Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolically stable phosphorothioate tetramer analogues of (2'-5')(A)n with Rp and/or Sp chirality in the 2'-5'-phosphodiester linkages constitute a new class of antiviral agents since they mimic the effects of interferons. Three of the diastereomeric 5'-monophosphates (i.e., pRpRpRp, pSpRpRp, and pRpSpSp) bind to and activate RNase L from extracts of HeLa cells. However, the pSpSpSp (2'-5')-(A)4-phosphorothioate is unique in that it binds to, but cannot activate, RNase L to cleave rRNA. When microinjected into the cytoplasm of HeLa cells followed by virus infection, the pRpRpRp, pSpRpRp, and pRpSpSp (2'-5')(A)4-phosphorothioates demonstrate antiviral activity, as does (2'-5')(A)4ox-red, an active (2'-5')(A)n analogue. When microinjected simultaneously with (2'-5')(A)nox-red, an active the pSpSpSp (2'-5')(A)4-phosphorothioate inhibits activation of RNase L in HeLa cells, thereby blocking direct protection of vesicular stomatitis virus. The agonist and antagonist properties of pRpRpRp and pSpSpSp, respectively, are transient probably as a consequence of the hydrolysis of the 5'-monophosphate and formation of the less active (2'-5')(A)4-phosphorothioate cores. The possible use of these (2'-5')(A)4-phosphorothioates as tools for dissecting the biological significance of the (2'-5')(A)n system or in antiviral chemotherapy is discussed.
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PMID:Phosphorothioate analogues of (2'-5')(A)4: agonist and antagonist activities in intact cells. 215 24

Treatment of cells with interferons (IFNs) induces resistance to virus infection. The 2'-5'oligo A (2-5A) synthetase/RNase L is one of the pathways leading to translation inhibition induced by IFN treatment. A murine cDNA encoding the 43-kDa 2-5A synthetase was cloned and sequenced. NIH-3T3 cell clones transfected with this cDNA expressed the enzymatic activity to various extents and exhibited resistance to encephalomyocarditis virus (EMCV) but not to vesicular stomatitis virus replication. The specific resistance to EMCV can be attributed to 2-5A synthetase.
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PMID:A full-length murine 2-5A synthetase cDNA transfected in NIH-3T3 cells impairs EMCV but not VSV replication. 217 Dec 6

Effect of (2'-5')oligoadenylate (2-5A) on cellular and viral protein and RNA syntheses was investigated with two mouse cell lines, L929 and Lz (a subclone of L929). The oligonucleotide was introduced into the cells either by using calcium phosphate coprecipitation technique or by microinjection method. In L929 cells protein and viral RNA syntheses were severely inhibited by 2-5A, whereas in Lz cells, both were only slightly inhibited. The activities of 2-5A synthetase and double-stranded (ds)RNA-dependent protein kinase were enhanced by interferon (IFN) treatment roughly to the same extent and there was no significant difference in the level of 2'-5' phosphodiesterase activity either. On the other hand, 2-5A-dependent RNase (RNase L) activity in Lz cells was low, being about 10-20% of that of L929 cells. It was increased twofold after IFN treatment, but protein synthesis of Lz cells was not as sensitive to 2-5A as that of L929 cells even after IFN treatment. L929 and Lz cells were sensitive to the antiviral effect of mouse IFN against vesicular stomatitis virus (VSV) and Mengovirus. In contrast, however, Lz cells were relatively insensitive to the antiviral effect of IFN on vaccinia virus, whereas L929 cells were sensitive.
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PMID:Comparative studies on (2'-5')oligoadenylate-related enzyme systems and the antiviral effect of interferon in two mouse cell lines which differ in (2'-5')oligoadenylate sensitivity of their protein synthesizing system. 241 28

From the NIH 3T3 clone 1 line which is normally unprotected by interferon (IFN) against lytic virus infection we have selected subclones which show high sensitivity to IFN. The selection procedure was based on encephalomyocarditis virus (EMCV) as selection agent. In the IFN-sensitive subclones thus obtained EMCV replication was inhibited by IFN to a similar degree as observed in L929 cells. Like in the original NIH 3T3 clone 1 line, however, replication of vesicular stomatitis virus (VSV) and cell multiplication were only marginally affected by IFN. We measured the levels of known IFN-induced enzymes (2-5A-synthetase, dsRNA protein kinase and 2-5A-dependent RNase) in a number of subclones and found no consistent differences to the original population. Thus, the newly acquired IFN-dependent protection against EMCV may be mediated by a different antiviral mechanism.
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PMID:Studies on interferon-sensitive cells derived from the interferon-resistant NIH 3T3 clone 1 line. 242 4

We have developed a selection protocol to isolate interferon (IFN)-sensitive subclones directly from an IFN-resistant cell population. The protocol uses encephalomyocarditis virus (EMCV) as a selection agent in combination with pretreatment with low doses of IFN and subsequent growth in the presence of virus-neutralizing antiserum. We have applied this protocol to the partially IFN-resistant NIH 3T3 clone 1 line and have obtained a number of IFN-sensitive subclones. Sensitivity to IFN was restricted to protection against EMCV. Replication of vesicular stomatitis virus as well as cell growth were resistant to IFN treatment as in the original clone 1 line. We have compared levels of 2',5'-oligoadenylate (2-5A) synthetase, dsRNA-activated protein kinase and 2-5A-dependent RNase in some IFN-sensitive subclones and found no difference from the resistant clone 1 cells. Markedly decreased levels of 2-5A-dependent RNase and thus a defective 2-5A pathway have been implicated as a possible cause for the partial resistance of clone 1 cells to IFN. Since the selected IFN-sensitive subclones are of the same phenotype in this respect as the clone 1 line we suggest that inhibition of EMCV in these lines occurs through a mechanism independent of the 2-5A system.
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PMID:Selection and characterization of interferon-sensitive cells derived from an interferon-resistant NIH 3T3 line. 244 7

Interferons inhibit the replication of vesicular stomatitis virus (VSV), but not of encephalomyocarditis virus (EMCV), in mouse JLSV-11 cells. We report the isolation of clonal derivatives from this cell line in which the replication of both viruses is impaired by interferons. These clones were selected from the parental line by virtue of their rescue by interferon treatment from the cytopathic effects of EMCV infection. In one such clone, RK8, the replication of VSV and EMCV and the production of resident murine leukemia virus were inhibited by interferon. On the other hand, in clone RK6, which was isolated without any selection, the replication of VSV, but not of EMCV, was impaired by interferons. The levels of 2'-5'-oligoadenylate synthetase mRNA and enzyme activity were similarly elevated upon interferon treatment in the two clones. However, the level of RNase L, as determined by binding and cross-linking of a radiolabeled 2'-5'-oligoadenylate derivative, was much lower in RK6 cells than in RK8 cells. In accord with this observation, the introduction of 2'-5'-oligoadenylates into cells inhibited protein synthesis much less strongly in RK6 cells than in RK8 cells. These results are consistent with the notion that the 2'-5'-oligoadenylate-dependent RNase L may be a mediator of the inhibition of EMCV replication by interferons.
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PMID:Studies on the role of the 2'-5'-oligoadenylate synthetase-RNase L pathway in beta interferon-mediated inhibition of encephalomyocarditis virus replication. 284 70

Molecular hybrids were synthesized by coupling (2'-5')(A)n oligoadenylates or 2-5A, an intracellular mediator involved in antiviral activity of interferons (IFNs), with poly(L-lysine) used as a membrane carrier. (2'-5')(A)n in its free form was not taken up by cells, probably because of its ionic character. Conjugation with the polypeptide carrier overcame this problem and enabled its pharmacological properties to be developed. The alpha-glycol group of individual (2'-5')(A)n oligomers was oxidized by periodate oxidation and conjugated by an amino reductive reaction to poly(L-lysine), Mr 14 000, in a molar ratio of 5:1. These hybrid molecules left the biologically active 5' end moiety of the (2'-5')(A)n molecule unchanged, and in particular its triphosphate group, and stabilized the molecule by increasing its resistance to phosphodiesterase hydrolysis. A dose-dependent inhibition of virus growth was observed on concomitant incubation of (2'-5')(A)n-poly(L-lysine) conjugates with vesicular stomatitis virus infected L1210 cell cultures. This was a result of the activation of the (2'-5')(A)n-dependent endoribonuclease (RNase L) by intracellularly delivered (2'-5')(A)n as in some IFN-treated virus-infected cells. Indeed, (2'-5')(A)n-poly(L-lysine) conjugates bind RNase L effectively as can be seen from their ability to compete with authentic (2'-5')(A)n in a cell-free radiobinding assay. Moreover, (2'-5')(A)n-poly(L-lysine) conjugates promote transient inhibition of protein synthesis and a characteristic cleavage pattern of ribosomal RNAs in intact cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of ribonuclease L by (2'-5')(A)4-poly(L-lysine) conjugates in intact cells. 301 97

To screen for cells with different sensitivities to interferon (IFN), NIH 3T3 mouse fibroblasts were subcloned and examined for their response to IFN treatment. Of 30 clones tested, 2 appeared to be relatively resistant to IFN, since the replication of both vesicular stomatitis virus and mengovirus was not inhibited, even in the presence of 1,000 U of IFN per ml. One resistant (A10) and one sensitive (A5) clone were further analyzed. In both clones, murine leukemia virus replication was equally inhibited by IFN, indicating the presence of functional receptors for IFN in the resistant clone. Using the (2'-5')oligoadenylate (2-5A) radiobinding assay, we could demonstrate that both clones contained the RNase L protein. Furthermore, this enzyme appears to be active, since a similar reduction in the rate of protein synthesis was evident after the introduction of exogenous 2-5A to the cells. We also analyzed the activity of another enzyme in the 2-5A pathway, namely, 2-5A synthetase. In the sensitive cells (A5), the induction of enzyme activity was proportional to the IFN concentration used, reaching a maximum of more than a 10-fold increase over the background of untreated cells. However, little if any induction over the basal activity was observed in the resistant cells (A10) when similar doses of IFN were used. It is thus probable that the lack of induction of 2-5A synthetase activity by IFN in A10 cells is at least partly responsible for their relative resistance to IFN treatment.
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PMID:Isolation and characterization of an interferon-resistant cell line deficient in the induction of (2'-5')oligoadenylate synthetase activity. 664 21

The vaccinia virus (VV) E3L gene, which encodes a potent inhibitor of the interferon (IFN)-induced, double-stranded RNA (dsRNA)-dependent protein kinase, PKR, is thought to be involved in the IFN-resistant phenotype of VV. The E3L gene products, p25 and p20, act as inhibitors of PKR, presumably by binding and sequestering activator dsRNA from the kinase. In this study we demonstrate that VV with the E3L gene specifically deleted (vP1080) was sensitive to the antiviral effects of IFN and debilitated in its ability to rescue vesicular stomatitis virus from the antiviral effects of IFN. Infection of L929 cells with E3L-minus virus led to rRNA degradation typical of activation of the 2'-5'-oligoadenylate synthetase/RNase L system, and extracts of infected cells lacked the PKR-inhibitory activity characteristic of wild-type VV. The reovirus S4 gene, which encodes a dsRNA-binding protein (sigma 3) that can also inhibit PKR activation by binding and sequestering activator dsRNA, was inserted into vP1080. The resultant virus (vP1112) was partially resistant to the antiviral effects of IFN in comparison with vP1080. Further studies demonstrated that transient expression of the reovirus sigma 3 protein rescued E3L-minus VV replication in HeLa cells. In these studies, rescue by sigma 3 mutants correlated with their ability to bind dsRNA. Finally, vP112 was also able to rescue the replication of the IFN-sensitive virus vesicular stomatitis virus in a manner similar to that of wild-type VV. Together, these results suggest that the reovirus S4 gene can replace the VV E3L gene with respect to interference with the IFN-induced antiviral activity.
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PMID:Reversal of the interferon-sensitive phenotype of a vaccinia virus lacking E3L by expression of the reovirus S4 gene. 752 85

The 2-5A/RNase L system is considered as a central pathway of interferon (IFN) action and could possibly play a more general physiological role as for instance in the regulation of RNA stability in mammalian cells. We describe here the expression cloning and initial characterization of RLI (for RNase L inhibitor), a new type of endoribonuclease inhibitor. RLI cDNA codes for a 68-kDa polypeptide whose expression is not regulated by IFN. Its expression in reticulocyte extracts antagonizes the 2-5A binding ability and the nuclease activity of endogenous RNase L or the cloned 2DR polypeptide. The inhibition requires the association of RLI with the nuclease and is dependent on the ratio between the two proteins. Likewise RLI is coimmunoprecipitated with the RNase L complex by a nuclease-specific antibody. RLI does not lead to 2-5A degradation or to irreversible modification of RNase L. The overexpression of RLI in stably transfected HeLa cells inhibits the antiviral activity of IFN on encephalomyocarditis virus but not on vesicular stomatitis virus. RLI therefore appears as the first described and potentially important mediator of the 2-5A/RNase L pathway.
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PMID:Cloning and characterization of a RNAse L inhibitor. A new component of the interferon-regulated 2-5A pathway. 753 25


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