Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine whether a nontoxic derivative of pertussis toxin obtained by recombinant DNA technology, PT-9K/129G, is a good candidate for a new pertussis vaccine, we examined the safety and the immunogenicity in children of a vaccine containing 15 micrograms of PT-9K/129G protein and 0.5 mg of aluminum hydroxide per dose. Fifty-three children 12 to 24 months of age and 21 infants aged 2 to 4 months were injected with two and three doses, respectively. The vaccine did not induce significant local or systemic reactions and elicited an increase of antibody titer in more than 98% of the children. The geometric mean of the toxin-neutralizing titers increased after each dose and was 85 units in children given two doses and 196 units in those given three doses. Two children who had detectable antibody levels before the first immunization had a high response (greater than 320 units) to the first vaccine dose. The findings suggest that PT-9K/129G is a promising antigen to be included in the development of acellular pertussis vaccines.
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PMID:Acellular pertussis vaccine composed of genetically inactivated pertussis toxin: safety and immunogenicity in 12- to 24- and 2- to 4-month-old children. 157 1

The subunits that make up the pentameric B oligomer of pertussis toxin (S2, S3, S4, and S5) were individually synthesized as recombinant polypeptides in Escherichia coli, isolated as insoluble inclusion bodies, and assembled into a multimeric form in vitro by spontaneous association following treatment with a chaotropic agent, reduction, and reoxidation. The recombinant B multimer, purified by fetuin-Sepharose affinity chromatography, contained all four of the individual subunits and possessed the mitogenic and hemagglutinating activities characteristic of the native B oligomer. Immunization of mice with the recombinant B oligomer elicited antibodies that neutralized pertussis toxin in vitro and, moreover, provided protection in vivo against the leukocytosis-promoting activity of the toxin. These results demonstrate the potential for assembly of complex multimeric proteins from recombinant DNA-derived polypeptides and provide a novel means for production of an acellular pertussis vaccine component.
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PMID:Properties of pertussis toxin B oligomer assembled in vitro from recombinant polypeptides produced by Escherichia coli. 158 92

To determine whether a cloned receptor coupled to pertussis toxin (PTx)-sensitive G-proteins can induce cell proliferation and oncogenic transformation, as observed for receptors that elicit PTx-insensitive enhancement of phosphatidyl inositol (PI)-specific phospholipase-C (PLC) activity, nontransformed murine BALB/c-3T3 cells were transfected with the rat serotonin-1A (5-HT1A) receptor. The 5-HT1A receptor is coupled to PTx-sensitive G-proteins to induce a cell-specific activation of PLC. While 1 microM 5-HT induced no change in PI turnover or cytosolic free calcium levels ([Ca2+]i) in receptor-negative nontransfected 3T3 cells, 5-HT induced a 2-fold increase in inositol trisphosphate accumulation and a 2.5-fold increase in [Ca2+]i in the 3T3-ZD8 clone, which expressed 0.6 +/- 0.2 pmol/mg protein of specific 5-HT1A binding sites. The stimulatory actions of 5-HT on PI turnover and [Ca2+]i in 3T3ZD8 cells displayed the pharmacology of the 5-HT1A receptor and were abolished by pretreatment with PTx. Thus, BALB/c-3T3 fibroblast cells express the PLC-linked pathway of the 5-HT1A receptor. Overnight treatment with 5-HT (1 microM) enhanced incorporation of [3H]thymidine into DNA extracted from serum-starved 3T3ZD-8 cells, an action that was also blocked by pretreatment with pertussis toxin. Long term (1-2 weeks) exposure to 5-HT in the medium led to phenotypic transformation of the cells, including the formation of foci with 1 microM 5-HT. These actions of 5-HT were not observed in untransformed 3T3 cells. We conclude that the PTx-sensitive PLC-linked pathway of the 5-HT1A receptor expressed in nontransformed BALB/c-3T3 cells, in concert with other serum-derived factors, predisposes the cells to enhanced proliferation and transformation.
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PMID:Conditional transformation mediated via a pertussis toxin-sensitive receptor signalling pathway. 160 83

We have examined the phosphorylation and protein kinase activity of p44 mitogen-activated protein kinase (p44mapk) in growth factor-stimulated hamster fibroblasts using a specific antiserum. The activity of p44mapk was stimulated both by receptor tyrosine kinases and G protein-coupled receptors. Detailed kinetics revealed that alpha-thrombin induces a biphasic activation of p44mapk in CCL39 cells: a rapid phase appearing at 5-10 min was followed by a late and sustained phase still elevated after 4 h. Inactivation of alpha-thrombin with hirudin after 30 sec, which prevented DNA synthesis, did not alter the early p44mapk response but completely abolished the late phase. Pretreatment of the cells with pertussis toxin, which inhibits by more than 95% alpha-thrombin-induced mitogenicity, resulted in the complete loss of late phase activity, while the early peak was partially attenuated. Treatment of CCL39 cells with basic fibroblast growth factor also induced a strong activation of p44mapk. Serotonin, which is not a mitogen by its own, had no effect on late phase p44mapk activity, but synergized with basic fibroblast growth factor to induce late kinase response and DNA synthesis. Both early and late phase activation of p44mapk were accompanied by tyrosine phosphorylation of the enzyme. Together, the results indicate that there is a very close correlation between the ability of a growth factor to induce late and sustained p44mapk activation and its mitogenic potential. Therefore, we propose that sustained p44mapk activation is an obligatory event for growth factor-induced cell cycle progression.
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PMID:Biphasic and synergistic activation of p44mapk (ERK1) by growth factors: correlation between late phase activation and mitogenicity. 160 90

In FRTL-5 thyroid cells, thyrotropin (TSH) stimulates I- efflux in association with phospholipase C activation and Ca2+ mobilization. TSH also stimulates DNA synthesis, accompanied by cAMP accumulation. Significant activation of the phospholipase C-Ca2+ pathway requires 10-100 nM TSH a concentration 10(3) to 10(4) times higher than necessary to stimulate the cAMP pathway. When the P1-purinergic agonist, phenylisopropyladenosine (PIA) is added to the reaction medium, the former pathway is markedly enhanced, whereas the latter pathway is inhibited. As a result, in the presence of PIA, both TSH-induced pathways are activated at similar TSH concentrations. These PIA actions are completely reversed by a prior treatment of cells with islet-activating protein (IAP); pertussis toxin. When adenosine deaminase is added to the reaction medium, TSH-induced cAMP accumulation is significantly enhanced, suggesting an autocrine action of adenosine. In IAP-treated cells, the level of TSH-induced cAMP accumulation reaches that of deaminase-treated control cells, and no further increase is observed when adenosine deaminase is added. We conclude that in the thyroid, either an neural or autocrine adenosine signal, mediated by an IAP-sensitive G-protein, switches TSH signal transduction from the cAMP pathway to the phospholipase C-Ca2+ pathway.
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PMID:Reciprocal modulation of thyrotropin actions by P1-purinergic agonists in FRTL-5 thyroid cells. Inhibition of cAMP pathway and stimulation of phospholipase C-Ca2+ pathway. 164 85

An egg-specific NADase has been purified to homogeneity from the ovotestis of the opisthobranch mollusk Aplysia californica. Unlike other NADases, the Aplysia enzyme generates primarily cyclic-ADP-ribose (cADPR) rather than ADP-ribose from NAD. cADPR has been shown to stimulate the release of Ca2+ from microsomes prepared from sea urchin egg and, when injected into intact eggs, to activate the cortical reaction, multiple nuclear cycles, and DNA synthesis. The Aplysia enzyme was initially identified as an inhibitor of cholera and pertussis toxin-catalyzed ADP-ribosylation. By the use of an NADase assay, it was purified from the aqueous-soluble fraction of ovotestis by sequential column chromatography. The enzyme has an apparent molecular mass of 29 kDa, a Km for NAD of 0.7 mM, and a turnover rate of approximately 27,000 mol NAD.min-1.mol enzyme-1 at 30 degrees C. Monoclonal antibodies were generated to the NADase. Immunoblots of two-dimensional gels revealed multiple isoforms of the enzyme, with pls ranging from 8.1 to 9.8. The multiple isoforms were resolved with a cation exchange high-pressure liquid chromatography column and shown to generate cADPR. Immunohistochemical analysis of cryostat sections of Aplysia ovotestis shows that the enzyme is specific to the eggs and restricted to large 5- to 10-microns granules or vesicles. To date the cADPR-generating enzyme activity has been identified in various organisms, including mammals. The Aplysia enzyme is the first example in which the enzyme that generates cADPR has been purified. All of the available evidence indicates that this NADase is a second-messenger enzyme, implying that other NADases may serve a similar function.
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PMID:Purification and characterization of a molluscan egg-specific NADase, a second-messenger enzyme. 165 Feb 54

P2-purinoceptor agonists stimulated the DNA synthesis of Jurkat cells via a pathway independent of cAMP and intracellular free calcium. The response was greatly enhanced by the synergistic action between adenine and guanine nucleotides, suggesting that binding sites of these nucleotides are different from each other, and the proliferation is stimulated by a novel interaction between adenine and guanine nucleotide receptors. The stimulatory effects of P2-agonists on proliferation was completely abolished by cholera toxin and attenuated by pertussis toxin, which suggests that substrates for cholera toxin and pertussis toxin are involved in the proliferative pathways associated with P2-purinoceptors.
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PMID:Stimulation of DNA synthesis in Jurkat cells by synergistic action between adenine and guanine nucleotides. 165 82

It has been proposed that the cytokine interleukin-1 beta (IL-1 beta), secreted by islet-infiltrating macrophages, may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in beta-cell destruction. Addition of IL-1 beta to isolated pancreatic islets in vitro results in cytotoxic effects on beta-cell function, but there is little information on the intracellular events that convey the actions of the cytokine. In the present study, fetal rat pancreatic islets containing a high fraction of beta-cells were exposed in culture to IL-1 beta. It was found that IL-1 beta markedly decreased beta-cell DNA synthesis, insulin secretion and cyclic AMP content. In order to explore whether the decrease in cAMP resulted from IL-1 beta interaction with GTP-binding proteins coupled to adenylyl cyclase, islets were treated for 24 h with pertussis toxin prior to addition of cytokine. While this treatment restored the decrease in cAMP, the reduced DNA synthesis and insulin secretion persisted. Pertussis toxin treatment without the addition of IL-1 beta resulted in increases in cAMP, DNA synthesis and insulin secretion. Addition of the stimulatory cAMP analog Sp-cAMPS also increase DNA synthesis and insulin secretion, but failed to affect the decrease in these functions evoked by IL-1 beta. The protease inhibitor N alpha-p-tosyl-L-lysine chloromethyl ketone, recently shown to protect completely against IL-1 beta-induced suppression of insulin production and secretion, was found to markedly reduce DNA synthesis without affecting insulin secretion. When the protease inhibitor was combined with IL-1 beta, the suppressed secretion was counteracted while DNA synthesis inhibition was not. It is concluded that cAMP stimulates DNA synthesis and insulin secretion in beta-cells, but that the inhibitory effect of IL-1 beta on these functions cannot be ascribed to the decrease in cAMP evoked by the cytokine. However, the repressive effect of the cytokine on insulin secretion, but not DNA synthesis, may be prevented by protease inhibition.
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PMID:Inhibition of fetal rat pancreatic beta-cell replication by interleukin-1 beta in vitro is not mediated through pertussis toxin-sensitive G-proteins, a decrease in cyclic AMP, or protease activation. 165 27

A complementary DNA encoding a G protein-coupled glutamate receptor from rat brain, GluGR, was cloned by functional expression in Xenopus oocytes. The complementary DNA encodes a protein of 1199 amino acids containing a seven-transmembrane motif, flanked by large amino- and carboxyl-terminal domains. This receptor lacks any amino acid sequence similarity with other G protein-coupled receptors, suggesting that it may be a member of a new subfamily. The presence of two introns flanking the central core suggests that GluGR may have evolved by exon shuffling. Expressed in oocytes, GluGR is activated by quisqualate greater than glutamate greater than ibotenate greater than trans-1-aminocyclopentyl-1,3-dicarboxylate, and it is inhibited by 2-amino-3-phosphonopropionate. Activation is blocked by Bordella pertussis toxin. These properties are typical of some metabotropic glutamate receptors.
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PMID:Cloning, expression, and gene structure of a G protein-coupled glutamate receptor from rat brain. 165 24

Bordetella pertussis produces a porin protein which is a prominent outer membrane component found in both virulent and avirulent strains. N-terminal amino acid analysis of purified B. pertussis porin was performed and this amino acid sequence was used to design an oligonucleotide that was then utilized to screen a lambda gt11 library containing randomly sheared fragments of DNA from B. pertussis strain 347. One clone, lambda BpPor, was identified and subcloned into pUC18. A portion of the DNA insert in this subclone, pBpPor1, was sequenced and shown to contain the N-terminal region of the structural porin gene. This truncated gene sequence was used to design an additional oligonucleotide that was used to identify a clone, pBpPor2, which overlapped with pBpPor1 and contained a termination codon. The structural gene deduced from this sequence would encode a 365-amino-acid polypeptide with a predicted mass of 39,103 daltons. The predicted product also contains a signal sequence of 20 residues that is similar to that found in other porin genes. The predicted B. pertussis porin protein sequence contains regions that are homologous to regions found in porins expressed by Neisseria species and Escherichia coli, including the presence of phenylalanine as the carboxy-terminal amino acid. DNA hybridization studies indicated that both virulent and avirulent strains of B. pertussis contain only one copy of this gene and that Bordetella bronchiseptica and Bordetella parapertussis contain a similar gene.
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PMID:Cloning and sequencing of the structural gene for the porin protein of Bordetella pertussis. 165 37


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