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 mechanisms by which interferon inhibits viral growth are only partially understood. Several enzymatic activities increase in cells shortly after treatment with interferon. One of these enzymes, oligo-isoadenylate synthetase, synthesizes (2'-5') isoadenylate oligomers which strongly stimulate the activity of a cellular ribonuclease, RNase F (ref. 7). Interferon also significantly increases the activity of a protein kinase which phosphorylates the initiation factor eIF-2 and can inhibit in vitro protein synthesis. Such interferon-induced enzymes, which affect RNA and protein metabolism, might be responsible for many of its effects on viruses. Indeed, inhibition of viral protein and RNA synthesis appears to have a major role in the antiviral state. We have now investigated possible interactions of the two enzymes with viral constituents during the course of infection and found that in two different membrane-coated RNA viruses, vesicular stomatitis virus (VSV) and Moloney murine leukaemia virus (M-MuLV), there is an accumulation of the 2'-5') oligo-isoadenylate synthetase (E) in the virions. Most of the enzyme is bound to the virion ribonucleoprotein core. The incorporation of E into the virions suggests a direct involvement of the enzyme in regulation of virus functions.
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PMID:An interferon-induced cellular enzyme is incorporated into virions. 615 96

Intraperitoneal administration of ribosomal RNA (rRNA) was found to protect mice against subsequent lethal infection by encephalomyocarditis (EMC) virus without induction of detectable amounts of circulating interferon. The nature of this effect was examined in terms of the types of natural polyribonucleotides which could afford such protection. rRNA prepared from E. coli was slightly more effective than chicken liver rRNA which was, in turn, more effective than yeast rRNA. 5S ribosomal RNA was not effective, whereas the slightly smaller 4S transfer RNA was as good as E. coli rRNA, suggesting that molecular size is not the sole criterion for the protective effect. The separated 16S and 23S E. coli rRNAs where each as effective as the unfractionated RNA. Anti-viral activity was lost after complete hydrolysis with alkali and nucleoside monophosphates were also inactive. Digestion of rRNA with pancreatic ribonuclease greatly decreased its antiviral activity whereas digestion with T1 ribonuclease had no effect indicating that fairly short oligonucleotides, but not of random nucleotide sequence, are active components in the protection of mice against infection by EMC virus. In vitro, no antiviral effect against EMC virus infection was observed in treatment of L cells under various conditions.
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PMID:The antiviral activity of ribosomal polynucleotides against encephalomyocarditis virus infection of mice. 616 Aug 32

The oligonucleotides pppA2'p5'A2'p5'A and related oligomers (2-5A) are synthesized by an enzyme that is widely distributed in a variety of cells, the activity of which varies with interferon treatment, growth and hormone status. Because significant amounts of 2-5A have recently been detected in interferon-treated cells, it has been suggested that the oligonucleotides may be involved in interferon action and in the control of cell metabolism. In both intact cells and cell-free systems 2-5A has been shown to activate a ribonuclease. We report here investigations of the sequence specificities of the 2-5A-dependent ribonucleases in extracts of rabbit reticulocytes, mouse ascites tumour cells and human lymphoblastoid cells in conditions of partial digestion using terminally labelled RNA substrates. The enzymes cleaved on the 3'-side of UN sequences to yield UpNp terminated products. Cleavage was observed predominantly at UA and UU sequences.
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PMID:Interferon action--sequence specificity of the ppp(A2'p)nA-dependent ribonuclease. 616 2

Extracts of interferon-treated cells synthesize unique 2',5'-linked oligo(adenylic acid) 5'-phosphates in the presence of ATP and double-stranded RNA. 2',5'-linked oligo(adenylic acid) 5'-triphosphate inhibits protein synthesis at nanomolar concentrations by activating RNase. We have observed that oligo(adenylic acid) 5'-monophosphate and 5'-triphosphate are potent inhibitors of vaccinia mRNA methylation in vitro. Both the methylation of mRNA methylation is not due to degradation of the mRNA. Inhibition of the 5'-terminal guanine at the 7 position and the 2'-O-ribose methylation of the penultimate nucleoside are inhibited. Such inhibition of the requisite modification of the 5' terminus of mRNA by 2',5'-linked oligo(adenylic acids) may be a mechanism of interferon action against both DNA and RNA viruses in which mRNAs derived from them are capped.
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PMID:Inhibition of vaccinia mRNA methylation by 2',5'-linked oligo(adenylic acid) triphosphate. 616 3

A mouse cell line, NIH 3T3, does not respond to some of the activities of interferon. Even after treatment with high concentrations of interferon the replication of lytic viruses, such as encephalomyocarditis virus (EMCV) and vesicular stomatitis virus (VSV) is not inhibited in these cells. In contrast, interferon treatment of these same cells results in the inhibition of Moloney murine leukemia virus (MMuLV) production. We have analyzed enzymatic pathways which are induced by interferon in these cells. After interferon treatment, the level of the (2'-5')oligoadenylate [(2'-5)An] synthetase activity and the phosphorylation of the 67000-dalton protein (P1) are enhanced in NIH 3T3 cells to approximately the same level as interferon-sensitive mouse L-cells. Moreover, NIH 3T3 and L-cells, contain approximately the same levels of enzymes which inactivate (2'-5')An. Both exogenously added (2'-5')A3 or double-stranded RNA (dsRNA) failed to inhibit protein synthesis in NIH 3T3 extracts even though they were potent inhibitors of L-cell extract-directed protein synthesis. Direct measurements of the (2'-5')An-dependent ribonuclease F (RNase F) failed to detect such activity in NIH 3T3 cells. Our results, therefore, suggest that the presence of RNase F activity is necessary for the interferon-induced antiviral activity against EMCV and against VSV. The induction of protein kinase activity by interferon treatment of NIH 3T3 cells appears to have no direct effect on EMCV and VSV replication.
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PMID:A mouse cell line, which is unprotected by interferon against lytic virus infection, lacks ribonuclease F activity. 616 26

Two series of interferon-inducing complexes containing polyriboinosinic and polyribocytidylic acids, poly-L-lysine, and carboxymethyl cellulose were prepared. One series contained carboxymethyl cellulose, 27,000-molecular-weight poly-L-lysine, and either 4S, 6S, or 9S polyriboinosinic and polyribocytidylic acids. The other series contained carboxymethyl cellulose, 9S polyriboinosinic and polyribocytidylic acids, and poly-L-lysine, whose molecular weights ranged from 2,000 to 27,000. The homogeneity of these double-stranded polynucleotide complexes was confirmed by single-step thermal denaturation profiles and by single peaks in sucrose gradient velocity sedimentation. The complexes have a greater resistance to hydrolysis by ribonuclease than does polyriboinosinic-polyribocytidylic acid. The resistance to ribonuclease increased with the increasing size of polynucleotide homopolymers and poly-L-lysine. In monkeys and, to a lesser extent, in mice, serum interferon levels induced by the different complexes were related to the degree of resistance of the complexes to hydrolysis by ribonuclease. In mice, 4S, 6S, and 9S complexes of polyriboinosinic-polyribocytidylic acid, poly-L-lysine, and carboxymethyl cellulose had a higher level of toxicity than did polyriboinosinic-polyribocytidylic acid as measured by 50% lethal dose. The toxicity was parallel to the ribonuclease resistance of the complexes. It was concluded that an increase in the size of the polynucleotides and the polyamino acids in these complexes leads to higher resistance to hydrolysis by ribonuclease and to greater interferon responses in mice and rhesus monkeys.
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PMID:Interferon induction in primates by stabilized polyriboinosinic acid-polyribocytidylic acid: effect of component size. 617 19

HeLa cells have an unusually high level of ppp(A2'p)nA synthetase (n = 2 to greater than or equal to 4) even in the absence of interferon treatment. In accord with this ppp(A2'p)nA and ppp(A2'p)nA-mediated ribosomal RNA cleavage occur naturally in response to encephalomyocarditis virus infection in control as well as in interferon-treated cells. Despite this, in the absence of interferon treatment, encephalomyocarditis virus grows well in these cells. A possible explanation for this paradox is that the ppp(A2'p)nA dependent RNase is lost or inactivated at later times post-infection in control but not in interferon-treated cells. It appears, therefore, to be the prevention by interferon of the virus-mediated inhibition of the ppp(A2'p)n-dependent nuclease rather than the absolute level or induction of the ppp(A2'p)nA synthetase which is crucial for the activity of the ppp(A2'p)nA system in HeLa cells. These results provide evidence for a further level of control in the ppp(A2'p)nA system and show that limited ppp(A2'p)nA-mediated ribosomal RNA cleavage alone is not sufficient to cause an inhibition of virus growth.
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PMID:Control of the ppp(a2'p)nA system in HeLa cells. Effects of interferon and virus infection. 617 33

Interferon treatment of mouse JLS-V9R cells resulted in a 10- to 20-fold increase in the levels of the 2-5A (ppp(A2'p)nA)-dependent RNase. The nuclease was monitored in cell extracts by covalent and noncovalent binding of 32P-labeled 2-5A derivatives to the nuclease and by the appearance of 2-5A-mediated ribosomal RNA cleavage products. Untreated JLS-V9R cells contained very low levels of the nuclease (5-10% of that found in control Ehrlich ascites tumor cells). An increase in the nuclease was first detected between 3 and 6 hr after interferon treatment and was completely inhibited by actinomycin D. Control experiments indicated that the increase in the nuclease was not due to an intracellular redistribution of the enzyme. The results indicate that in JLS-V9R cells, interferon controls the activity of the 2-5A system at two levels: by inducing the synthesis of both the 2-5A-dependent RNase and the 2-5A-synthetase.
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PMID:Interferon-induced synthesis of 2-5A-dependent RNase in mouse JLS-V9R cells. 618 72

Cell-free cytoplasmic extracts of the Syrian hamster cell lines C13/SV28 and BHK-21F were immunogenic in Syrian hamsters. The resulting antisera cross-reacted completely with antisera against lymphocytic choriomeningitis virus (LCMV) in an immunoradiometric assay employing BHK-21F antigen. Several other Syrian hamster cell lines not previously known to be infected with LCMV were also strongly positive when assayed for viral antigens. Also, several mouse sera and antisera raised in Syrian hamsters against cells transformed by papovaviruses had high titers of anti-LCMV activity. No cytopathic effect was evident in any of the persistently infected cell lines. Culture media from these cells were not infectious and showed no evidence of defective interfering particles. However, cell-free extracts of all the persistently infected cells contained material capable of transmitting the persistent infection to uninfected cells of Syrian hamsters, rats, mice, green monkeys, and humans. The onset of infection is much slower than when LCMV virions are used. When 2 X 10(6) uninfected BHK cells were treated with an extract from 100 persistently infected cells, the new infection was apparent within about 12 days. When an extract from 10(6) cells was used, the new infection was apparent within about 5 days, but not sooner. The intracellular infectious material was sensitive to treatment with deoxycholate, Nonidet P-40, or ether but resistant to treatment with RNase or trypsin. It was also large (5,000S) and heterodisperse on sucrose gradients. The infectious material was probably contained in large lipid vesicles and their integrity was probably essential for infection. When a few persistently infected cells were cocultivated with many uninfected cells, a few discrete colonies positive for LCMV antigens were observed after about 5 days. Since the culture media were not infectious, the infection probably spread by cell-cell contact. Several different experiments indicated that interferon did not play a major role in mediating persistence in this case. Persistent infections by LCMV can be maintained without expression of extracellular virus particles and without appearance of large amounts of viral antigens on the cell surface. Cell-cell contact could still allow transmission of intracellular infectious material. In an animal, these properties could circumvent immune surveillance.
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PMID:Persistent infection of some standard cell lines by lymphocytic choriomeningitis virus: transmission of infection by an intracellular agent. 619 87

Concanavalin A, endotoxin, poly I: C, and tumour necrosis serum (TNS) were compared for antitumour activity against Meth A sarcoma transplanted in syngeneic BALB/c mice and their capacity to induce tumour necrosis factor (TNF), heat-stable cytostatic factors, and heat-labile interferon in the blood of normal and Corynebacterium parvum-pretreated mice. All the agents induced hyperemia and inhibition of mitosis at 4 h, and by 24 h many tumours had a dark necrotic centre. Subsequent tumour growth was inhibited and in some of the treated mice tumours regressed completely. Poly A: U and normal mouse serum did not induce regression and their effects were less marked in all other respects, suggesting that these events may be linked. The necrotizing effects of concanavalin A and poly I: C are unlikely to be mediated by TNF, because neither agent could mimic endotoxin in eliciting RNase-resistant necrotizing and regressing activity in the serum of mice pretreated with C. parvum. Poly I: C did not induce strong cytostatic activity in the sera of C. parvum-treated mice, and for this and other reasons these factors are unlikely to be responsible for the observed effects. Concanavalin A, endotoxin, and poly I: C induced high levels of serum interferon but purified interferon had only weak antitumour activity in the Meth A system, suggesting that interferon may not be the mediator. From these and other data it is concluded that there is no clear relationship between the capacity of the agents to induce tumour necrosis and their capacity to elicit TNF, cytostatic factors, and interferon.
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PMID:Antitumour activity of endotoxin, concanavalin A and poly I: C and their ability to elicit tumour necrosis factor, cytostatic factors, and interferon in vivo. 619 6


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