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)

Several cAMP-elevating agents such as cholera toxin (CT), forskolin and 3-isobutyl-1-methylxanthine (IBMX) exhibited weak mitogenic activity on bovine undifferentiated mammary epithelial cells in three-dimensional collagen culture. CT and IBMX strongly synergized with epidermal growth factor (EGF), insulin-like growth factor I (IGF-I) or both, but not with 10% fetal calf serum (FCS). Permeable cAMP analogs also synergized with IGF-I. Other hormones such as ovine prolactin, bovine growth hormone, estrogen or progesterone were not mitogenic and not synergistic with EGF, IGF-I, CT and FCS. Pertussis toxin (PT) reduced the DNA synthesis in cells cultured in the basal medium and attenuated 40-90% of the mitogenic activity stimulated by 10% FCS. PT inhibition of DNA synthesis was accompanied by ADP-ribosylation of 40 kDa and 41 kDa membrane proteins. The 41 kDa protein cross-reacted with antibodies that recognize the Gi-protein of the adenylate cyclase system, indicating the involvement of the latter in the mitogenic process. The nature of the second protein remains unknown. The present results suggest that the mitogenesis of normal mammary epithelial cells which is stimulated by IGF-I, EGF and other factors found in FCS is mediated through both cAMP-dependent and independent pathways. These pathways include PT-sensitive GTP-binding proteins.
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PMID:Proliferation of bovine undifferentiated mammary epithelial cells in vitro is modulated by G-proteins. 169 21

Recent data have shown that pretreatment of bovine adrenal fasciculata cells with insulin-like growth factor I (IGF-I) or insulin enhances the steroidogenic response to angiotensin II (A-II). In the present work we have studied the effects of both peptides on the first steps of the mechanism of action of A-II and on the amounts of pertussis toxin (PT)-sensitive guanine nucleotide binding proteins (Gi proteins). Both peptides increased A-II-induced phosphoinositide breakdown without modification of either A-II-induced Ca2+ uptake or the A-II-potentiating effect on ACTH-induced cAMP production. The effects of IGF-I at a nanomolar concentration were higher than those induced by insulin at a micromolar concentration, which in turn was higher than those induced by a nanomolar concentration of this peptide. Treatment of cells with pertussis toxin (0.5 microgram/ml) for 24 h reduced by 25% of the A-II-induced phosphoinositide breakdown in control cells and 32% and 28% in cells pretreated with insulin at nanomolar and micromolar concentrations, respectively, but had no significant effect in cells pretreated with IGF-I. No effect of pertussis toxin was observed on A-II-induced Ca2+ uptake or on its potentiating action on ACTH-induced cAMP production. Moreover, both IGF-I and insulin enhanced the amounts of Gi protein(s) evaluated by pertussis toxin ADP-ribosylation or immunoblotting. Again, the effects of insulin at nanomolar concentrations were lower than those induced by the same concentrations of IGF-I or insulin at micromolar concentrations. These results suggest that, in bovine adrenal fasciculata cells, A-II receptors are coupled to the phosphoinositide pathway through pertussis toxin sensitive and insensitive Gp protein(s). Moreover, the findings also indicate that the enhanced A-II responsiveness of IGF-I or insulin treated cells is in part mediated through an increase in the amount of G protein(s).
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PMID:Stimulatory effect of insulin and insulin-like growth factor I on Gi proteins and angiotensin-II-induced phosphoinositide breakdown in cultured bovine adrenal cells. 215 69

Polymorphonuclear neutrophils (PMNs) were isolated from human blood, and PMN phagocytosis was assessed by measuring the chemiluminescence (CL) response in the presence of ZAP (opsonized zymosin particles containing luminol). The administration of 6.5 nM of insulin-like growth factor I (IGF-I), des(1-3)-IGF-I, IGF-II or insulin to PMNs for 20 min resulted in significant increases of the CL response for all test preparations. Des(1-3)-IGF-I, a truncated IGF-I with low affinity binding to IGF binding proteins (IGFBPs), was the most potent CL stimulator. The CL production evoked by 6.5 nM of des(1-3)-IGF-I was inhibited significantly by both 0.25 and 1.0 nM of EGTA (Ca2+ chelator), or 10 microM nifedipine (Ca2+ channel inhibitor), pertussis toxin (0.05 and 1.0 micrograms/ml) or cholera toxin (5 micrograms/ml). These results suggest that IGF-I and its homologues are potent stimulators of phagocytosis and that this action is modulated by IGFBP, and may require extracellular Ca2+ and/or IGF-I receptor G-protein coupling.
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PMID:Insulin-like growth factors enhance phagocytosis by human neutrophils in vitro. 813 15

We compared the effects of insulin-like growth factor I (IGF-I) and II (IGF-II) on DNA synthesis and proliferation and investigated various signal transduction mechanisms involved in insulin-like growth factor-induced mitogenesis in primary cultures of adult rat hepatocytes. IGF-I stimulated hepatocyte DNA synthesis and proliferation with an EC50 of 75 ng/ml within 4 h of culture. These effects were sensitive to the IGF-I concentration and cell density. Hepatocyte proliferation induced by IGF-I was potentiated by metaproterenol (10(-6) M) as well as by 8-bromo-cAMP, phorbol 12-myristate 13-acetate (PMA; 10(-8) M) and was inhibited by U-73122 (1-(-[[17beta-3-methoxyestra-1,3,5(10)-triene-17-yl]amino]hexyl]-+ ++1Hpyrrol-2,5-dione)), genistein, wortmannin, PD98059 (2'-amino-3'-methoxyflavone) and rapamycin. The IGF-I effect was independent of pertussis toxin (100 ng/ml). IGF-II also dose dependently stimulated hepatocyte DNA synthesis and proliferation with an EC50 of 0.75 ng/ml within 4 h of culture. However, these effects were not dependent on the initial plating density. The stimulatory effects of IGF-II were potentiated by UK-14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline) (10(-5) M) and inhibited by phenylephrine, PMA, metaproterenol, 8-bromo-cAMP, PD98059, rapamycin, and pertussis toxin. The IGF-II effects were not affected by genistein, U-73122, and wortmannin. These results suggest that IGF-I and IGF-II rapidly stimulate the DNA synthesis and proliferation of adult rat hepatocytes by separate mechanisms.
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PMID:Effects of insulin-like growth factor I and II on DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. 975 29

Glucocorticoid hormones influence manifold neuronal processes including learning, memory, and emotion via the glucocorticoid receptor (GR). Catecholamines further modulate these functions, although the underlying molecular mechanisms are poorly understood. Here, we show that epinephrine and norepinephrine potentiate ligand-dependent GR transactivation in a hippocampal cell line (HT22) via beta(2)-adrenergic receptors. This enhancement was strongest at low concentrations of glucocorticoids and was accompanied by increased GR binding to a glucocorticoid-responsive element (GRE). beta(2)-Adrenergic receptor-mediated GR enhancement was relayed via G protein beta gamma-subunits, insensitive to pertussis toxin and independent of protein kinase A (PKA). In contrast, the catecholamine-evoked GR enhancement was strongly reduced by wortmannin, suggesting a critical role for phosphoinositide 3-kinase (PI3-K). In agreement, epinephrine directly activated PI3-K in vivo. Similarly, stimulation of tyrosine kinase receptors coupled to PI3-K activation, e.g. receptors for insulin-like growth factor I (IGF-I) or fibroblast growth factor (FGF), increased GR transactivation. Further analysis indicated that G protein-coupled receptor (GPCR) and tyrosine kinase receptor signals converge on PI3-K through separate mechanisms. Blockade of GR enhancement by wortmannin was partially overcome by expression of the downstream-acting protein kinase B (PKB/Akt). Collectively, our findings demonstrate that GPCRs can regulate GR transactivation by stimulating PI3-K. This novel cross-talk may provide new insights into the molecular processes of learning and memory and the treatment of stress-related disorders.
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PMID:Beta(2)-adrenergic receptors potentiate glucocorticoid receptor transactivation via G protein beta gamma-subunits and the phosphoinositide 3-kinase pathway. 1126 7

We examined the role of heterotrimeric G protein signaling components in insulin and insulin-like growth factor I (IGF-I) action. In HIRcB cells and in 3T3L1 adipocytes, treatment with the Galpha(i) inhibitor (pertussis toxin) or microinjection of the Gbetagamma inhibitor (glutathione S-transferase-betaARK) inhibited IGF-I and lysophosphatidic acid-stimulated mitogenesis but had no effect on epidermal growth factor (EGF) or insulin action. In basal state, Galpha(i) and Gbeta were associated with the IGF-I receptor (IGF-IR), and after ligand stimulation the association of IGF-IR with Galpha(i) increased concomitantly with a decrease in Gbeta association. No association of Galpha(i) was found with either the insulin or EGF receptor. Microinjection of anti-beta-arrestin-1 antibody specifically inhibited IGF-I mitogenic action but had no effect on EGF or insulin action. beta-Arrestin-1 was associated with the receptors for IGF-I, insulin, and EGF in a ligand-dependent manner. We demonstrated that Galpha(i), betagamma subunits, and beta-arrestin-1 all play a critical role in IGF-I mitogenic signaling. In contrast, neither metabolic, such as GLUT4 translocation, nor mitogenic signaling by insulin is dependent on these protein components. These results suggest that insulin receptors and IGF-IRs can function as G protein-coupled receptors and engage different G protein partners for downstream signaling.
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PMID:Insulin and insulin-like growth factor I receptors utilize different G protein signaling components. 1127 73

Amyloid precursor protein (AbetaPP), a precursor of amyloid beta (Abeta) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AbetaPP have been found in patients inheriting familial AD (FAD). These mutant AbetaPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AbetaPP mutant, V642I-AbetaPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AbetaPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AbetaPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AbetaPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Abeta does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AbetaPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AbetaPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AbetaPP and the artificial dimerization of cytoplasmic domain of AbetaPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.
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PMID:Characterization of V642I-AbetaPP-induced cytotoxicity in primary neurons. 1519 38