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)

A retroviral etiology might explain why amyloid plaque and/or spongiosis are or are not associated with neuronal death in prion diseases. While retroviral genes themselves may be responsible for neuronal death, a retrovirus may also cause mutations in cellular genes. Hence, the prion gene may be altered by a retrovirus in the same way as a cellular proto-oncogene is altered to produce an oncogene, either by transduction or by integration of the provirus in its vicinity. In both cases, the resulting abnormal prion protein, acting as a catalyst, may induce the formation of amyloid plaques. In addition, a wild type retrovirus may recombine to the vesicular stomatitis virus (VSV) to give rise to a pseudotyped retrovirus able to induce spongiosis. It is reported here that in scrapie, a blood monocytoid cell proliferates in vitro. If confirmed in other species, this raises the question of the potential link between prion disease and leukemia. Indeed neurovirulent strains of murine leukemia virus, a slow acting retrovirus, are known to induce spongiform encephalopathies. A preliminary attempt to purify reverse transcriptase by chromatography, using the classical protocol, failed because of the presence of a prion-like protein secreted by the blood mononuclear cells which stuck to the phosphocellulose column. Therefore, if a retrovirus is present in prion diseases, it would be evidenced only in animals developing the disease in the absence of prion protein. From this point of view, mice obtained in 1997 by the group of D. Dormont in France, offer a unique opportunity to test the retroviral hypothesis.
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PMID:Possible retroviral origin of prion disease: could prion disease be reconsidered as a preleukemia syndrome? 1022 Nov 68

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases associated with the accumulation of a protease-resistant form of the prion protein (PrP). Although PrP is conserved in vertebrates, its function remains to be identified. In vitro PrP binds large nucleic acids causing the formation of nucleoprotein complexes resembling human immunodeficiency virus type 1 (HIV-1) nucleocapsid-RNA complexes and in vivo MuLV replication accelerates the scrapie infectious process, suggesting possible interactions between retroviruses and PrP. Retroviruses, including HIV-1 encode a major nucleic acid binding protein (NC protein) found within the virus where 2000 NC protein molecules coat the dimeric genome. NC is required in virus assembly and infection to chaperone RNA dimerization and packaging and in proviral DNA synthesis by reverse transcriptase (RT). In HIV-1, 5'-leader RNA/NC interactions appear to control these viral processes. This prompted us to compare and contrast the interactions of human and ovine PrP and HIV-1 NCp7 with HIV-1 5'-leader RNA. Results show that PrP has properties characteristic of NCp7 with respect to viral RNA dimerization and proviral DNA synthesis by RT. The NC-like properties of huPrP map to the N-terminal region of huPrP. Interestingly, PrP localizes in the membrane and cytoplasm of PrP-expressing cells. These findings suggest that PrP is a multifunctional protein possibly participating in nucleic acid metabolism.
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PMID:The prion protein has RNA binding and chaperoning properties characteristic of nucleocapsid protein NCP7 of HIV-1. 1127 62

The transmissible spongiform encephalopathies are fatal neurodegenerative diseases that are associated with the accumulation of a protease-resistant form of the cellular prion protein (PrP). Although PrP is highly conserved and widely expressed in vertebrates, its function remains a matter of speculation. Indeed PrP null mice develop normally and are healthy. Recent results show that PrP binds to nucleic acids in vitro and is found associated with retroviral particles. Furthermore, in mice the scrapie infectious process appears to be accelerated by MuLV replication. These observations prompted us to further investigate the interaction between PrP and nucleic acids, and compare it with that of the retroviral nucleocapsid protein (NC). As the major nucleic acid-binding protein of the retroviral particle, NC protein is tightly associated with the genomic RNA in the virion nucleocapsid, where it chaperones proviral DNA synthesis by reverse transcriptase. Our results show that the human prion protein (huPrP) functionally resembles NCp7 of HIV-1. Both proteins form large nucleoprotein complexes upon binding to DNA. They accelerate the hybridization of complementary DNA strands and chaperone viral DNA synthesis during the minus and plus DNA strand transfers necessary to generate the long terminal repeats. The DNA-binding and strand transfer properties of huPrP appear to map to the N-terminal fragment comprising residues 23 to 144, whereas the C-terminal domain is inactive. These findings suggest that PrP could be involved in nucleic acid metabolism in vivo.
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PMID:The prion protein has DNA strand transfer properties similar to retroviral nucleocapsid protein. 1128 52

A synthetic peptide consisting of amino acid residues 106-126 of the human prion protein (PrP-(106--126)) has been previously demonstrated to be neurotoxic and to induce microglial activation. The present study investigated the expression of the inducible form of the nitric-oxide synthase (NOS-II) in human microglial cells treated with PrP-(106--126). Using reverse transcriptase-polymerase chain reaction, we found that PrP-(106--126) induces NOS-II gene expression after 24 h of treatment and that this effect is accompanied by a peak of nuclear factor kappa B (NF-kappa B) binding at 30 min as evaluated by electrophoretic mobility shift assay. Since our previous data demonstrated tumor necrosis factor-alpha (TNF-alpha) to be a potent inducer of NOS-II in these cells, we analyzed the expression of this cytokine in PrP-(106--126)-treated microglia. PrP-(106--126) caused the release of TNF-alpha as detected by enzyme-linked immunosorbent assay, and a blocking antibody, anti-TNF-alpha, abolished NOS-II induction elicited by this peptide. Moreover, PrP-(106-126) activates p38 mitogen-activated protein kinase, and the inhibition of this pathway determines the ablation of NF-kappa B binding induced by this fragment peptide.
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PMID:The stimulation of inducible nitric-oxide synthase by the prion protein fragment 106--126 in human microglia is tumor necrosis factor-alpha-dependent and involves p38 mitogen-activated protein kinase. 1131 2

All lentiviruses and oncoretroviruses examined so far encode a major nucleic-acid binding protein (nucleocapsid or NC* protein), approximately 2500 molecules of which coat the dimeric RNA genome. Studies on HIV-1 and MoMuLV using in vitro model systems and in vivo have shown that NC protein is required to chaperone viral RNA dimerization and packaging during virus assembly, and proviral DNA synthesis by reverse transcriptase (RT) during infection. The human cellular prion protein (PrP), thought to be the major component of the agent causing transmissible spongiform encephalopathies (TSE), was recently found to possess a strong affinity for nucleic acids and to exhibit chaperone properties very similar to HIV-1 NC protein in the HIV-1 context in vitro. Tight binding of PrP to nucleic acids is proposed to participate directly in the prion disease process. To extend our understanding of lentiviruses and of the unexpected nucleic acid chaperone properties of the human prion protein, we set up an in vitro system to investigate replication of the feline immunodeficiency virus (FIV), which is functionally and phylogenetically distant from HIV-1. The results show that in the FIV model system, NC protein chaperones viral RNA dimerization, primer tRNA(Lys,3) annealing to the genomic primer-binding site (PBS) and minus strand DNA synthesis by the homologous FIV RT. FIV NC protein is able to trigger specific viral DNA synthesis by inhibiting self-priming of reverse transcription. The human prion protein was found to mimic the properties of FIV NC with respect to primer tRNA annealing to the viral RNA and chaperoning minus strand DNA synthesis.
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PMID:Functional interactions of nucleocapsid protein of feline immunodeficiency virus and cellular prion protein with the viral RNA. 1205 75

Our interest in the male accessory glands (MAGs) of Leptinotarsa decemlineata was raised recently by our finding that certain cells produce a secretory substance that is recognized by one of our monoclonal antibodies (MAC-18), developed for the immunohistochemical demonstration of peptidergic neurons in the brain. We undertook to isolate this substance, presumably a peptide, to find out more about its role in the post-mating physiology of the recipient of this peptide, the mated female. This paper describes the purification and chemical characterization of the immunoreactive peptide from 100 pairs of male accessory glands. The peptide was purified by two subsequent reversed-phase-HPLC runs, and fractions were analyzed on Western blots that were immunostained by MAC-18. This indicated the presence of an 8 kDa peptide in the MAG. Partial analysis of the N-terminal amino acids by automated Edman degradation revealed a sequence of 40 amino acid residues. To obtain the full amino acid sequence of this peptide, the technique of reverse transcriptase PCR (3'RACE) was used. A PCR product of 350 bp was obtained, which encoded the 3'-end of the mRNA. After cloning and sequencing, this product contained most of the genetic information of the MAG peptide. The PCR product was also used as a probe for screening a cDNA library constructed from mRNA extracted from MAGs. The nucleotide sequence coding for the signal peptide was elucidated by 5'RACE. The cDNA and 5'RACE clones were analyzed and sequenced. The sequence of the cDNA clone contained an insert of 411 bp, which agreed well with the mRNA size measured by Northern blotting. Translation of the DNA sequences confirmed the data from partial amino acid sequence analyses and also predicted the remainder of the amino acid sequence. The entire peptide, designated Led-MAGP, consists of 74 residues; its mass was calculated and confirmed by mass spectrometry at 7971 Da. The peptide contains seven imperfect hexa-repeats, and this hexa-repeat sequence shows remarkable similarity to the hexa-repeat section of the chicken prion protein. The physiological function of the peptide has yet to be determined, but the hexa-repeat motif has recently been identified as the signal that induces internalization of the prion protein by coated-pit mediated endocytosis. Possible implications for the control of reproductive activities in L. decemlineata are discussed. Copyright 1997 Elsevier Science Ltd. All rights reserved
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PMID:A Peptide from the Male Accessory Gland in Leptinotarsa decemlineata: Purification, Characterization and Molecular Cloning. 1276 97

The present work is a critical survey answering a recent paper published by Stanley Prusiner's team in Science magazine. The authors claim that they used synthetic prions, instead of which they have tailored a particular recombinant protein, produced in E. coli, and devoid of its N-terminal part, therefore mimicking a truncated protein described by another team who isolated it from an iatrogenic TSE patient. This recombinant prion was lethal in normal mice, perhaps partly because, contrarily to what happens with the whole-length normal protein, these proteins are both neurotoxic, fibrillogenic and insensitive to proteolysis. Moreover, an accompanying nucleic acid could explain the infection, because, since 1982 and until now, the protein-only hypothesis has never been supported by any positive mechanism and experimental proof, and is becoming inadequate. Therefore, we have tried to elaborate an alternative hypothesis for the specific mechanism of infection in TSE. The transfer of at least a piece of nucleic acid from the infecting subject, perhaps the mRNA coding for the truncated protein described in human patients, could then reach the corresponding gene in the infected subject, where an endogenous reverse transcriptase would be able to integrate it. Once altered and stimulated, this last gene could, in turn, participate in the generation of nucleic acids able to code the generation of the truncated forms of the prion protein.
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PMID:A new momentum in the field of transmissible spongiform encephalopathies (TSEs). 1597 94

Expression of the goat prion protein gene locus was assessed by reverse transcriptase-polymerase chain reaction on testes and ovaries at various developmental stages. A weak and stochastic expression of the PRNP and PRNT genes was observed. For PRNT, it is consistent with the detected deletions of two single nucleotides within its open reading frame in ruminant genes. PRND was expressed in both tissues at all stages. Whereas its expression is constant in the ovaries, it increases in testes between 36 and 46 days postcoitum (dpc) and remains high thereafter. In testes, Doppel was found in the nucleus of germinal cells and in the cytoplasm of Leydig cells at 44 dpc. It was detected in the cytoplasm of Leydig cells and of some Sertoli and germinal cells at 62 dpc. In the ovaries, it was observed in the nucleus of germinal cells at 44 dpc and mainly in their cytoplasm at 62 dpc. This expression pattern was shown to parallel that of C-kit and suggests Doppel involvement in early testis differentiation.
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PMID:Goat PRND expression pattern suggests its involvement in early sex differentiation. 1722 16

Prion diseases are a group of neurodegenerative disorders characterized by astrocytosis and progressive neuronal degeneration. As a causative agent, prions have been intensely investigated in different experimental models. However, the mechanisms and pathways involved in the prion-induced neurological dysfunction are poorly understood. In this work we have investigated the influence of prion infection on the gene expression profile in a human neuroblastoma cell line. Using a DNA microarray and quantitative reverse transcriptase-polymerase chain reaction methods, we have analysed in SH-SY5Y cells the effects of a synthetic peptide corresponding to the 106-126 neurotoxic region of the cellular human prion protein. Our results show that addition of this peptide to the neuronal culture specifically changes the expression of a relative high number of genes, and causes a progressive neuronal death even in the absence of microglia.
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PMID:Identification of genes differentially expressed in SH-SY5Y neuroblastoma cells exposed to the prion peptide 106-126. 1759 92

The present study was conducted to test the hypothesis whether prion protein gene (PRNP) associated scrapie susceptibility is connected with physiological changes in tissue involved in pathogen uptake, migration and propagation. Jejunum, ileal Peyer's patches, retropharyngeal lymph nodes, brain stem and liver of healthy and non scrapie-infected sheep with PRNP genotypes representing the scrapie risk class R1 (scrapie-resistant) and R5 (scrapie-susceptible), respectively, were comparatively analysed by microarray technology and quantitative reverse transcriptase polymerase chain reaction (RT qPCR). Significantly higher expression levels of genes involved in immune response and cell communication pathways in retropharyngeal lymph nodes of R1 sheep in comparison with R5 animals strongly suggest PRNP associated physiological processes with impact as an early barrier in pathogen defence. Equal expression patterns in brain stem suggest no physiological differences in brain of healthy R1 and R5 animals. In addition, similar expression pattern in liver indicates that there are no transcriptional differences in genes of the hepatic energy metabolism between animals of scrapie classes R1 and R5.
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PMID:Healthy sheep that differ in scrapie associated PRNP genotypes exhibit significant differences of expression pattern associated with immune response and cell-to-cell signalling in retropharyngeal lymph nodes. 2342 61


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