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Showing papers on "Tyrosine-kinase inhibitor published in 1993"


Journal ArticleDOI
TL;DR: It is suggested that increased protein tyrosine phosphorylation occurs rapidly after LPS binds to CD14 and is likely to be an important event in mediating LPS-induced cell activation.

319 citations


Journal ArticleDOI
15 Aug 1993-Blood
TL;DR: Evidence is provided that the tyrosine kinase inhibitor herbimycin A and the free radical scavenger N-acetyl-cysteine inhibit both radiation-induced and H2O2-induced activation of NF-kappa B, indicating that activation triggered by ROI is dependent on tyrosin kinase activity.

258 citations


Journal ArticleDOI
TL;DR: It is suggested that tyrosine phosphorylation is a critical signaling event that underlies Fc receptor-mediated phagocytosis in mouse macrophages, and is necessary for the engulfment per se.
Abstract: Although Fc receptor-mediated phagocytosis is accompanied by a variety of transmembrane signaling events, not all signaling events are required for particle ingestion. For example, Fc receptor-mediated phagocytosis in mouse inflammatory macrophages (Di Virgilio, F., B. C. Meyer, S. Greenberg, and S. C. Silverstein. 1988. J. Cell Biol. 106:657; Greenberg, S., J. El Khoury, F. Di Virgilio, and S. C. Silverstein. 1991. J. Cell Biol. 113:757) and neutrophils (Della Bianca, V., M. Grzeskowiak, and F. Rossi. 1990. J. Immunol. 144:1411) occurs in the absence of cytosolic calcium transients. We sought to identify transmembrane signaling events that are essential for phagocytosis. Here we show that tyrosine phosphorylation is an early event after Fc receptor ligation in mouse inflammatory macrophages, and that the formation of tyrosine phosphoproteins coincides temporally with the appearance of F-actin beneath phagocytic cups. The distribution of tyrosine phosphoproteins that accumulated beneath phagocytic cups was punctate and corresponded to areas of high ligand density on the surface of the antibody-coated red blood cells, which provided the phagocytic stimulus. A tyrosine kinase inhibitor, genistein, but not several inhibitors of protein kinase C, blocked the appearance of tyrosine phosphoproteins as assessed by immunofluorescence, the focal accumulation of F-actin beneath immunoglobulin G-opsonized particles, and the ingestion of these particles as well. We suggest that tyrosine phosphorylation is a critical signaling event that underlies Fc receptor-mediated phagocytosis in mouse macrophages, and is necessary for the engulfment per se.

201 citations


Journal ArticleDOI
TL;DR: It is found that calcium entry in HSWP (human foreskin fibroblast) cells can also be stimulated by emptying the intracellular calcium stores with thapsigargin, and genistein also inhibits the plateau phase of the thapsicargin-induced calcium response while leaving the transient phase intact.

200 citations


Journal Article
TL;DR: It is demonstrated that LPS also increases protein tyrosine phosphorylation in human monocyte-derived macrophages and in the human monocytic cell line, THP-1, and this response was rapidly elicited by biologically active forms of LPS or lipid A, at concentrations of these bacterial components that stimulate anti-bacterial responses by human Macrophages.
Abstract: Induced protein tyrosine phosphorylation is an early intracellular event in LPS-stimulated murine macrophages that appears to play a role in signal transduction. We have now demonstrated that LPS also increases protein tyrosine phosphorylation in human monocyte-derived macrophages and in the human monocytic cell line, THP-1. This response was rapidly elicited by biologically active forms of LPS or lipid A, at concentrations of these bacterial components that stimulate anti-bacterial responses by human macrophages. Inhibition of the LPS-induced tyrosine phosphorylation response with the tyrosine kinase inhibitor, herbimycin A, was accompanied by the inhibition of the secretion of TNF-alpha by human macrophages. These results extend previous work with murine macrophages and provide further support for the hypothesis that induced protein tyrosine phosphorylation is an important signaling reaction in macrophages after LPS exposure. In addition, CD14, which is thought to be a receptor for LPS, appeared to mediate the induced phosphorylation response in human macrophages and THP-1 cells at low LPS concentrations. Two antibodies against CD14, 3C10 and 60b, which have been shown to prevent LPS binding to CD14, specifically inhibited the protein tyrosine phosphorylation induced by nanogram per milliliter concentrations of LPS in these cells. The antibody-mediated inhibition did not appear to involve engagement of surface FcR because a preparation of F(ab')2/Fab fragments of the 60b antibody also prevented LPS-induced tyrosine phosphorylation. At higher concentrations of LPS (> or = 10 ng/ml), however, anti-CD14 antibodies did not prevent the induction of protein tyrosine phosphorylation, suggesting that a lower affinity CD14-independent pathway also mediates the tyrosine phosphorylation response. Because CD14-dependent and CD14-independent recognition of LPS appear to lead to the same functional responses by macrophages, induced protein tyrosine phosphorylation may be part of a shared intracellular signaling pathway.

185 citations


Journal ArticleDOI
TL;DR: The findings that the p72syk tyrosine kinase responds to H2O2 treatment of cells suggest that this kinase is likely to contribute to cellular tyosine phosphorylation and calcium signaling induced by oxidizing conditions.

163 citations


Journal ArticleDOI
15 Sep 1993-Blood
TL;DR: Findings show that p210 bcr-abl transduces proliferative signals, in part, through downstream activation of p21 RAS, which is linked to pathways that regulate c-jun and c-fos expression.

160 citations


Journal ArticleDOI
TL;DR: The toxicity of genistein, an inhibitor of tyrosine kinases and topoisomerase-II, on human thymocytes was investigated and the thymocyte subpopulation most sensitive to genisteIn-induced apoptosis exhibited a CD3-CD4+CD8+ phenotype.

118 citations


Journal ArticleDOI
TL;DR: The data suggest that pp60c-src tyrosine kinase inhibitors may be useful pharmacologic inhibitors of osteoclastic bone resorption and hypercalcemia.
Abstract: Since absence of expression of the c-src gene product in mice indicates that the pp60c-src tyrosine kinase is required and essential for osteoclastic bone resorption, we tested the effects of the antibiotic herbimycin A, which is an inhibitor of pp60c-src on osteoclastic bone resorption in vitro and on hypercalcemia in vivo. We examined the effects of herbimycin A on the formation of bone resorbing osteoclasts in mouse long-term marrow cultures, on isolated rodent osteoclasts and on bone resorption in organ cultures of fetal rat long bones stimulated by parathyroid hormone. We found that herbimycin A in concentrations of 1-100 ng/ml inhibited bone resorption in each of these systems. We determined the effects of herbimycin A (100 ng/ml) on src tyrosine kinase activity in mouse marrow cultures and found that it was decreased. Herbimycin A also decreased elevated blood calcium levels that were induced either by repeated subcutaneous injections of recombinant human interleukin-1 alpha or by a human tumor. There was no evidence for toxicity in any of these culture systems or in mice treated with herbimycin A. A different tyrosine kinase inhibitor that does not inhibit pp60c-src was used as a control and caused none of these effects. These data suggest that pp60c-src tyrosine kinase inhibitors may be useful pharmacologic inhibitors of osteoclastic bone resorption and hypercalcemia.

103 citations


Journal ArticleDOI
TL;DR: It is concluded that herbimycin A-sensitive protein tyrosine kinases are involved in the regulation of apoptosis and bcl-2 expression, but these protein tyrose kinases appear not to be required for the action of B cl-2 since Bcl-1 can exert its growth survival effect even in the presence of herbimYcin A.

97 citations


Journal ArticleDOI
TL;DR: Genistein and geldanamycin inhibited cGMP accumulation even when added 90 min after LPS exposure, but no inhibition was observed when they were included at later time points, suggesting that the inhibitors had no direct effect on iNOS activity after its induction.
Abstract: Nitric oxide (NO) formation via the expression of an endotoxin- and cytokine-inducible NO synthase (iNOS) within the vascular smooth muscle is thought to be responsible for the cardiovascular collapse that occurs during septic shock and antitumor therapy with cytokines. Because the molecular mechanisms that underlie induction of iNOS are still unclear and because tyrosine kinases are implicated in interleukin-1 beta (IL-1 beta)-induced prostaglandin synthesis in mesangial cells and in NO generation by an insulinoma cell line, we investigated the influence of tyrosine kinase inhibitors on iNOS induction in cultured rat aortic smooth muscle cells (RASMC). The production of biologically active NO was demonstrated by L-arginine-dependent guanosine 3',5'-cyclic monophosphate (cGMP) accumulation after a 3-h exposure to either IL-1 beta or lipopolysaccharide (LPS). Pretreatment of RASMC for 30 min with the tyrosine kinase inhibitor genistein prevented both IL-1 beta- and LPS-elicited cGMP accumulation in a concentration-dependent manner. Geldanamycin, a chemically different tyrosine kinase inhibitor, also blocked cGMP formation in response to both LPS and IL-1 beta at nanomolar concentrations. Genistein and geldanamycin inhibited cGMP accumulation even when added 90 min after LPS exposure, but no inhibition was observed when they were included at later time points (120-180 min), suggesting that the inhibitors had no direct effect on iNOS activity after its induction. Formation of cGMP in response to sodium nitroprusside and to NO released from bovine aortic endothelial cells remained virtually unaffected by genistein and geldanamycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal ArticleDOI
TL;DR: Results suggest that compounds that inhibit the ras-dependent elevation in the level of tyrosine phosphorylated proteins may prove to be useful chemotherapeutic agents and may exhibit selective cytotoxicity against cancer cells with an activated ras oncogene.

Journal ArticleDOI
TL;DR: Results show that vanadate-induced contraction of smooth muscle is probably coupled to enhanced protein tyrosine phosphorylation, and suggest that tyrosines may participate in Ca(2+)-dependent signalling mechanisms which regulate contraction of Smooth muscle.

Journal ArticleDOI
TL;DR: The results provide the first evidence for a direct or indirect regulation of PtdIns(3,4)P2 accumulation and PLC gamma 1 activity by tyrosine phosphorylation during thrombin stimulation of human platelets.
Abstract: In this study we have examined the implication of tyrosine kinase activities in aggregation, 5-hydroxytryptamine secretion and mainly phosphoinositide metabolism in response to human platelet stimulation by thrombin. Using the potent tyrosine kinase inhibitor tyrphostin AG-213, we have observed a significant inhibition of aggregation and 5-hydroxytryptamine release; however, this percentage inhibition was lower at high thrombin concentrations. On the other hand, tyrphostin treatment of metabolically 32P-labelled platelets significantly inhibited the thrombin-dependent accumulation of PtdIns(3,4)P2, which involves at least a PtdIns 3-kinase and/or a PtdIns3P 4-kinase, whereas the synthesis of phosphatidic acid (PtdOH), a good reflection of the phospholipase C (PLC) activation in platelets, was partially blocked. Inositol phosphate production was also inhibited by about 40% when tyrphostin-treated platelets were stimulated with thrombin. In addition, we show by Western-blot analysis that PLC gamma 1, as well as the regulatory subunit (p85) of the PtdIns 3-kinase, were present in the anti-phosphotyrosine immunoprecipitate isolated from thrombin-stimulated platelets. Furthermore, tyrphostin treatment clearly decreased the PLC gamma 1 and p85 contents in such an anti-phosphotyrosine immunoprecipitate. Our results provide the first evidence for a direct or indirect regulation of PtdIns(3,4)P2 accumulation and PLC gamma 1 activity by tyrosine phosphorylation during thrombin stimulation of human platelets.

Journal ArticleDOI
TL;DR: The results suggest that growth stimulation of MCF‐7 cells by IGF‐I is accompanied by tyrosine phosphorylation and nuclear exclusion of p53.
Abstract: Human breast cancer MCF-7 cells, growth-arrested by serum starvation, were stimulated with recombinant human insulin-like growth factor-I (IGF-I). An increase in DNA synthesis was induced 20 hr later, which was as effective as that induced by serum. The increase in DNA synthesis was significantly inhibited either by antibody to the IGF-I receptor or by the tyrosine kinase inhibitor, methyl-2,5-dihydroxycinnamate (2,5-MeC). The IGF-I-induced DNA synthesis coincided with an elevated level of phosphorylation of p53 on tyrosine and an alteration in the subcellular distribution of the protein from the nucleus to the cytoplasm. Whereas the increases in DNA synthesis and p53 phosphorylation were inhibited by antibody to the IGF-I receptor and by 2,5-Mec, the nuclear exclusion of p53 was prevented by the antibody and also, although not significantly, by 2,5-Mec. The results suggest that growth stimulation of MCF-7 cells by IGF-I is accompanied by tyrosine phosphorylation and nuclear exclusion of p53.

Journal ArticleDOI
TL;DR: Genistein, a tyrosine kinase inhibitor, had no or only slight inhibitory effects on platelet aggregation or serotonin release induced by thrombin, while intracellular Ca2+ concentration ([Ca2+]i) elevation was substantially attenuated as discussed by the authors.

Journal ArticleDOI
TL;DR: It is proposed that in contrast to CD3/Ti stimulation, UV aberrantly triggers lymphocyte signal transduction pathways by a mechanism that bypasses normal receptor control.
Abstract: UV radiation is known to induce lymphocyte nonresponsiveness both in vitro and in vivo. We have found that UV radiation rapidly induced tyrosine phosphorylation and calcium signaling in normal human peripheral blood lymphocytes. In the leukemic T cell line Jurkat and the Burkitt's lymphoma cell line Ramos, UV rapidly induced tyrosine phosphorylation in a wavelength-dependent manner, giving strong signals after UVB and UVC, but not UVA, irradiation. Similarly, in Jurkat cells UV-induced calcium signals were dependent on the dose of UVB or UVC irradiation over a range of 150-1200 J/m2, but only a small signal was observed for UVA at a dose of 1200 J/m2. The UV-induced calcium signals were blocked by the tyrosine kinase inhibitor herbimycin A, indicating that they were dependent on tyrosine phosphorylation. Phospholipase C (PLC) gamma 1 was tyrosine phosphorylated in response to UV irradiation but to a lesser extent than observed after CD3 cross-linking. However, PLC gamma 1-associated proteins demonstrated to bind to the PLC gamma 1 SH2 domain were tyrosine phosphorylated strongly after UV irradiation. A similar dose response was observed for the inhibition by herbimycin A of UV-induced calcium signals and UV-induced tyrosine phosphorylation of PLC gamma 1 and associated proteins. We propose that in contrast to CD3/Ti stimulation, UV aberrantly triggers lymphocyte signal transduction pathways by a mechanism that bypasses normal receptor control.

Journal ArticleDOI
TL;DR: The results suggests that PLC gamma in normal hepatocytes was activated by HGF through tyrosine kinase of HGF receptor, and in human hepatocarcinoma HepG2 cells, HGF, which suppresses cell growth, causes neither phosphorylation of PLC Gamma nor InsP3 formation.

Journal ArticleDOI
TL;DR: The results show that the IL-6/IL-6-R system-induced signal transduction pathway in the placenta probably stimulates hCG production by activating a tyrosine kinase pathway.
Abstract: Interleukin-6 (IL-6) may play an important role in human CG (hCG) production by activating the IL-6-receptor (-R) system on human trophoblasts. Trophoblasts produced hCG in response to rIL-6 as well as to 8-bromo cAMP (8-Br-cAMP), 12-O-tetradecanoyl phorbol-13-acetate (TPA), and calcium ionophore A23187. To determine whether the signal transduction pathway activated by the IL-6-R system depends on protein kinases such as protein kinase A, protein kinase C, and Ca2+/calmodulin-dependent kinase, trophoblasts were stimulated with recombinant (r-) IL-6 in the presence or absence of protein kinase inhibitors such as N(2-methyl-aminoethyl)-5-isoquinoline sulfonamide dihydrochloride (H8), and 1-(5-isoquinolinesulfomyl)-2-methylpiperazine (H7) and a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1- napthalenesulfonamide (W7), H8, H7, and W7 failed to suppress rIL-6-induced hCG production but completely inhibited hCG production induced by 8-Br-cAMP, TPA, and the GnRH agonist (GnRHa), respectively. In contrast, genistein, a tyrosine kinase inhibitor, completely suppressed rIL-6-induced hCG production but failed to inhibit hCG production induced by 8-Br-cAMP, TPA, and A23187. Genistein also did not suppress GnRH-induced hCG production. The addition of genistein to rIL-1- and rTNF-alpha-stimulated trophoblasts inhibited rIL-1-induced and rTNF-alpha induced hCG production but maintained rIL-1- and rTNF-alpha-induced IL-6 production. These results show that the IL-6/IL-6-R system-induced signal transduction pathway in the placenta probably stimulates hCG production by activating a tyrosine kinase pathway. The experiment with genistein shows that the GnRH/GnRH-R system activates a signal transduction pathway distinct from that activated by the IL-6/IL-6-R system.

Journal ArticleDOI
TL;DR: In the course of a screening program for tyrosine kinase inhibitors, the chloroform extract of a tropical plant, Desmos chinensis, strongly inhibited the enzyme activity, and the active substance was purified by silica gel, gel filtration, and finally crystallized.

Journal Article
TL;DR: A specific tyrosine kinase inhibitor, methyl 2,5-dihydroxycinnamate (mDHC), has been used to investigate the role of tyrosines in monosodium urate monohydrate and calcium pyrophosphate dihydrate (CPPD) crystal-induced neutrophil activation.
Abstract: A specific tyrosine kinase inhibitor, methyl 2,5-dihydroxycinnamate (mDHC), has been used to investigate the role of tyrosine kinases in monosodium urate monohydrate and calcium pyrophosphate dihydrate (CPPD) crystal-induced neutrophil activation. Both uncoated and plasma protein-coated CPPD crystals increased protein tyrosine phosphorylation in human neutrophils. Neutrophils pretreated with mDHC or control neutrophils were stimulated by plasma-opsonized CPPD, uncoated CPPD, or uncoated monosodium urate monohydrate, and chemiluminescence, superoxide generation, intracellular calcium concentration, degranulation (myeloperoxidase and lysozyme release), and protein tyrosine phosphorylation were monitored. mDHC strongly inhibited all neutrophil responses and tyrosine phosphorylation was reduced to the basal levels seen in control unstimulated neutrophils. The possible role of tyrosine kinases in the regulation of crystal-induced neutrophil activation is discussed.

Journal ArticleDOI
TL;DR: The results with tyrosine kinase inhibitors support the concept that multiple tyrosin kinases participate in the Fc epsilon RI-dependent signal transduction process, suggesting that these agents share similar loci of action.

Journal ArticleDOI
Toru Takano1, K. Takada1, Hisato Tada1, S. Nishiyama1, Nobuyuki Amino1 
TL;DR: Data demonstrate that the signal transduction pathway induced by BAY K8644 or IGF-I may possibly involve genistein-sensitive process at the downstream step of Ca2+ entry.

Journal ArticleDOI
TL;DR: In rabbit aorta RG50864 is an inhibitor of EGF-induced vasoconstriction; this inhibitory effect does not appear to be mediated through inhibition of E GF-receptor autophosphorylation but may involve a 55 kD cytosolic protein substrate.

Journal Article
TL;DR: The results indicate that the stable analogues of erbstatin suppress oncogene functions of Abl by inhibiting its tyrosine kinase.
Abstract: The authors examined the effect of a tyrosine kinase inhibitor, erbstatin, and its analogues on abl oncogene functions. Erbstatin and its stable analogue methyl 2,5-dihydroxycinnamate (2,5-MeC) inhibited the growth of v-ablts-NIH3T3 cells at the permissive temperature (33 degrees C) at lower concentrations than at the non-permissive temperature (39 degrees C). 2,5-MeC inhibited the morphological transformation and the activation of v-abl tyrosine kinase by the temperature shift (39 degrees C to 33 degrees C) more effectively than erbstatin. Previously the authors reported that erbstatin induced erythroid differentiation of K562 human chronic myelogenous leukaemia cells, so they examined the effect of erbstatin analogues on the erythroid differentiation. Among eight erbstatin analogues studied, ethyl 2,5-dihydroxycinnamate induced erythroid differentiation of K562 cells most effectively. Ethyl 2,5-dihydroxycinnamate also inhibited bcr-abl tyrosine kinase. These results indicate that the stable analogues of erbstatin suppress oncogene functions of Abl by inhibiting its tyrosine kinase.

Journal ArticleDOI
T. Koike1, T. Mizutani1, K. Hirai1, Y. Morita1, Yoshinori Nozawa1 
TL;DR: Results indicate that 1,2-DG generated via the phospholipase D pathway activated by tyrosine phosphorylation is a principle source for AA released in response to SCF in mast cells.

Journal Article
TL;DR: Treatment with tetradecanoyl phorbol acetate (TPA), a potent activator of protein kinase C (PKC), in combination with IL-7 induced a level of c-myc expression greater than that elicited by either factor alone, suggesting that TPA andIL-7 utilize cooperative signaling pathways to increase c- myc gene expression.

Journal ArticleDOI
TL;DR: Inhibition of angiogenesis was determined in a bioassay system involving chorioallantoic membranes of growing chick embryos and data indicate that erbstatin-sensitive tyrosine kinase(s) is involved in angiogenic endothelial cell proliferation, and that experiments involving erbStatin will provide an important due to understand a mechanism of ang iogenesis.
Abstract: Here we describe the inhibitory effect of erbstatin, a specific tyrosine kinase inhibitor, on in vivo angiogenesis. Inhibition of angiogenesis was determined in a bioassay system involving chorioallantoic membranes of growing chick embryos. Erbstatin produced a dose-dependent inhibitory action on embryonic angiogenesis. This inhibition occurred at as small a dose as 10 ng/egg and the ID50 value was 80 ng/egg. To analyze this inhibition, in vitro experiments involving vascular endothelial cells were also performed. Erbstatin affected the proliferation of vascular endothelial cells, one of angiogenic components. This inhibition was dose-dependent, the IC50 value being 3.6 microM. These data indicate that erbstatin-sensitive tyrosine kinase(s) is involved in angiogenic endothelial cell proliferation, and that experiments involving erbstatin will provide an important due to understand a mechanism of angiogenesis.

Journal ArticleDOI
TL;DR: Genistein inhibited PHA-stimulated bovine peripheral blood mononuclear cell proliferation, interleukin-2 (IL-2) production, phosphorylation of PTK p56lck, and inhibited leukotriene B4 production from A-23187 stimulated cultures, suggesting that the PTK plays an important role in the signal transduction of bovines PBMC proliferation.

Journal ArticleDOI
TL;DR: A role for tyrosine kinases in regulation of cellular events by GM-CSF in monoblasts is supported using anti-phosphotyrosine monoclonal antibody and autoradiography.