Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytoplasmic iron regulatory protein (IRP) modulates iron homeostasis by binding to iron-responsive elements (IREs) in the transferrin receptor and ferritin mRNAs to coordinately regulate transferrin receptor mRNA stability and ferritin mRNA translational efficiency, respectively. These studies demonstrate that thyroid hormone (T3) can modulate the binding activity of the IRP to an IRE in vitro and in vivo. T3 augmented an iron-induced reduction in IRP binding activity to a ferritin IRE in RNA electrophoretic mobility shift assays using cytoplasmic extracts from human liver hepatoma (HepG2) cells. Hepatic IRP binding to the ferritin IRE also diminished after in vivo administration of T3 with iron to rats. In transient transfection studies using HepG2 cells and a human ferritin IRE-chloramphenicol acetyltransferase (H-IRE-CAT) construct, T3 augmented an iron-induced increase in CAT activity by approximately 45%. RNase protection analysis showed that this increase in CAT activity was not due to a change in the steady state level of CAT mRNA. Nuclear T3-receptors may be necessary for this T3-induced response, because the effect could not be reproduced by the addition of T3 directly to cytoplasmic extracts and was absent in CV-1 cells which lack T3-receptors. We conclude that T3 can functionally regulate the IRE binding activity of the IRP. These observations provide evidence of a novel mechanism for T3 to up-regulate hepatic ferritin expression, which may in part contribute to the elevated serum ferritin levels seen in hyperthyroidism.
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PMID:Thyroid hormone modulates the interaction between iron regulatory proteins and the ferritin mRNA iron-responsive element. 866 26

Alzheimer's disease (AD)-specific or characteristic gene expression was explored by the identification of cDNA clones by means of differential screening for embryonic brain cDNA library with 32P-labeled cDNA probes prepared from mRNA of AD and normal human brains. To isolate neuronal genes in degenerating neurons, we used rat embryonic cDNA library at stage day 15 when glial cells developed poorly in the brain. Seventeen embryonic genes were identified as embryonic alpha-tubulin, embryonic beta-tubulin, hnRNP, protein L-isoaspartyl methyltransferase (PIMT), ferritin heavy chain, type IV collagen, actin-binding protein cofilin, profilin and nine novel sequences designated as A1-9. We characterized these genes by Northern blot analysis, RNase protection assay and immunohistochemical studies, showing that PIMT and a novel gene designated as A5 showed the transcriptional up-regulation in AD brains. In addition, the immunohistochemical studies showed PIMT, type IV collagen, and cofilin were associated with neurofibrillary tangles in degenerating neurons, brain vessels in affected regions, and synaptosomal structures in AD brains, respectively. The catalogue presented here also showed the involvement of cytoskeletal proteins, cytoskeleton-associated proteins, and an iron-storage protein, suggesting the presence of regenerating activity and the abnormal metabolisms in affected neurons of AD brains.
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PMID:Embryonic genes expressed in Alzheimer's disease brains. 873 34

Lactoferrin (LF) is an iron-binding protein found in milk and other secretory fluids of mammals as well as in secondary granules of neutrophils. Receptors for LF were detected and isolated on activated T and B cells, monocytes, intestinal brush border cells, platelets and neoplastic cells. Very low physiologic serum levels of LF increase significantly upon infection. Serum concentration of LF is also elevated in rheumatoid patients. It is suggested that the ability of LF to bind an excess of Fe() ions, needed for growth of microorganisms and tumors, represents an important defence mechanism in humans. LF, in addition, may contribute to the protection against pathogens and their metabolites by enhancing phagocytosis, cell adherence and controlling release of proinflammatory cytokines such as IL-1, IL-6 and TNF-alpha. The protein diminishes also damaging effects of free radical release. LF possesses interesting immunotropic properties with regard to immature T and B cells by promoting phenotypic and functional maturation of these cells. LF also controls the effector phase of cellular immune response and inhibits manifestations of autoimmune response in mice. One molecular form of LF with a ribonuclease activity may have a prognostic value in breast cancer. Lactoferrin may be potentially applied in neutropenic patients or in patients with bleeding disorders as a preoperative immunomodulator.
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PMID:[Lactoferrin--its role in defense against infection and immunotropic properties]. 877 12

Because the ferric uptake regulator (fur) appears to be an essential gene in Pseudomonas aeruginosa, resistance to manganese was used as an enrichment to isolate strains carrying point mutations in the fur gene in order to assess its role in the co-ordinate expression of siderophores and exotoxin A (ETA). This report describes a detailed molecular and phenotypic characterization of four mutants and one revertant, which carry point mutations in the fur gene. Two parental strains were used in this study. Three mutants were isolated from the widely used strain, PAO1. One of these, CS (cold sensitive), has a mutation in the 5' non-coding region of the fur gene while the two other mutants derived from this parent have mutations resulting in the following deduced changes in Fur: mutant A2, H86-->R; mutant A4, H86-->Y. The other mutant (C6) and its revertant (C6Rv) were derived from PAO6261, a mutant of PAO1 with a deletion in the anr gene (anaerobic regulation of arginine deiminase and nitrate reduction) that controls anaerobic respiration in P. aeruginosa. Fur from the C6 mutant has an A10-->G mutation while in the C6Rv spontaneous revertant the mutant Gly residue has been changed to Ser at this position. All mutants were examined for alterations in the iron-regulated expression of siderophores and ETA. The A2 and A4 mutants expressed higher levels of siderophores in iron-deficient media and in iron-replete media. The CS mutant constitutively expressed siderophores at 25 degrees C. At 42 degrees C siderophore biosynthesis was iron repressed as in the parental strain PAO1. The deletion of anr in PAO6261 had no apparent effect on the iron-mediated regulation of siderophore synthesis, but the C6 mutant derived from this strain produces siderophores constitutively. The iron-regulated production of siderophores by C6Rv was similar to the parental strain PAO6261 and PAO1. Because one of the parental strains used in this study is an Anr mutant, regulation of ETA production was assessed under aerobic and microaerobic conditions. Iron-dependent repression of ETA synthesis in both parental strains and A2 and A4 mutants was found to be 50-100-fold under aerobic and microaerobic conditions, as assayed by quantitative Western dot-blot assays. By contrast in the CS and C6 mutants, while iron-dependent repression os ETA synthesis was similar to both parental strains under aerobic conditions, ETA production in these mutants was constitutive in a microaerobic environment. RNase protection analysis of toxA and regAB transcription in PAO1, PAO6261 and the C6 mutant corroborated the results of quantitative dot-blot assays of ETA. The mutant Fur proteins were purified and examined for their ability to bind to the promoter of a gene (pvdS) that positively regulates the expression of siderophores and ETA. Fur from the A2 and A4 mutants and from the C6Rv revertant was able to bind to the target DNA, but with reduced affinity by comparison to wild-type Fur. Fur from the C6 mutant in DNase I footprint experiments failed to protect the promoter region of the pvdS gene, but it retained some weak binding activity in gel mobility shift assays. The data presented in this study not only furnish some additional insights into the structure-function relationships of Fur, but also afford novel perspectives of virulence factors in P. aeruginosa under environmental conditions that have not previously been considered.
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PMID:Ferric uptake regulator mutants of Pseudomonas aeruginosa with distinct alterations in the iron-dependent repression of exotoxin A and siderophores in aerobic and microaerobic environments. 888 70

Regulation of iron absorption occurs mainly at the level of duodenal enterocytes. Several proteins including ferritin, the iron-storing molecule, have been implicated in the uptake, cellular processing, and transfer of iron by the mucosal cells. H and L ferritin subunits assemble in various proportions to form a 24-subunit protein shell which can store up to 4500 iron atoms. Although tissue-specific distribution of H and L ferritin mRNAs has been widely described, little is known of ferritin gene expression in duodenal cells. In this study, we performed quantitative measurements of H and L ferritin mRNAs levels in mouse duodenum, ileum, and liver by ribonuclease protection assay. In addition, we assessed the relative subcellular distribution of these two mRNAs in mouse duodenal and ileal sections by in situ hybridization. The results show that in duodenal cells, the level of H ferritin mRNA is higher than the L ferritin level (H/L ratio of about 5). Moreover, expression of the H mRNA is regulated along both axes of the small intestine: the level increases sharply from the crypt to the apex of the villus, thus following the general differentiation pathway of these cells, and decreases from the proximal to the distal small intestine. In contrast, the L ferritin mRNA level does not change along the cryptovillus axis and increases in value in the ileum. These results suggest that expression of the H ferritin gene is dependent on the differentiation of the enterocytes but, as yet, the regulatory elements remain to be identified.
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PMID:Expression of H and L ferritin mRNAs in mouse small intestine. 889 64

The PrfA protein, which is a member of the Crp/Fnr family of prokaryotic transcription activators, regulates the virulence genes of Listeria monocytogenes. In this work, specific binding of PrfA to its target DNA was determined by electrophoretic mobility-shift assays (EMSAs) using cell-free extracts from the two L. monocytogenes strains EGD and NCTC 7973. PrfA-specific binding differs between the two strains, even when the concentration of PrfA was adjusted to similar levels. Both strains exhibited increased PrfA-specific binding after a shift into minimal essential medium (MEM) without showing a significant change in the amount of PrfA protein, relative to extracts from bacteria grown in brain-heart infusion (BHI). The purified PrfA protein from strain EGD produced in Escherichia coli did not exhibit specific binding to the target DNA but did so upon addition of PrfA-free extracts from various Listeria species and Bacillus subtilis. The observed activation of PrfA seems to be caused by a PrfA-activating factor (Paf), which is probably a protein since elevated temperature, but not RNase treatment, destroyed the activation potential of such PrfA-free extracts. Moreover, fractionation of these extracts by sucrose gradient centrifugation yielded the Paf activity in a fraction sedimenting at 3.2 S. Specific binding of PrfA-containing extracts from strain EGD to the hly and actA promoter sequences was strongly inhibited by iron, whereas that of extracts from strain NCTC 7973 was only slightly reduced. The iron effect seems to be mediated by Paf rather than by PrfA itself.
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PMID:Specific binding of the Listeria monocytogenes transcriptional regulator PrfA to target sequences requires additional factor(s) and is influenced by iron. 895 12

Erythropoietin (Epo) is the central regulator of red blood cell production and acts primarily by inducing proliferation and differentiation of erythroid progenitor cells. Because a sufficient supply of iron is a prerequisite for erythroid proliferation and hemoglobin synthesis, we have investigated whether Epo can regulate cellular iron metabolism. We present here a novel biologic function of Epo, namely as a potential modulator of cellular iron homeostasis. We show that, in human (K562) and murine erythroleukemic cells (MEL), Epo enhances the binding affinity of iron-regulatory protein (IRP)-1, the central regulator of cellular iron metabolism, to specific RNA stem-loop structures, known as iron-responsive elements (IREs). Activation of IRP-1 by Epo is associated with a marked increase in transferrin receptor (trf-rec) mRNA levels in K562 and MEL, enhanced cell surface expression of trf-recs, and increased uptake of iron into cells. These findings are in agreement with the well-established mechanism whereby high-affinity binding of IRPs to IREs stabilizes trf-rec mRNA by protecting it from degradation by a specific RNase. The effects of Epo on IRE-binding of IRPs were not observed in human myelomonocytic cells (THP-1), which indicates that this response to Epo is not a general mechanism observed in all cells but is likely to be erythroid-specific. Our results provide evidence for a direct functional connection between Epo biology and iron metabolism by which Epo increases iron uptake into erythroid progenitor cells via posttranscriptional induction of trf-rec expression. Our data suggest that sequential administration of Epo and iron might improve the response to Epo therapy in some anemias.
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PMID:Regulation of cellular iron metabolism by erythropoietin: activation of iron-regulatory protein and upregulation of transferrin receptor expression in erythroid cells. 900 72

The activities of fumarase- and manganese-cofactored superoxide dismutase (SOD), encoded by the fumC and sodA genes in Pseudomonas aeruginosa, are elevated in mucoid, alginate-producing bacteria and in response to iron deprivation (D. J. Hassett, M. L. Howell, P. A. Sokol, M. L. Vasil, and G. E. Dean, J. Bacteriol. 179:1442-1451, 1997). In this study, a 393-bp open reading frame, fagA (Fur-associated gene), was identified immediately upstream of fumC, in an operon with orfX and sodA. Two iron boxes or Fur (ferric uptake regulatory protein) binding sites were discovered just upstream of fagA. Purified P. aeruginosa Fur caused a gel mobility shift of a PCR product containing these iron box regions. DNA footprinting analysis revealed a 37-bp region that included the Fur binding sites and was protected by Fur. Primer extension analysis and RNase protection assays revealed that the operon is composed of at least three major iron-regulated transcripts. Four mucoid fur mutants produced 1.7- to 2.6-fold-greater fumarase activity and 1.7- to 2.3-greater amounts of alginate than wild-type organisms. A strain devoid of the alternative sigma factor AlgT(U) produced elevated levels of one major transcript and fumarase C and manganase-cofactored SOD activity, suggesting that AlgT(U) may either play a role in regulating this transcript or function in some facet of iron metabolism. These data suggest that the P. aeruginosa fagA, fumC, orfX, and sodA genes reside together on a small operon that is regulated by Fur and is transcribed in response to iron limitation in mucoid, alginate-producing bacteria.
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PMID:An operon containing fumC and sodA encoding fumarase C and manganese superoxide dismutase is controlled by the ferric uptake regulator in Pseudomonas aeruginosa: fur mutants produce elevated alginate levels. 904 99

The heme biosynthesis enzyme delta-aminolevulinic acid dehydratase (ALAD) requires magnesium or zinc for activity, depending on the organism, and the heme moiety contains iron. Thus, metals are important for heme formation in at least two different ways. Bradyrhizobium japonicum ALAD* is an engineered derivative of wild-type ALAD that requires Zn2+ for activity rather than Mg2+ (S. Chauhan and M. R. O'Brian, J. Biol. Chem. 270:19823-19827, 1995). The pH optimum for ALAD* activity was over 3.5 units lower than for that of the wild-type enzyme, and ALAD* activity was inhibited by lead and cadmium, as reported for the zinc-containing dehydratases of animals. In addition, ALAD* was significantly more thermostable than ALAD; the temperature optima are 50 and 37 degrees C, respectively. These observations strongly suggest that the metal contributes to both catalysis and structure, and this conclusion may be extrapolated to ALADs in general. Although iron did not affect the activity of the preformed protein, enzyme assays and immunoblot analysis demonstrated that the iron concentration in which the cells were grown had a strong positive effect on ALAD activity and the protein level. RNase protection analysis showed that the transcript quantity of hemB, the gene encoding ALAD, was iron dependent; thus, iron regulates hemB at the mRNA level. Induction of hemB mRNA in response to iron was rapid, suggesting that the factor(s) needed to mediate iron control was present in iron-limited cells and did not need to be synthesized de novo. ALAD protein levels and enzyme activities were similar in cells of the wild type and a heme-defective strain, indicating that control by iron is not an indirect effect of the cellular heme status. We conclude that the heme biosynthetic pathway is coordinated with cellular iron levels and that this control may prevent the accumulation of toxic porphyrin intermediates.
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PMID:Metals control activity and expression of the heme biosynthesis enzyme delta-aminolevulinic acid dehydratase in Bradyrhizobium japonicum. 928 8

Friedreich ataxia (FRDA), an autosomal recessive, neurodegenerative disease is the most common inherited ataxia. The vast majority of patients are homozygous for an abnormal expansion of a polymorphic GAA triplet repeat in the first intron of the X25 gene, which encodes a mitochondrial protein, frataxin. Cellular degeneration in FRDA may be caused by mitochondrial dysfunction, possibly due to abnormal iron accumulation, as observed in yeast cells deficient for a frataxin homologue. Using RNase protection assays, we have shown that patients homozygous for the expansion have a marked deficiency of mature X25 mRNA. The mechanism(s) by which the intronic GAA triplet expansion results in this reduction of X25 mRNA is presently unknown. No evidence was found for abnormal splicing of the expanded intron 1. Using cloned repeat sequences from FRDA patients, we show that the GAA repeat per se interferes with in vitro transcription in a length-dependent manner, with both prokaryotic and eukaryotic enzymes. This interference was most pronounced in the physiological orientation of transcription, when synthesis of the GAA-rich transcript was attempted. These results are consistent with the observed negative correlation between triplet-repeat length and the age at onset of disease. Using in vitro chemical probing strategies, we also show that the GAA triplet repeat adopts an unusual DNA structure, demonstrated by hyperreactivity to osmium tetroxide, hydroxylamine, and diethyl pyrocarbonate. These results raise the possibility that the GAA triplet-repeat expansion may result in an unusual yet stable DNA structure that interferes with transcription, ultimately leading to a cellular deficiency of frataxin.
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PMID:The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. 944 73


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