than with iron metabolism. MtF does not seem to be an obligatory intermediate in transfer of free iron to heme and other iron compounds in mitochondria. However, its level increases dramatically in sideroblastic anemia when heme synthesis is disrupted. This increased synthesis does not appear to involve the classical translational control since MtF mRNA lacks an apparent iron response element. In transfected HeLa cells added iron is incorporated as quickly into MtF as into cytosolic ferritin. In addition, increased levels of MtF cause a redistribution of iron from cytosol to mitochondria and this effect is enhanced by iron chelation. Thus high levels of MtF result in an iron deficient phenotype in cytosol with decreased expression of ferritin and increased expression of transferrin receptor. This avidity for iron may explain why MtF levels are maintained at low levels in most normal cells. The regulation of MtF expression and possible therapeutic applications of MtF in neurological disorders involving increased iron deposition are topics for future research.
Blood Cells Mol Dis
PMID:Mitochondrial ferritin: a new player in iron metabolism. 1254 28

Hephaestin is the gene affected in the sex-linked anemic (sla) mouse. These animals have a defect in the export of iron from intestinal enterocytes into the circulation and this implicates hephaestin in the basolateral transfer step of iron absorption. Hephaestin is homologous to the plasma copper-containing protein ceruloplasmin, and all residues involved in copper binding and disulfide bond formation in ceruloplasmin are conserved in hephaestin. Unlike ceruloplasmin, hephaestin is an integral membrane protein with a single trans-membrane domain. It is highly expressed throughout the small intestine, to a lesser extent in the colon, and at low levels in several other tissues. Surprisingly, most hephaestin appears to be located intracellularly in a perinuclear distribution. Like ceruloplasmin, hephaestin has a ferroxidase activity which is predicted to underlie its biological function. In addition, its expression is stimulated under iron deficient conditions. Analysis of the sla mouse has supported our model for the regulation of intestinal iron absorption whereby changes in systemic iron requirements alter the levels of basolateral transport components with subsequent regulation of brush border transport.
Blood Cells Mol Dis
PMID:The ceruloplasmin homolog hephaestin and the control of intestinal iron absorption. 1254 27

Aceruloplasminemia is characterized by iron accumulation in the brain as well as in visceral organs, due to the absence of ceruloplasmin ferroxidase activity. The neurological symptoms, which include involuntary movements, ataxia, and dementia, reflect the sites of iron deposition. The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Excess iron functions as a potent catalyst of biologic oxidation. An increased iron concentration was associated with increased lipid peroxidation in the brains of three aceruloplasminemia patients. Positron emission tomography showed brain glucose and oxygen hypometabolism. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to about 50 and 43%, respectively, for complexes I and IV. Those of the cerebral and cerebellar cortices also were decreased approximately 62 and 65%. These findings suggest that iron-mediated free radicals may contribute to neuronal cell damage through increased lipid peroxidation and the impairment of mitochondrial energy metabolism in aceruloplasminemia brains.
Blood Cells Mol Dis
PMID:Increased lipid peroxidation and mitochondrial dysfunction in aceruloplasminemia brains. 1254 32

Hereditary hemochromatosis is characterized by marked variation of expression of the defect: very few homozygotes with the C282Y/C282Y HFE genotype have full-blown clinical disease, a larger number show biochemical stigmata of iron overload, and some seem normal biochemically. The following candidate genes have been examined in detail to determine whether polymorphisms in them may be responsible for this variation: transferrin, transferrin receptor 1, transferrin receptor 2, ferritin-L, ferritin-H, IRP1, IRP2, HFE, beta(2) microglobulin, mobilferrin/calreticulin, ceruloplasmin, ferroportin, NRAMP1, NRAMP2 (DMT1), haptoglobin, heme oxygenase-1, heme oxygenase-2, hepcidin, USF2, ZIRTL, duodenal cytochrome b ferric reductase (DCYTB), TNFalpha, keratin 8, and keratin 18. The coding sequence, exon-intron junctions, and promoters of each of these genes was sequenced in DNA from 20 subjects: 5 HFE C282Y/C282Y with clinical disease, 5 HFE C282Y/C282Y with normal/low ferritin levels and no disease, 5 wt/wt with high ferritin and transferrin saturation, and 5 wt/wt normal controls. When coding or promoter polymorphisms were encountered, DNA from large numbers of ethnically defined subjects was examined for these polymorphisms and a relationship between their existence and abnormalities of iron homeostasis was sought. Only in the case of one transferrin mutation did we find a strong relationship between the polymorphism and iron deficiency anemia. The putative genes that affect the expression of HFE mutations remain elusive.
Blood Cells Mol Dis
PMID:Seeking candidate mutations that affect iron homeostasis. 1254 38

Transcript-selective translational control of eukaryotic gene expression is often directed by a structural element in the 3' untranslated region (3'-UTR) of the mRNA. In the case of ceruloplasmin (Cp), induced synthesis of the protein by gamma interferon (IFN-gamma) in U937 monocytic cells is halted by a delayed translational silencing mechanism requiring the binding of a cytosolic inhibitor to the Cp 3'-UTR. Silencing requires the essential elements of mRNA circularization, i.e., eukaryotic initiation factor 4G, poly(A)-binding protein, and poly(A) tail. We here determined the minimal silencing element in the Cp 3'-UTR by progressive deletions from both termini. A minimal, 29-nucleotide (nt) element was determined by gel shift assay to be sufficient for maximal binding of the IFN-gamma-activated inhibitor of translation (GAIT), an as-yet-unidentified protein or complex. The interaction was shown to be functional by an in vitro translation assay in which the GAIT element was used as a decoy to overcome translational silencing. Mutation analysis showed that the GAIT element contained a 5-nt terminal loop, a weak 3-bp helix, an asymmetric internal bulge, and a proximal 6-bp helical stem. Two invariant loop residues essential for binding activity were identified. Ligation of the GAIT element immediately downstream of a luciferase reporter conferred the translational silencing response to the heterologous transcript in vitro and in vivo; a construct containing a nonbinding, mutated GAIT element was ineffective. Translational silencing of Cp, and possibly other transcripts, mediated by the GAIT element may contribute to the resolution of the local inflammatory response following cytokine activation of macrophages.
Mol Cell Biol 2003 Mar
PMID:Transcript-selective translational silencing by gamma interferon is directed by a novel structural element in the ceruloplasmin mRNA 3' untranslated region. 1258 72

The crystallization of cellular components represents a unique survival strategy for bacterial cells under stressed conditions. A highly ordered, layered structure is often formed in such a process, which may involve one or more than one type of bio-macromolecules. The main advantage of biocrystallization has been attributed to the fact that it is a physical process and thus is independent of energy consumption. Dps is a protein that crystallizes to form a multi-layered structure in starved cells in order to protect DNA against oxidative damage and other detrimental factors. The multi-layered crystal structure of a Dps protein from Bacillus brevis has been revealed for the first time at atomic resolution in the absence of DNA. Inspection of the structure provides the first direct evidence for the existence of a di-nuclear ferroxidase center, which possesses unique features among all the di-iron proteins identified so far. It constitutes the structural basis for the ferroxidase activity of Dps in the crystalline state as well as in solution. This finding proves that the enzymatic process of detoxification of metal ions, which may cause severe oxidative damage to DNA, is the other important aspect of the defense mechanism performed by Dps. In the multi-layered structure, Dps dodecamers are organized in a highly ordered manner. They adopt the classic form of hexagonal packing in each layer of the structure. Such arrangement results in reinforced structural features that would facilitate the attraction and absorption of metal ions from the environment. The highly ordered layered structure may provide an ideal basis for the accommodation of DNA between the layers so that it can be isolated and protected from harmful factors under stress conditions.
J Mol Biol 2003 Jun 06
PMID:The multi-layered structure of Dps with a novel di-nuclear ferroxidase center. 1276 29

In the present study, oxidative stress in diabetic model and the effect of garlic oil or melatonin treatment were examined. Streptozotocin (60 mg/kg body weight, i.p.)-induced diabetic rats, showed a significant increase of plasma glucose, total lipids, triglyceride, cholesterol, lipid peroxides, nitric oxide and uric acid. Concomitantly, significant decreases in the levels of antioxidants ceruloplasmin, albumin and total thiols were found in the plasma of diabetic rats. Lipid peroxide levels were significantly increased in erythrocyte lysate and in homogenates of liver and kidney, while superoxide dismutase (SOD) activities were decreased in tissue homogenates of liver and kidney. Treatment of diabetic rats with garlic oil (10 mg/kg i.p.) or melatonin (200 microg/kg i.p.) for 15 days significantly increased plasma levels of total thiol, ceruloplasmin activities, albumin. Lipid peroxides, uric acid, blood glucose, total lipid, triglyceride and cholesterol were decreased significantly after treatment with garlic oil or melatonin. Nitric oxide levels were decreased significantly in rats treated with melatonin only. In erythrocytes lysate, glutathione S-transferase (GST) activities were increased significantly in rats treated with garlic oil or melatonin, while lipid peroxides decreased significantly and total thiol increased significantly in melatonin or garlic oil treatment, respectively. In liver homogenates of rats treated with garlic or melatonin, lipid peroxides were decreased significantly, and GST activities increased significantly, while SOD activities were increased significantly in liver and kidney after garlic or melatonin treatment. The results suggest that garlic oil or melatonin may effectively normalize the impaired antioxidants status in streptozotocin induced-diabetes. The effects of these antioxidants of both agents may be useful in delaying the complicated effects of diabetes as retinopathy, nephropathy and neuropathy due to imbalance between free radicals and antioxidant systems. Moreover, melatonin may be more powerful free radical scavenger than garlic oil.
Comp Biochem Physiol A Mol Integr Physiol 2003 Aug
PMID:Oxidative stress in streptozotocin-induced diabetic rats: effects of garlic oil and melatonin. 1289 May 44


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