UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-8 (IL-8) and the structurally related cytokines neutrophil-activating peptide-2 (NAP-2) and GRO alpha are powerful chemotactic agents for human neutrophils. Although these three chemokines act by binding to overlapping but not identical receptor subsets, the data available to date have stressed the similarities in their mechanisms of action. The present studies were undertaken to further our understanding of the signal transduction mechanisms associated with these neutrophil agonists. IL-8, NAP-2, and GRO alpha stimulated similar increases in the level of cytoplasmic free calcium. They were also shown to stimulate qualitatively similar increases in the levels of protein tyrosine phosphorylation. In contrast, only IL-8 enhanced the formation of phosphatidylethanol (PEt), the product catalyzed by phospholipase D (PLD) in the presence of ethanol. The formation of PEt stimulated by IL-8 was inhibited by pertussis toxin and the tyrosine kinase inhibitors erbstatin and herbimycin A. The ability of IL-8 to stimulate the activity of PLD was additively enhanced, or primed, by cytochalasin B and by tumor necrosis factor alpha. Although all three chemokines increased the level of free cytoplasmic calcium to the same extent, IL-8 was significantly more potent than either NAP-2 or GRO alpha with respect to its ability to enhance CD11b expression and to stimulate chemotactic and oxidative responses. The differences between IL-8, NAP-2, and GRO alpha in their ability to stimulate PLD is likely to be related to their respective binding affinities for the two IL-8 receptors (IL-8R-A and IL-8R-B). These results suggest that the signalling pathways activated by IL-8R-A and IL-8R-B diverge at a step preceding the activation of PLD.
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PMID:Diverging signal transduction pathways activated by interleukin-8 and related chemokines in human neutrophils: interleukin-8, but not NAP-2 or GRO alpha, stimulates phospholipase D activity. 781 7

Lysophosphatidic acid (LPA) is a biologically active phospholipid known to have growth factor-like activity on fibroblasts. Although the intracellular signal transduction pathways affected by LPA have been well characterized, the possibility that peptide growth factors are involved in the proliferative response of cells to LPA has not been thoroughly investigated. The focus of this work was to determine the effects of LPA on the proliferation and differentiation of early passage cultured human keratinocytes with emphasis on determining if transforming growth factors (TGF), types alpha and beta, are induced by LPA. The effects of LPA are compared with all-trans-retinoic acid (RA), a structurally unrelated lipid that has previously been shown to induce both TGF alpha and TGF beta and have pronounced effects on keratinocyte proliferation and differentiation. Treatment of cultured human keratinocytes with LPA or RA induced the production of TGF alpha by four- to eightfold. A number of structurally related phospholipids did not mimic the TGF alpha-inducing activity of LPA. LPA is mitogenic for keratinocytes and its stimulatory effect could be blocked with an inhibitory antibody to the EGF/TGF alpha receptor, suggesting that the induction of TGF alpha mediates LPA stimulation of keratinocyte proliferation. LPA and RA also induced both the active and latent forms TGF beta from cultured keratinocytes. Induction of TGF beta may mediate the effects LPA had on keratinocyte differentiation which were apparent by inhibition of proliferation (confluent cultures) and increased involucrin synthesis. Dramatic morphological changes were also observed after LPA treatment. Mechanistic studies suggest that LPA activates both pertussis toxin-sensitive and -insensitive signaling pathways involving protein kinase C activation and protein tyrosine phosphorylation. The effects of LPA on TGF alpha and TGF beta production by keratinocytes likely have in vivo relevance as concluded from rodent studies involving topical LPA treatments.
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PMID:Lysophosphatidic acid induction of transforming growth factors alpha and beta: modulation of proliferation and differentiation in cultured human keratinocytes and mouse skin. 781 33

Bacterial toxin ADP-ribosyltransferases, e.g. diphtheria toxin (DT) and pertussis toxin, have in common consensus sequences involved in catalytic activity, which are localized to three regions. Region I is notable for a histidine or arginine; region II, approximately 50-75 amino acids downstream, is rich in aromatic/hydrophobic amino acids; and region III, further downstream, has a glutamate and other acidic amino acids. A similar motif was observed in the sequence of the glycosylphosphatidylinositol-linked muscle ADP-ribosyltransferase. Site-directed mutagenesis was performed to verify the role of this motif. Proteins were expressed in rat adenocarcinoma cells, released from the cell with phosphatidylinositol-specific phospholipase C, and quantified with polyclonal antibodies. Transferase His114 in region I aligned with His21 of DT; as with DT, the H114N mutant was active. Aromatic/hydrophobic amino acids (region II) were found approximately 30-50 amino acids downstream of this histidine. Although transferase has a Glu278-Tyr-Ile sequence characteristic of region III in DT, Glu278 was not critical for activity. In an alternative region III containing Glu238-Glu239-Glu240, Glu238 and Glu240 but not Glu239 were critical. Glu240 aligned with critical glutamates in DT, Pseudomonas exotoxin, and C3 transferase. Thus, the mammalian ADP-ribosyltransferases have motifs similar to toxin ADP-ribosyltransferases, suggesting that these sequences are important in ADP-ribose transfer reactions.
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PMID:Conservation of a common motif in enzymes catalyzing ADP-ribose transfer. Identification of domains in mammalian transferases. 782 77

Somatostatin receptors are abundantly expressed on a variety of human endocrine and epithelial tumors. The ability of these receptors to couple to effector pathways that inhibit the growth of these tumor cells has prompted the use of somatostatin agonists in the treatment of human neoplasms. It has been demonstrated that somatostatin stimulates a phosphotyrosine phosphatase in human tumor cells through a receptor-mediated process. This stimulation may counteract the growth-promoting properties of growth factors and the receptor tyrosine kinases that they activate. The recent cloning and characterization of distinct somatostatin receptor subtypes raise the possibility that different receptor subtypes mediate distinct effector pathways. To determine whether cloned somatostatin receptors could mediate coupling to phosphotyrosine phosphotyrosine phosphatase activity, we examined phosphatase activity after somatotostatin activation of the rat somatostatin receptors SSTR1 and SSTR2 after their stable expression in heterologous Chinese Hamster Ovary (CHO-K1) cells. We found that stimulation of SSTR1 cells was capable of increasing phosphotyrosine phosphatase activity, despite the coupling of both receptors to the inhibition of adenylyl cyclase in these cells. This activation was characterized by an EC50 of 70 nM and was sensitive to pertussis toxin. In addition, we demonstrate that activation of phosphotyrosine phosphatase activity in pituitary cell lines correlates with the endogenous expression of the SSTR1 gene within these cells.
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PMID:The somatostatin receptor SSTR1 is coupled to phosphotyrosine phosphatase activity in CHO-K1 cells. 785 46

In the thyroid, thyrotropin (TSH) stimulates both growth and function, and stimulates the production of cAMP which reproduces most of the effects of TSH. Here, we report evidence that TSH stimulates the mitogen-activated protein (MAP) kinase cascade through a cAMP-independent pathway, in human thyroid. TSH stimulated MAP kinase activity (4-9-fold the basal level) measured in the cytosolic fractions of primary cultured thyroid follicles. Maximal activity was reached after 20 min and remained sustained for 1-3 h, TSH being as potent as EGF; EC50 was 1.5 nM TSH. Only a single isoform of MAP kinase (p42) was detected in the follicles. p42 was phosphorylated on tyrosine residues and showed a reduced electrophoretic mobility in follicles stimulated by TSH. All these effects on MAP kinase were decreased by preincubation of the follicles with human anti-TSH receptor antibodies. The stimulation of MAP kinase by TSH was neither blocked by pertussis toxin nor reproduced by forskolin, cholera toxin, or 8-bromo-cAMP. In conclusion, in human thyroid cells, in contrast with previous observations on dog thyroid cells, TSH stimulates strongly MAP kinase through a pertussis toxin-insensitive and cAMP-independent pathway.
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PMID:Stimulation of mitogen-activated protein kinase by thyrotropin in primary cultured human thyroid follicles. 787 8

Treatment of vascular smooth muscle cells (SMC) with angiotensin II (AII) leads to an increase in the tyrosine phosphorylation of multiple cellular substrates. Here, we have demonstrated that AII stimulates tyrosine phosphorylation of the focal adhesion-associated protein paxillin in rat aortic SMC. AII-induced phosphorylation of paxillin was detectable within 1 min and was sustained up to 60 min. Preincubation with the AT1-selective antagonist losartan abolished this response. The stimulatory effect of AII on paxillin tyrosine phosphorylation was observed only in aortic SMC and not in other target cells such as adrenal zona glomerulosa cells, chromaffin cells, or hepatocytes. The effect of AII was dependent on the activation of phospholipase C. Chelation of intracellular calcium completely inhibited the ability of AII to stimulate paxillin tyrosine phosphorylation, while selective inhibition of protein kinase C partially attenuated the response. In contrast, treatment of the cells with pertussis toxin had no effect on AII-induced paxillin tyrosine phosphorylation. These findings identify paxillin as a new substrate for AII-stimulated tyrosine phosphorylation and suggest a role for cytoskeleton-associated proteins in the growth response of aortic SMC.
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PMID:Angiotensin II stimulates tyrosine phosphorylation of the focal adhesion-associated protein paxillin in aortic smooth muscle cells. 787 4

We have recently reported the expression of the thyrotropin (TSH) receptor and the stimulation by TSH of type-II iodothyronine 5'-deiodinase in astrocytes. In these cells, TSH stimulated arachidonate release, but neither cAMP production, nor phosphatidylinositolbisphosphate hydrolysis, as described in the human thyroid gland. Here we report, in contrast to a recent observation made in dog thyroid cells, that TSH stimulates mitogen-activated protein kinase (MAP kinase) in astrocytes. Indeed, TSH increases the tyrosine phosphorylation of the two isoforms of MAP kinase expressed in these cells, in correlation with both a slower electrophoretic migration of the tyrosine phosphorylated species and an enhanced enzymic activity measured on a specific substrate peptide. This stimulation of MAP kinase by TSH was specifically inhibited by incubation of astrocytes in the presence of human blocking anti-(TSH receptor) IgG, and by immunoprecipitation of TSH with monoclonal anti-TSH IgG. In astrocytes, TSH was neither mitogenic by itself, nor modified significantly the basic-fibroblast-growth-factor-induced mitogenesis. The stimulation of MAP kinase by TSH was not affected by treatment with pertussis toxin, suggesting guanine-nucleotide-binding-regulatory protein i/o was not implicated in this TSH effect. Our model will allow the study of the stimulation of MAP kinase by TSH without interference either from cAMP or from phosphoinositide signalling pathways.
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PMID:Stimulation of mitogen-activated protein kinase by thyrotropin in astrocytes. 788 98

Several neurotransmitters that act through G protein-linked receptors have been shown to affect the growth rate of dividing cells. An analysis of the early signaling events that mediate this response revealed some novel activities for G protein-linked receptors. Activation of D2 receptors heterologously expressed in CHO cells also stimulates the synthesis of DNA, which results in increased proliferation. Pertussis toxin pretreatment abolishes D2 agonist-stimulated mitogenesis, which indicates the need for a G protein. D2 receptor-stimulated mitogenesis occurs in the presence of a membrane-soluble cyclic AMP analog and, in Chinese hamster ovary cells with a mutated protein kinase A, which is resistant to the growth effects of cyclic AMP. Therefore, the proliferative response is independent of changes in cyclic AMP. It was determined that a number of other signaling pathways commonly used by Gi-linked receptors are not involved in the D2-mediated mitogenic response. These include arachidonic acid release, stimulation of protein kinase C, stimulation of inositol phosphates, opening of K+ channels and activation of amiloride sensitive Na+/H+ exchange. D2 receptor-stimulated mitogenesis is blocked by genistein, a tyrosine kinase inhibitor, at the same concentrations that block thrombin-stimulated mitogenesis. In fact, dopamine and thrombin stimulate a rapid increase in tyrosine phosphorylation of a number of substrates in the transfected Chinese hamster ovary cells. These results reveal a novel signaling event for D2 dopamine receptors, activation of tyrosine phosphorylations. They suggest the importance of these events for D2 dopamine receptor-stimulated mitogenesis.
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PMID:D2 dopamine receptor stimulation of mitogenesis in transfected Chinese hamster ovary cells: relationship to dopamine stimulation of tyrosine phosphorylations. 790 93

Platelet-activating factor (PAF; sn-1-O-alkyl-2-acetyl-sn-glycero-3- phosphocholine) is thought to be an important mediator of embryo-endometrial interactions in early pregnancy, and an understanding of its role in the establishment of early human pregnancy can only follow an understanding of its mechanism of action. In a human endometrial epithelial cell line, HEC-1B, the presence of mRNA encoding the platelet-activating factor receptor was demonstrated by reverse transcription-polymerase chain reaction. The presence of functional receptors was shown by inositol trisphosphate accumulation and a rise in the concentration of intracellular free calcium evoked by platelet-activating factor in myo-[2-3H]inositol-labelled and fura-2-loaded cells, respectively. Platelet-activating factor evoked rapid and concentration-dependent increases in the concentration of intracellular free calcium and inositol trisphosphate that were inhibited by the platelet-activating factor receptor antagonist WEB 2086, indicating that the responses are receptor mediated. Inositol trisphosphate accumulation evoked by platelet-activating factor was unaffected by pretreatment with pertussis toxin. Platelet-activating factor also stimulated the tyrosine phosphorylation of at least two major proteins of 80 kDa and 44 kDa; the smaller protein is an isoform of mitogen-activated protein kinase. These results show that functional platelet-activating factor receptors are located on the endometrial epithelial cell line HEC-1B and are linked to inositol lipid hydrolysis, calcium mobilization and tyrosine kinase activity.
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PMID:Functional platelet-activating factor receptors linked to inositol lipid hydrolysis, calcium mobilization and tyrosine kinase activity in the human endometrial HEC-1B cell line. 793 82

Calcium transients in single, human gingival fibroblasts were studied after mechanical stretching of flexible culture substrates. A model system was developed to reproducibly stretch and rapidly (<1 sec) refocus cells in the same focal plane so that changes in the concentration of free intracellular calcium ions ([Ca2+]i) were monitored without delay. Attached cells were grown on flexible bottom Petriperm dishes, loaded with fura-2/AM, and stretched by 1% or 2.8% of substrate area. The stretch caused no significant cell detachment or membrane lesions. A 1% stretch induce no calcium response, but a 2.8% stretch stimulated an initial calcium transient and the subsequent generation of [Ca2+]i oscillations of up to 2,000 sec. At 1% stretch, there was no calcium response. Cell shape and plating time were important determinants in the calcium response to mechanical stimulation: the responder cells were small and round without long processes. Major calcium transients were inhibited completely by 5 mM EGTA or by 10 microM gadolinium ions, by 50 microM nifedipine, or 250 microM verapamil, suggesting an influx of calcium through stretch-activated (SA) channels and L-type calcium channels. Depolarization by high KCl (144 mM) in the extracellular medium enhanced the amplitude of calcium transients by 54%. Calcium oscillations were not inhibited by preincubation with thapsigargin, caffeine, cholera toxin, staurosporine or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), indicating that IP3 sensitive pools, IP3 insensitive pools, GS alpha subunits, and protein kinase C, respectively, were not involved in the generation of calcium oscillations. Pretreatment with genistein, a specific tyrosine kinase inhibitor or cytochalasin D, an inhibitor of actin polymerization, or pertussis toxin, an inhibitor of Gi alpha and G(o) alpha subunits, completely abolished calcium transients and oscillations. These results indicate that Ca2+ flux due to mechanical stretching is likely mediated through SA ion channels and is dependent on tyrosine kinases, pertussis toxin-sensitive subunits of G-proteins, and actin filaments.
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PMID:Slow oscillations of free intracellular calcium ion concentration in human fibroblasts responding to mechanical stretch. 796 3

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