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)

Conditional lethal amber nonsense mutants of vesicular stomatitis virus, Indiana serotype, classified in complementation group I (the L gene), synthesize truncated versions of the L protein. This paper reports further characterization of mutants AmbL1, AmbL2 and AmbL3 by nucleic acid sequence analysis, which was achieved by sequencing L mRNA directly using appropriate synthetic oligonucleotides. In each case a single point mutation altered a glutamine-specifying codon to an amber stop codon. The L mRNA from wild-type and revertant viruses was sequenced for comparison. Of the revertants sequenced, each had reverted by back mutation within the same codon as the original mutation. A revertant of AmbL2 reverted by a second site mutation, also within the same codon as the original mutation. These mutants may be useful for assigning functions to different parts of the L polypeptide chain.
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PMID:Further characterization of conditional lethal amber nonsense mutants of vesicular stomatitis virus: nucleotide sequence analysis. 166 89

The membrane-spanning domain of the vesicular stomatitis virus glycoprotein (G protein) consists of a continuous stretch of 20 uncharged and mostly hydrophobic amino acids. We examined the effects of two mutations which change the amino acid sequence in this domain. These mutations were generated by oligonucleotide-directed mutagenesis of a cDNA clone encoding the G protein, and the altered G proteins were then expressed in animal cells. Replacement of an isoleucine residue in the center of this domain with a strongly polar but uncharged amino acid (glutamine) had no effect on membrane anchoring or transport of the protein to the cell surface. Replacement of this same isoleucine residue with a charged amino acid (arginine) generated a G protein that still spanned intracellular membranes but was not transported efficiently to the cell surface. The protein accumulated in the Golgi region in about 50% of the cells, and about 20% of the cells had detectable protein levels in a punctate pattern on the cell surface. In the remaining cells the protein accumulated in a vesicular pattern throughout the cytoplasm. Models which might explain the abnormal behavior of this protein are discussed.
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PMID:Incorporation of a charged amino acid into the membrane-spanning domain blocks cell surface transport but not membrane anchoring of a viral glycoprotein. 299 64

The effects of 6-diazo-5-oxo-L-norleucine (DON), 2-deoxy-D-glucose (DOG), and tunicamycin (TM) on the replication of poliovirus (PV) and vesicular stomatitis virus (VSV) were examined. During a 48-hr replication period, TM, DON, and DOG inhibit VSV plaque formation in HEp-2 cells by 99.9%, 99.8%, and 99.9% respectively. Inhibition of VSV by DON is reversed with glutamine. Although all three agents are known to affect glycoprotein synthesis, DON and DOG also inhibit plaque formation of viruses devoid of structural glycoproteins. Thus, plaque formation of PV types 1 and 3 and Coxsackie B3 virus is delayed in HEp-2 and Buffalo green monkey kidney cells during exposure to these agents. Since these viruses do not contain glycoproteins and since concentrations up to 10 micrograms TM/ml cause no significant inhibition of PV, DON and DOG are affecting another viral or cellular process. Inhibition of PV replication by DON is reversed by addition of 25 mM glutamine or marginally by exposure to a combination of 5 mM concentrations of cytidine, uridine, adenosine monophosphate, and guanosine monophosphate. Inhibition of PV replication by DOG is reversed with 5 mM uridine alone. During DON exposure of HEp-2 cells infected with PV, the amount of 3H-uridine incorporation at 5.5 hr postinfection (pi) is reduced to 53% of untreated controls, an amount 11% greater than incorporation in cultures infected with PV but not treated with DON. These data indicate that the inhibition of PV replication by DON or DOG occurs at the level of viral RNA synthesis, while the primary target of these agents during VSV replication is probably glycosylation.
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PMID:Poliovirus and vesicular stomatitis virus replication in the presence of 6-diazo-5-oxo-L-norleucine or 2-deoxy-D-glucose. 620 20

6-Diazo-5-oxo-L-norleucine (DON), an L-glutamine antagonist, was administered to 25 evaluable patients with refractory advanced solid tumors in a phase I trial. A total of 58 evaluable courses of five daily iv injections every 3-4 weeks were given, at doses ranging from 7.5 to 90 mg/m2/day. The major dose-limiting toxicity was a syndrome of nausea, vomiting, malaise, and anorexia, which became severe at doses greater than 52.5 mg/m2/day. Diarrhea and stomatitis were less frequent. Hematologic toxicity included mild leukopenia with nadir on Day 6-8 and mild thrombocytopenia with nadir on Day 7-12. Transient decreases in serum calcium to 8.5--8.9 mg/dl were seen in seven of 12 patients receiving greater than or equal to 67.5 mg/m2/day. Dose reduction was required for all patients who received a course of DON at greater than 67.5 mg/m2/day, and a maximum tolerated total dose of 250 mg/m2 (50 mg/m2/day x 5) is suggested for this schedule. Mixed responses were seen in one patient with bladder carcinoma and in one with pulmonary adenocarcinoma.
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PMID:Phase I trial of 6-diazo-5-oxo-L-norleucine (DON) administered by 5-day courses. 708 23

A transgenic mouse has been made that expresses a mutant MHC class I H-2Kb molecule with glutamic acid at position 65 (E65) in place of glutamine. The side chain at position 65, on the outward face of the alpha-helix of the alpha 1 domain of the class I molecule, interacts with the TCR, and not with the peptide binding groove. The transgenic mouse, on a DBA/2 background, mounts Kb,E65-restricted Ag-specific responses to conventional Kb-restricted Ag such as OVA and vesicular stomatitis virus, and shows strong alloreactivity to wild-type Kb. The transgenic mouse also mounts a primary in vitro alloreactive response directed to a mutant molecule with aspartic acid at position 65 (D65). This response is relatively weak, probably because of the structural similarities between aspartic and glutamic acid side chains; both have carboxylic termini, and the aspartic acid side chain is shorter by a single secondary carbon. The alloreactive CTL lines elicited by this conservative change are cross-reactive among several position-65 variants of H-2Kb. Individual CTL clones are specific for self peptides that can be extracted from cells expressing Kb,E65, and from purified wild-type Kb molecules, and that are recognized in the context of the D65 residue. Thus, the smallest variance from self in a class I molecule, even outside the peptide binding groove, can be antigenic.
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PMID:A conservative mutation in a class I MHC molecule outside the peptide binding groove stimulates responses to self peptides. 840 80

Mucositis is a common toxicity of cancer chemotherapy. Glutamine appears to be the major energy source for intestinal epithelium, and animal studies have suggested that dietary supplementation with glutamine may protect the gut from both radiation and chemotherapy. Patients experiencing stomatitis after a course of chemotherapy were offered the opportunity to enter the current study if no clinical parameters precluded receiving the same chemotherapy doses during the next course of treatment. Patients received the same chemotherapy regimen as during the previous treatment but in addition received a suspension of L-glutamine, 4 gm swish and swallow twice a day, from day 1 of chemotherapy for 28 days or for 4 days past the resolution of any post-chemotherapy mucositis. Twelve patients receiving doxorubicin, 1 receiving etoposide, and 1 receiving ifosfamide, etoposide, and carboplatinum were entered into the study. The maximum grade (CALGB criteria) of mucositis decreased in 12 of 14 patients with glutamine supplementation (median score 2A vs 0.5, p < 0.001). Similarly, after glutamine supplementation, the total number of days of mucositis was decreased in 13 of 14 patients (2.7 +/- 0.8 (mean +/- SEM) vs 9.9 +/- 1.1, p > or = 0.001). Thirteen of the 14 patients felt that the mucositis was less severe with the addition of glutamine. No change in the nadir neutrophil count was noted with glutamine, and no toxicity of glutamine was observed. We conclude that oral supplementation with glutamine can significantly decrease the severity of chemotherapy-induced stomatitis, an important cause of morbidity in the treatment of patients with cancer. Glutamine supplementation in patients receiving therapy for cancer warrants further study.
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PMID:Oral glutamine to prevent chemotherapy induced stomatitis: a pilot study. 863 52

Hepatitis delta virus (HDV) is a defective virus requiring the hepatitis B virus (HBV) to provide hepatitis B surface antigens as the envelope protein. The hepatitis B surface antigens are posttranslationally modified by N-linked glycosylation, and its significance in HDV assembly was investigated with a cotransfection system using human hepatoma cell line Huh-7. After the N-linked glycosylation of HBsAg was blocked by tunicamycin treatment, the packaging of HDV in the culture system could be suppressed to a level as low as 5-10% of the untreated control. The extent of inhibition correlated with the increased concentrations of tunicamycin. In contrast, the loss of HBsAg glycosylation did not affect the efficiency of assembly of HBV particles. When the N-linked glycosylation site of small HBsAg at amino acid 146 was mutated from asparagine to glutamine, the mutant HBsAg packaged only a modest amount of HDV particles. The quantity and kinetics of formation of HDV particles in culture system were reduced by the depletion of HBsAg glycosylation. Therefore HDV, similar to influenza and vesicular stomatitis viruses, depends on glycosylation of the envelope proteins as a signal for envelope protein maturation and for virion formation.
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PMID:N-linked glycosylation of hepatitis B surface antigens is involved but not essential in the assembly of hepatitis delta virus. 865 25

An L-glutamine antagonist, 6-diazo-5-oxo-L-norleucin (L-DON), inhibits replication of vesicular stomatitis virus, poliovirus and paramyxoviruses in cultured cells. We tested the antiviral activity of L-DON against different strains of herpes simplex virus type 1 (HSV-1) in Vero cells. In the presence of a physiological plasma concentration of L-glutamine (0.5mM) L-Don inhibited 50% production of virus plaques at concentrations ranging from 7.9 to 16 microM. At concentrations of 40 microM L-Don inhibited infectious virus yield by 99%. The antiviral activity of L-DON decreased with increasing L-glutamine concentrations. A concentration of 5000 microM of L-Don had no significant effects on the viability of Vero cells. Transmission electron microscopical investigations showed that L-DON prevented mainly envelopment of viral nucleocapsids in the cytoplasm. The immunoprecipitation experiments demonstrated selective inhibition of synthesis of HSV-1 glycoproteins in L-DON treated cells. The results showed that L-DON inhibits HSV-1 replication at a late stage in the virus replication cycle, probably the cytoplasmic maturation of virions and subsequent virion egress from the cells.
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PMID:Antiviral effects of 6-diazo-5-oxo-L-norleucin on replication of herpes simplex virus type 1. 903 73

The vesicular stomatitis virus (VSV) octapeptide RGYVYQGL binds to H-2K(b) and triggers a cytotoxic T cell response in mice. A variant peptide, RGYVYEGL (E6) with a glutamic acid for glutamine replacement at position 6 of the VSV peptide, elicits a T cell response with features that are quite different from those elicited by the wild-type VSV peptide. The differences found in the nature of the T cells responding to the E6 peptide include changes in both the V beta elements and the sequences of the complementarity-determining region 3 loops of their TCRs. Further experiments found that the E6 peptide can act as an antagonist for VSV-specific T cell hybridomas. To determine whether these differences in V beta usage, complementarity-determining region 3 sequences, and the switch from agonism to antagonism are caused by a conformational change on the MHC, the peptide, or both, we determined the crystal structure of the variant E6 peptide bound to H-2K(b). This structure shows that the only significant structural difference between H-2K(b)/E6 and the previously determined H-2K(b)/VSV is limited to the side chain of position 6 of the peptide, with no differences in the MHC molecule. Thus, a minor conformational change in the peptide can profoundly alter the biological outcome of the TCR-peptide/MHC interaction.
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PMID:A structural difference limited to one residue of the antigenic peptide can profoundly alter the biological outcome of the TCR-peptide/MHC class I interaction. 1123 45

We have previously reported a functional role associated with hepatitis C virus (HCV) E1 glycoprotein using vesicular stomatitis virus (VSV)/HCV pseudotype. In this study, we have investigated the role of glycosylation upon intracellular transport of chimeric E1-G, and in infectivity of the pseudotyped virus. Interestingly, surface expressed E1-G exhibited sensitivity to Endoglycosidase H (Endo H) treatment, which was similar to full-length E1, suggesting that additional complex oligosaccharides were not added while E1-G was in transit from the endoplasmic reticulum (ER) to the mammalian cell surface. As a next step, each of the four potential N-linked glycosylation sites located at amino acid position 196, 209, 234, or 305 of the E1 ectodomain were mutated separately (asparagine --> glutamine), or in some combination. FACS analysis suggested that mutation(s) of the glycosylation sites affect the translocation of E1-G to the cell surface to different extents, with no single site being particularly essential. VSV pseudotype virus generated from glycosylation mutants exhibited a decrease in titer with an increasing number of mutations at the glycosylation sites on chimeric E1-G. In a separate experiment, N-glycosidase F treatment of pseudotype generated from the already synthesized E1-G or its mutants decreased virus titer by approximately 35%, and the neutralization activity of patient sera was not significantly altered with N-glycosidase F-treated pseudotype virus. Taken together, our results suggested that E1-G does not add complex sugar moieties during transport to the cell surface and retain the glycosylation profile of its parental E1 sequence. Additionally, the removal of glycans from the E1-G reduced, but does not completely impair, virus infectivity.
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PMID:Influence of N-linked glycans on intracellular transport of hepatitis C virus E1 chimeric glycoprotein and its role in pseudotype virus infectivity. 1520 15


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