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

In the present study we demonstrate that a murine proximal tubular cell line (MCT cells), expressing angiotensin II (ANG II) receptors [dissociation constant (Kd) = 0.89 nM; receptor density (R0) = 46,900 receptors/cell] in culture, can be induced to hypertrophy after the daily addition of exogenous ANG II (10(-8) M). This hypertrophic response was characterized by an increase in total cellular protein content, by an enhancement of [3H]leucine incorporation into precipitable proteins, and by an augmentation in cell size by cytofluorography. This ANG II effect producing MCT cell enlargement was demonstrable in the absence of cellular proliferation. Proliferation of MCT cells, however, could be induced by epidermal growth factor (EGF) or platelet-derived growth factor (PDGF), and pretreatment of rested MCT cells with ANG II further enhanced EGF-induced cell division. ANG II-induced hypertrophy in MCT cells was factor specific, in that it could be blocked with saralasin, and not induced by angiotensin I (ANG I). This hypertrophic response was also independent of prostaglandin E2 synthesis but was transducible by pertussis toxin-sensitive G proteins and involved, to some extent, the activation of Na(+)-H+ exchange. ANG II, as well as EGF and/or PDGF, moreover, could induce the cellular oncogenes c-fos, c-myc, c-N-ras, but not c-cis, which suggests that early gene activation is probably not a specific prerequisite for hypertrophy. Our findings demonstrate that ANG II, in culture, can be a single-factor event capable of inducing hypertrophy in proximal tubular cells.
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PMID:Angiotensin II induces cellular hypertrophy in cultured murine proximal tubular cells. 170 Jun 29

Competitive inhibition binding studies on membranes from the rat pancreatic AR 4-2J cell line revealed the predominance (80%) of low selectivity CCK receptors (KD of 1 nM and 4 nM for, respectively, CCK-8 and gastrin-17I (G-17I] over selective receptors (20% with a KD of 1 nM and 1 microM for, respectively, CCK-8 and G-17I). Amylase secretion was stimulated by low concentrations of CCK-8, G-17I and CCK-4. G-17I-induced amylase secretion was unaffected by 100 nM of the selective peripheral CCK-A receptor antagonist L-364,718, suggesting that amylase hypersecretion followed non-selective CCK receptor activation, a function normally assumed by selective CCK-A receptors in rat pancreatic acini. Direct ultraviolet irradiation of AR 4-2J cell membranes preloaded with 125I-BH-CCK-33 or 125I(Leu)G(2-17)I resulted in covalent cross-linking with, respectively, a 90 kDa protein and a 106 kDa protein, both distinct from the 81 kDa CCK binding species revealed in normal rat pancreatic membranes. Gpp[NH]p increased the dissociation rate of CCK-8 and G-17I from AR 4-2J cell membranes, indicating a coupling of receptors with guanyl nucleotide regulatory protein(s) G. [32P]ADP-ribosylation of AR 4-2J cell membranes allowed to detect the presence of two Gs alpha (the 50 kDa form predominating over the 45 kDa form) and one Gi alpha (41 kDa). However, Gi and Gs may not be involved in gastrin stimulation of amylase secretion, as Bordetella pertussis toxin and cholera toxin pretreatment of cells did not suppress G-17I-dependent amylase secretion.
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PMID:Functional and molecular characterization of CCK receptors in the rat pancreatic acinar cell line AR 4-2J. 170 48

Epitopes defined by monoclonal antibodies (mAb) specific for the Bordetella pertussis outer membrane protein P.69 (pertactin) were mapped using a series of amino- and carboxy-terminal deletion mutants expressed in Escherichia coli. mAb were found to bind predominantly to a region of pertactin spanning a (Pro-Gln-Pro)5 repeat motif and one mAb was found to bind to another region spanning a (Gly-Gly-Xaa-Xaa-Pro)5 repeat motif. To localize further the mAb-binding sites, a panel of synthetic peptides, a series of 94 overlapping hexameric peptides, and a P.69 30-amino acid fusion to a hepatitis B core protein (HBcAg-69), were synthesized. This combined approach has identified the binding site for the mAb BBO5: Pro-Gly-Pro-Gln-Pro-Pro; mAb BBO7, E4A8 and E4D7: Ala-Pro-Gln-Pro-Pro-Ala-Gly-Arg; and mAb BPE3: Thr-Leu-Trp-Tyr-Ala-Glu-Ser-Asn-Ala-Leu-Ser-Lys-Arg. We have used a non-lethal murine respiratory model of B. pertussis infection to investigate the ability of a peptide containing the epitope of the mAb BBO5 to elicit protective immunity. Immunization of mice with the HBcAg-69 protein prevented growth of B. pertussis in the lungs compared to mice receiving HBcAg alone, and protection correlated with high titers of anti-P.69 antibodies.
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PMID:Identification and characterization of a protective immunodominant B cell epitope of pertactin (P.69) from Bordetella pertussis. 170 65

CD69 is a phosphorylated disulfide-linked homodimer that appears on the surface of human T, B cells and thymocytes in the early steps of activation; its molecular mass is 28 to 34 kDa under reducing conditions. This molecule is able to mediate positive signals to the lymphocytes as the anti-CD69 mAb (MLR3, AIM, Leu 23) in synergism with phorbol esters induce IL-2 production and proliferation of lymphocytes. Here we show that this molecule is associated to a GTP binding protein that is a substrate for Bordetella pertussis toxin. The relevance of CD69 in the activation process is also suggested by the broad range of signals able to modulate CD69 on T cells. In fact, not only the mitogens or the CD3-promoted activation, but also the alternative pathways mediated by CD2 or CD28 are accompanied by CD69 expression; moreover a very rapid and transient appearance of CD69 on the cell surface is observed also in response to a stimulus not specifically involved in T cell activation such as heat shock. Finally we demonstrate that CD69 is present in the cytoplasm of nonactivated T cells; accordingly its surface expression at the onset of activation is independent on a new RNA or protein synthesis.
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PMID:CD69 in resting and activated T lymphocytes. Its association with a GTP binding protein and biochemical requirements for its expression. 171 Feb 39

The alpha-subunit of Gi-2, in addition to that of Gs (GTP-binding proteins involved in adenylate cyclase inhibition and stimulation, respectively) was ADP-ribosylated by cholera toxin in HL-60 cell membranes when a chemotactic receptor was stimulated by formyl-Met-Leu-Phe (fMLP), and the sites modified by cholera and pertussis toxins on the alpha-subunit of Gi-2 were different (Iiri, T., Tohkin, M., Morishima, N., Ohoka, Y., Ui, M., and Katada, T. (1989) J. Biol. Chem. 264, 21394-21400). In order to investigate how the functions of Gi-2 were modified by cholera toxin, the ADP-ribosylated and unmodified proteins were purified from HL-60 cell membranes that had been incubated in the presence and absence of cholera toxin, respectively. The modified Gi-2 displayed unique properties as follows. 1) The ADP-ribosylated alpha-subunit had a more acidic pI than the unmodified one, leading to a partial resolution of the modified Gir2 trimer from the unmodified protein by an anion column chromatography. 2) When the purified proteins were incubated with [gamma-32P]GTP, the radioactivity was more greatly retained in the modified Gi-2 than in the unmodified protein. 3) The actual catalytic rate (kcat) of GTP hydrolysis was, indeed, markedly inhibited by cholera toxin-induced modification. 4) There was an increase in the apparent affinity of Gi-2 for GDP by cholera toxin-induced modification. 5) The modified Gi-2 exhibited a low substrate activity for pertussis toxin-catalyzed ADP-ribosylation. 6) A high-affinity fMLP binding to HL-60 cell membranes was more effectively reconstituted with the ADP-ribosylated Gi-2 than with the unmodified protein. These results suggested that the agonist-fMLP receptor complex was effectively coupled with the ADP-ribosylated Gi-2, resulting in the GTP-bound form, and that the hydrolysis of GTP on the modified alpha-subunit was selectively attenuated. Thus, cholera toxin ADP-ribosylated Gi-2 appeared to be not only a less sensitive pertussis toxin substrate but also an efficient signal transducer between receptors and effectors.
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PMID:Modification of the function of pertussis toxin substrate GTP-binding protein by cholera toxin-catalyzed ADP-ribosylation. 173 Jun 31

Considerable evidence suggests that signal transduction pathways are targets of lithium (Li) action. A number of investigators have reported that Li attenuates both adenylate cyclase (AC) activity and phosphoinositide (PI) turnover in rodents and in humans, thus "dampening" these systems. We have studied selected components of these second-messenger systems in a series of clinical and preclinical investigations. To overcome confounding effects of alterations in mood state, we examined AC activity and G-protein ribosylation in peripheral blood cells from 10 healthy volunteers, prior to and following 14 days of Li administration. Basal and postreceptor [cesium fluoride (CsF) or Gpp(NH)p] stimulated AC activity were unaffected in lymphocytes. In contrast, both basal and stimulated AC activity in platelets were significantly augmented, compatible with an attenuation of Gi function. Ribosylation of platelet Gs by cholera toxin was unchanged, whereas that of Gi by pertussis toxin (PT) was increased. Given that undissociated G protein is the preferred substrate for PT, our results suggest that Li interferes with subunit dissociation and the subsequent activation of Gi. To determine if Li has similar effects on Gi in the central nervous system, we measured extracellular (EC) cyclic adenosine monophosphate (cAMP) in rat brain by in vivo microdialysis, revealing a dose-dependent increase in cAMP by norepinephrine (NE) antagonized by propranolol. Chronic (4-week) Li doubled basal EC cAMP, while decreasing the fractional response to 100 microM NE. Thus, using in vivo microdialysis, we observed the reported reduction in NE-stimulated AC activity, but only as a function of elevated basal cAMP. Increased basal AC activity has been observed following chronic Li in both humans and rat tissues but generally has not been considered relevant. The PI generating system is another proposed major target for Li that we have studied using an in vitro cell culture model of peripheral blood cells. Chronic (6-day) exposure of neutrophil-like HL60 cells to 1 mM LiCl did not affect agonist fMet-Leu-Phe (fMLP) induced PI turnover. In contrast, Li attenuated both agonist and phorbol ester stimulated Na+/H+ exchange, suggesting reduced protein kinase C (PKC) function. Western blot analysis revealed altered levels of PKC in both membrane and cytosolic fractions. The functional consequences of these complex effects on the two major signal transduction pathways and their interactions in the intact living organism remain to be elucidated.
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PMID:Signal transduction modulation by lithium: cell culture, cerebral microdialysis and human studies. 177 89

The effects of pertussis toxin (PT) on the growth and dimethylsulfoxide (Me2SO4)-induced differentiation of the HL-60 human promyelocytic leukemia cell line were tested. Cell growth was quantified by direct cell counts. Cell differentiation was estimated by measuring the expression of myeloid-specific cell-surface antigens (Mo-1 and fMet-Leu-Phe [fMLP] receptors), the ability of the cells to produce superoxide anions on stimulation with fMLP, the calcium ionophore A23187 and phorbol 12-myristate 13-acetate (PMA), and by monitoring the level of expression of messenger RNA (mRNA) for tumor necrosis factor alpha (TNF alpha). By itself, PT did not affect the proliferation of HL-60 cells in serum-containing medium. In contrast, PT (but not its B-oligomer) dose-dependently inhibited the Me2SO4-induced expression of Mo-1, fMLP receptors, and the oxidative responses to the chemotactic factor and to A23187, but not to PMA. The addition of Me2SO4 induced a significant increase in the steady-state levels of TNF alpha mRNA, and this effect was strongly inhibited by PT. Finally, the bacterial toxin did not reverse the block of cell division that follows the addition of Me2SO4. These results provide evidence for the involvement of a PT substrate (presumably a guanine nucleotide-binding protein) in the regulation of the maturation of the excitation-response coupling sequence in human myeloid cell precursors and show that the regulation of cell division and maturation of HL-60 cells are under distinct sets of control mechanisms.
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PMID:Pertussis toxin selectively interferes with the responses of the HL-60 human promyelocytic cell line to dimethylsulfoxide. 182 51

Since human polymorphonuclear neutrophils (PMN) exposed to ATP or its poorly hydrolyzable analogue, adenosine-5'-O-(3-thiotriphosphate) (ATP gamma S), respond with increases in intracellular calcium and enhanced O2- responses to the chemotactic peptide N'-formyl-Met-Leu-Phe (fMLP), we systematically evaluated responses of PMN to various nucleotides. The P2X and P2Y receptor agonists, 2-methylthioadenosine triphosphate and beta, gamma-methyleneadenosine triphosphate, failed to induce increases in intracellular calcium and did not desensitize PMN to increases in intracellular calcium induced by ATP gamma S. Since it has been suggested that P2Z receptor occupancy with the ATP4- species caused nonselective increases in cell permeability, the ability of ATP to induce increases in intracellular calcium was evaluated in the presence and absence of extracellular Ca2+ and Mg2+. In the presence of these cations, 5-fold greater concentrations of ATP were required. The effects of ATP4- were not associated with changes in cell membrane permeability. This suggests that ATP4- is the active species but that its effect on PMN is not linked to a nonselective increase in permeability of the cell membrane. With respect to responses of PMN to purine and pyrimidine nucleotides as defined by increases in intracellular calcium, the rank order of potency for the nucleotides was ATP = UTP greater than ATP gamma S greater than or equal to ITP greater than GTP greater than or equal to CTP. These responses were blocked by pretreatment of PMN with pertussis toxin. Prior exposure of PMN to ATP gamma S blocked cellular responses (calcium increases) to these nucleotides but not to fMLP. Likewise, exposure of PMN to any nucleotides blocked subsequent cellular responses to ATP gamma S but not to fMLP. These data support the concept that nucleotide responses of PMN utilize either a common receptor or a common signal transduction pathway involving a guanine nucleotide binding protein in events leading to elevations in intracellular calcium. Nucleotide interaction with PMN does not follow the established pattern of responses associated with P2X or P2Y purinergic receptor occupancy.
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PMID:Nucleotide responses of human neutrophils. 184 54

Stimulation by N-formyl-Met-Leu-Phe (fMLP) of rabbit peritoneal neutrophils, in which phosphatidylcholine was preferentially labeled with 1-O-[3H]octadecyl lyso platelet-activating factor, activated phospholipase D, resulting in the formation of [3H]PA from [3H]PC. A direct activator of GTP-binding proteins (G-proteins), NaF, also stimulated [3H]PA formation. fMLP-stimulated [3H]PA formation was inhibited by pertussis toxin (IAP) in a time- and dose-dependent manner. IAP also inhibited fMLP-stimulated IP3 formation, but the inhibition of IP3 formation was significantly greater than that of [3H]PA formation. These results indicate that activation of phospholipase D by fMLP in rabbit neutrophils is mediated by an IAP-sensitive G-protein that may be distinct from a phospholipase C-regulating protein.
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PMID:Activation of phospholipase D in rabbit neutrophils by fMet-Leu-Phe is mediated by a pertussis toxin-sensitive GTP-binding protein that may be distinct from a phospholipase C-regulating protein. 184 91

We investigated the requirement for N-formyl peptide receptor-mediated transmembrane signalling in transfected mouse fibroblasts that express the receptor. Stably transfected cells displayed specific binding for N-formyl-Met-Leu-[3H]Phe with a dissociation constant of 3 nM. The cells responded to ligand stimulation with mobilization of calcium from intracellular stores. Calcium mobilization was ligand dose-dependent (EC50 = 3 nM fMet-Leu-Phe) and could be inhibited by pertussis toxin treatment. These results provide the first demonstration that expression of the single-chain N-formyl peptide receptor in mouse fibroblasts is sufficient for mediating ligand-induced early transmembrane signalling events, which do not appear to require other neutrophil-specific cellular components.
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PMID:Transmembrane signalling by the N-formyl peptide receptor in stably transfected fibroblasts. 188 72


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