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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivating mutations of Phex cause X-linked hypophosphatemia (XLH) by increasing levels of a circulating phosphaturic factor. FGF23 is a candidate for this phosphaturic factor. Elevated serum FGF23 levels correlate with the degree of hypophosphatemia in XLH, suggesting that loss of Phex function in this disorder results in either diminished degradation and/or increased biosynthesis of FGF23. To establish the mechanisms whereby Phex regulates FGF23, we assessed Phex-dependent hydrolysis of recombinant FGF23 in vitro and measured fgf23 message levels in the Hyp mouse homologue of XLH. In COS-7 cells, overexpression of FGF23 resulted in its degradation into N- and C-terminal fragments by an endogenous decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone-sensitive furin-type convertase. Phex-dependent hydrolysis of full-length FGF23 or its N- and C-terminal fragments could not be demonstrated in the presence or absence of decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone in COS-7 cells expressing Phex and FGF23. In a reticulolysate system, apparent cleavage of FGF23 occurred with wild-type Phex, the inactive Phex-3'M mutant, and vector controls, indicating nonspecific metabolism of FGF23 by contaminating enzymes. These findings suggest that FGF23 is not a direct Phex substrate. In contrast, by real-time reverse transcriptase PCR, the levels of fgf23 transcripts were highest in bone, the predominant site of Phex expression. In addition, Hyp mice displayed a bone-restricted increase in fgf23 transcripts in association with inactivating Phex mutations. Increased expression of fgf23 was also observed in Hyp-derived osteoblasts in culture. These findings suggest that Phex, possibly through the actions of unidentified Phex substrates or other downstream effectors, regulates fgf23 expression as part of a potential hormonal axis between bone and kidney that controls systemic phosphate homeostasis and mineralization.
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PMID:Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. 1287 85

Borrelia burgdorferi contains a gene that codes for a Fur homologue. The function of this Fur protein is unknown; however, spirochetes grown at 23 or 35 degrees C expressed fur as determined by reverse transcriptase PCR. The fur gene (BB0647) was cloned and overexpressed as a His-Fur fusion protein in Escherichia coli. The fusion protein was purified by zinc-chelate chromatography, and the N-terminal His tag was removed to generate recombinant Fur for use in mobility shift studies. Fur bound DNA containing the E. coli Fur box sequence (GATAATGATAATCATTATC) or Bacillus subtilis Per box sequence (TTATAAT-ATTATAA) with an apparent Kd of approximately 20 nM. Fur also bound the upstream sequences of three Borrelia genes: BB0646 (gene encoding a hydrolase of the alpha/beta-fold family), BB0647 (fur), and BB0690 (napA). Addition of metal ions was not required. Binding activity was greatly decreased by either exposure to oxidizing agents (H2O2, t-butyl hydroperoxide, cumene hydroperoxide, or diamide) or by addition of Zn2+. B. burgdorferi NapA is a homologue of Dps. Dps functions in E. coli to protect DNA against damage during periods of redox stress. Fur may function in B. burgdorferi as a repressor and regulate oxidative stress genes. Additional genes (10 chromosomal and 15 plasmid) that may be Fur regulated were identified by in silico analysis.
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PMID:The fur homologue in Borrelia burgdorferi. 1537 25

The expression of iron regulated genes in bacteria is typically controlled by the ferric uptake regulator (Fur) protein, a global transcriptional repressor that regulates functions as diverse as iron acquisition, oxidative stress, and virulence. We have identified a fur homologue in Dichelobacter nodosus, the causative agent of ovine footrot, and shown that it complements an Escherichia coli fur mutant. Homology modeling of the D. nodosus Fur protein with the recently solved crystal structure of Fur from Pseudomonas aeruginosa indicated extensive structural conservation. As Southern hybridization analysis of different clinical isolates of D. nodosus indicated that the fur gene was present in all of these strains, the fur gene was insertionally inactivated to determine its functional role. Analysis of these mutants by various techniques did not indicate any significant differences in the expression of known virulence genes or in iron-dependent growth. However, we determined several Fur regulatory targets by two-dimensional gel electrophoresis coupled with mass spectrometry. Analysis of proteins from cytoplasmic, membrane, and extracellular fractions revealed numerous differentially expressed proteins. The transcriptional basis of these differences was analyzed by using quantitative reverse transcriptase PCR. Proteins with increased expression in the fur mutant were homologues of the periplasmic iron binding protein YfeA and a cobalt chelatase, CbiK. Down-regulated proteins included a putative manganese superoxide dismutase and ornithine decarboxylase. Based on these data, it is suggested that in D. nodosus the Fur protein functions as a regulator of iron and oxidative metabolism.
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PMID:Identification of a Dichelobacter nodosus ferric uptake regulator and determination of its regulatory targets. 1560 21

Baculovirus F (fusion) proteins are found in the envelopes of budded virions. Recently a Drosophila melanogaster gene (CG4715) that encodes a protein with sequence similarity to baculovirus F proteins was discovered. To examine similarities and differences with baculovirus F proteins, we cloned the D. melanogaster cellular F (Dm-cF) protein gene and analyzed Dm-cF expression and localization. The predicted Dm-cF protein sequence lacks a furin cleavage site, and transiently expressed Dm-cF showed no protein cleavage and no detectable membrane fusion activity. In cell localization studies, transiently expressed Dm-cF was localized to intracellular organelles in D. melanogaster S2 cells, unlike baculovirus F proteins, which localize to cellular plasma membranes. Using reverse transcriptase PCR and Western blot analysis to examine Dm-cF expression in animals, we detected Dm-cF expression in both larval and adult D. melanogaster cells. However, Dm-cF expression was detected only in third instar larvae and adults, suggesting that Dm-cF expression may be developmentally regulated. We also identified genes related to Dm-cF in the genomes of two other Drosophila species, Drosophila yakuba and Drosophila pseudoobscura, and the mosquito Anopheles gambiae. These observations suggest that f genes may be present in the genomes of many insects. Conservation within and between 22 baculovirus and 4 insect F proteins was examined in detail. These studies demonstrate that Dm-cF is expressed in D. melanogaster and suggest that if baculovirus f genes are derived from a host cellular f gene, the function appears to have changed substantially upon adaptation to the baculovirus infection cycle.
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PMID:A cellular Drosophila melanogaster protein with similarity to baculovirus F envelope fusion proteins. 1595 44

Iron is limiting in the human host, and bacterial pathogens respond to this environment by regulating gene expression through the ferric uptake regulator protein (Fur). In vitro studies have demonstrated that Neisseria gonorrhoeae controls the expression of several critical genes through an iron- and Fur-mediated mechanism. While most in vitro experiments are designed to determine the response of N. gonorrhoeae to an exogenous iron concentration of zero, these organisms are unlikely to be exposed to such severe limitations of iron in vivo. To determine if N. gonorrhoeae expresses iron- and Fur-regulated genes in vivo during uncomplicated gonococcal infection, we examined gene expression profiles of specimens obtained from male subjects with urethral infections. RNA was isolated from urethral swab specimens and used as a template to amplify, by reverse transcriptase PCR (RT-PCR), gonococcal genes known to be regulated by iron and Fur (tbpA, tbpB, and fur). The constitutively expressed gonococcal rmp gene was used as a positive control. RT-PCR analysis indicated that gonorrhea-positive specimens where rmp expression was seen were also 93% (51/55) fbpA positive, 87% (48/55) tbpA positive, and 86% (14 of 16 tested) tbpB positive. In addition, we detected a fur transcript in 79% (37 of 47 tested) of positive specimens. We also measured increases in levels of immunoglobulin G antibody against TbpA (91%) and TbpB (73%) antigens in sera from infected male subjects compared to those in uninfected controls. A positive trend between tbpA gene expression and TbpA antibody levels in sera indicated a relationship between levels of gene expression and immune response in male subjects infected with gonorrhea for the first time. These results indicate that gonococcal iron- and Fur-regulated tbpA and tbpB genes are expressed in gonococcal infection and that male subjects with mucosal gonococcal infections exhibit antibodies to these proteins.
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PMID:The gonococcal Fur-regulated tbpA and tbpB genes are expressed during natural mucosal gonococcal infection. 1597 20

The Fur protein is a global regulator of iron metabolism in many bacterial species. However, Fur homologs from some rhizobia appear not to mediate iron-dependent gene expression in vivo. Here, transcriptional profiling analysis showed that more than one-fourth of the genes within the iron stimulon of Bradyrhizobium japonicum were aberrantly controlled by iron in a fur mutant. However, Fur has only a modest role in regulating iron transport genes. Quantitative real time reverse transcriptase PCR measurements confirmed abnormal gene expression in iron-limited cells of the fur strain, thereby demonstrating that Fur must function under those conditions. The findings show that B. japonicum Fur is involved in iron-dependent gene expression, and support the conclusion that rhizobial Fur proteins have novel functions compared with well studied model systems.
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PMID:The Bradyrhizobium japonicum Fur protein is an iron-responsive regulator in vivo. 1703 78

Mutations in mouse Mahogunin Ring Finger-1 (Mgrn1) were first recognized for their effect on agouti-mediated pigment-type switching. Mgrn1 null mutants are completely black and develop spongiform degeneration of the brain. Mgrn1 hypomorphs have dark fur but do not develop neurodegeneration. We characterized a new Mgrn1 hypomorphic allele caused by a gene-trap insertion. Mice homozygous for this mutation are slightly darker than non-mutant animals. They show reduced overall expression of Mgrn1 and two of the four normal Mgrn1 isoforms are replaced by beta-GEO fusion proteins that differ from the normal proteins at their carboxy termini. To investigate the role of different Mgrn1 isoforms in pigment-type switching, we used quantitative relative reverse transcriptase polymerase chain reaction to examine their expression in the skin of Mgrn1 mutant and control mice. Most Mgrn1 mutants produce little or no normal Mgrn1 in the skin. Mgrn1 null mutant mice overexpressing isoform I or III, which are normally absent or weakly expressed in adult skin, had normal agouti-banded hairs. Our results indicate that reduced levels of MGRN1 cause the pigmentation phenotypes of Mgrn1 mutant mice and that there are no significant differences in the function of the four MGRN1 isoforms in pigment-type switching.
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PMID:Characterization of Mahogunin Ring Finger-1 expression in mice. 1708 90

The purpose of current experiment is the generation of insulin-producing human mesenchymal stem cells as therapeutic source for the cure of type 1 diabetes. Type 1 diabetes is generally caused by insulin deficiency accompanied by the destruction of islet beta-cells. In various trials for the treatment of type 1 diabetes, cell-based gene therapy using stem cells is considered as one of the most useful candidate for the treatment. In this experiment, human mesenchymal stem cells were transduced with AAV which is containing furin-cleavable human preproinsulin gene to generate insulin-producing cells as surrogate beta-cells for the type 1 diabetes therapy. In the rAAV production procedure, rAAV was generated by transfection of AD293 cells. Human mesenchymal stems cells were transduced using rAAV with a various multiplicity of infection. Transduction of recombinant AAV was also tested using beta-galactosidse expression. Cell viability was determined by using MTT assay to evaluate the toxicity of the transduction procedure. Expression and production of Insulin were tested using reverse transcriptase-polymerase chain reaction and immunocytochemistry. Secretion of human insulin and C-peptide from the cells was assayed using enzyme-linked immunosorbent assay. Production of insulin and C-peptide from the test group represented a higher increase compared to the control group. In this study, we examined generation of insulin-producing cells from mesenchymal stem cells by genetic engineering for diabetes therapy. This work might be valuable to the field of tissue engineering for diabetes treatment.
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PMID:Generation of insulin-producing human mesenchymal stem cells using recombinant adeno-associated virus. 1732 53

Strains of Francisella tularensis secrete a siderophore in response to iron limitation. Siderophore production is dependent on fslA, the first gene in an operon that appears to encode biosynthetic and export functions for the siderophore. Transcription of the operon is induced under conditions of iron limitation. The fsl genes lie adjacent to the fur homolog on the chromosome, and there is a canonical Fur box sequence in the promoter region of fslA. We generated a Deltafur mutant of the Schu S4 strain of F. tularensis tularensis and determined that siderophore production was now constitutive and no longer regulated by iron levels. Quantitative reverse transcriptase PCR analysis with RNA from Schu S4 and the mutant strain showed that Fur represses transcription of fslA under iron-replete conditions. We determined that fslE (locus FTT0025 in the Schu S4 genome), located downstream of the siderophore biosynthetic genes, is also under Fur regulation and is transcribed as part of the fslABCDEF operon. We generated a defined in-frame deletion of fslE and found that the mutant was defective for growth under iron limitation. Using a plate-based growth assay, we found that the mutant was able to secrete a siderophore but was defective in utilization of the siderophore. FslE belongs to a family of proteins that has no known homologs outside of the Francisella species, and the fslE gene product has been previously localized to the outer membrane of F. tularensis strains. Our data suggest that FslE may function as the siderophore receptor in F. tularensis.
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PMID:fslE is necessary for siderophore-mediated iron acquisition in Francisella tularensis Schu S4. 1853 39

Treatment of salmonellosis with antibiotics is controversial and may prolong carriage and shedding. Therefore, this study sought to investigate if exposure to antimicrobials influences the expression of factors involved in virulence and host colonization. The effect of subinhibitory tetracycline treatment (16 microg/ml, 30 min) on a multi-drug resistant Salmonella Typhimurium DT104 strain was investigated using a targeted microarray. Real-time reverse transcriptase PCR was used to confirm and further assess transcription of 10 selected genes. An in vitro cell invasion assay was performed to assess the invasiveness of the tetracycline-treated isolate. Out of 323 genes, 11 were significantly up-regulated and four were down-regulated in the microarray assays. The hilD and hilA genes, both regulators of Salmonella Pathogenicity Island 1, were up-regulated. Other up-regulated genes included the fliC, fliD, motA and motB genes, involved in motility, the fur gene, an important regulator of iron acquisition systems and of acid tolerance. The drug-exposed replicates showed a 2.5-fold increase in intracellular bacteria over the non-exposed control in cell cultures. These findings suggest a drug-induced expression profile consistent with the early stages of Salmonella infection and invasion concomitant with an increased ability to invade epithelial cells in vitro.
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PMID:Subinhibitory concentrations of tetracycline affect virulence gene expression in a multi-resistant Salmonella enterica subsp. enterica serovar Typhimurium DT104. 1865 7


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