Showing papers on "Tyrosine-kinase inhibitor published in 1996"
TL;DR: A significant post-transcriptional component to the regulation of VEGF is demonstrated, which demonstrates a discrepancy between the transcription rate and the steady-state mRNA level induced by hypoxia.
672 citations
Journal Article•
TL;DR: Findings show that in subconfluent Caco-2 cells, the estradiol-receptor complex activates the c-src, c-yes/MAP kinase pathway and activates growth, which could have important implications for the understanding of human intestinal carcinogenesis.
Abstract: This is the first report on estrogen-dependent growth of human-derived colon carcinoma cells. Under selected conditions, growth of subconfluent Caco-2 cells is triggered by estradiol. Cell growth is estradiol concentration dependent, with maximal effect occurring at about 0.4 nM. Growth is prevented by two different antiestrogens: the partial agonist, OH-Tamoxifen, and the pore antagonist, ICI 182,780. The growth effect is specific for estradiol since other hormonal steroids tested do not affect cell growth. The amount of estradiol receptor in subconfluent Caco-2 cells, detected by blot with monoclonal antibodies directed against the receptor as well as estradiol binding assays, is similar to that of the classical estradiol-responsive, human mammary cancer-derived MCF-7 cells. Estradiol treatment of subconfluent Caco-2 cells rapidly and reversibly stimulates four important intermediates in a signal transduction pathway that is known to trigger cell proliferation: two members of the large family of c-src-related tyrosine kinases, c-src and c-yes, and two serine/threonine kinases, the mitogen-activated protein (MAP) kinases, erk-1 and erk-2. Tyrosine kinases activated by estradiol are up-stream MAP kinases and Caco-2 cell proliferation. In fact, genistein, a specific tyrosine kinase inhibitor, abolishes the estradiol stimulatory effect on both erk-2 activity and cell proliferation. Our findings show that in subconfluent Caco-2 cells, the estradiol-receptor complex activates the c-src, c-yes/MAP kinase pathway and activates growth. This could have important implications for the understanding of human intestinal carcinogenesis.
176 citations
TL;DR: The data indicate that the isoflavone inhibitor genistein suppresses osteoclastic activity in vitro and in vivo at concentrations consistent with its ID50s on tyrosine kinases, with a low potential for toxicity.
Abstract: We compared the effects of the tyrosine kinase inhibitor genistein, a naturally occurring isoflavone, to those of tyrphostin A25, tyrphostin A47, and herbimycin on avian osteoclasts in vitro. Inactive analogs daidzein and tyrphostin A1 were used to control for nonspecific effects. None of the tyrosine kinase inhibitors inhibited bone attachment. However, bone resorption was inhibited by genistein and herbimycin with ID50s of 3 μM and 0.1 μM, respectively; tyrphostins and daidzein were inactive at concentrations below 30 μM, where nonspecific effects were noted. Genistein and herbimycin thus inhibit osteoclastic activity via a mechanism independent of cellular attachment, and at doses approximating those inhibiting tyrosine kinase autophosphorylation in vitro; the tyrphostins were inactive at meaningful doses. Because tyrosine kinase inhibitors vary widely in activity spectrum, effects of genistein on cellular metabolic processes were compared to herbimycin. Unlike previously reported osteoclast metabolic inhibitors which achieve a measure of selectivity by concentrating on bone, neither genistein nor herbimycin bound significantly to bone. Osteoclastic protein synthesis, measured as incorporation of 3H-leucine, was significantly inhibited at 10 μM genistein, a concentration greater than that inhibiting bone degradation, while herbimycin reduced protein synthesis at 10 nM. These data suggested that genistein may reduce osteoclastic activity at pharmacologically attainable levels, and that toxic potential was lower than that of herbimycin. To test this hypothesis in a mammalian system, bone mass was measured in 200 g ovariectomized rats treated with 44 μmol/day genistein, relative to untreated controls. During 30 d of treatment, weights of treated and control group animals were indistinguishable, indicating no toxicity, but femoral weight in the treated group was 12% greater than controls (P < 0.05). Our data indicate that the isoflavone inhibitor genistein suppresses osteoclastic activity in vitro and in vivo at concentrations consistent with its ID50s on tyrosine kinases, with a low potential for toxicity. © 1996 Wiley-Liss, Inc.
163 citations
TL;DR: It is demonstrated that cyclic strain induced tyrosine phosphorylation and reorganization of pp125FAK and paxillin and suggested that these focal adhesion proteins play a specific role in cyclic strains-induced morphological change and migration.
Abstract: The objective of this study was to determine whether focal adhesion proteins pp125FAK (focal adhesion kinase) and paxillin are phosphorylated on tyrosine and might play a role in the morphological change and cell migration induced by strain. Bovine aortic endothelial cells (EC) were subjected to 10% average strain at 60 cycles/min. Cyclic strain increased the tyrosine phosphorylation of pp125FAK at 30 min (3.4-fold) and 4 h (5.9-fold) and the tyrosine phosphorylation of paxillin at 4 h (2.0-fold). Confocal microscopy showed that, after 4-h exposure to strain, EC began to elongate and F-actin, pp125FAK, and paxillin aligned, although they randomly distributed in static condition. Tyrosine kinase inhibitor tyrphostin A25 (100 microM) inhibited not only the tyrosine phosphorylation of pp125FAK and paxillin but also the redistribution of pp125FAK and paxillin, morphological change, and migration of EC induced by strain. These data demonstrate that cyclic strain induced tyrosine phosphorylation and reorganization of pp125FAK and paxillin and suggest that these focal adhesion proteins play a specific role in cyclic strain-induced morphological change and migration.
143 citations
TL;DR: Results indicate that NMDA channel activity is reduced by a protein tyrosine phosphatase associated with the channel complex, and this decline is not dependent upon Ca2+.
Abstract: Regulation of ion channel function by intracellular processes is fundamental for controlling synaptic signaling and integration in the nervous system. Currents mediated by N-methyl-D-aspartate (NMDA) receptors decline during whole-cell recordings and this may be prevented by ATP. We show here that phosphorylation is necessary to maintain NMDA currents and that the decline is not dependent upon Ca2+. A protein tyrosine phosphatase or a peptide inhibitor of protein tyrosine kinase applied intracellularly caused a decrease in NMDA currents even when ATP was included. On the other hand, pretreating the neurons with a membrane-permeant tyrosine kinase inhibitor occluded the decline in NMDA currents when ATP was omitted. In inside-out patches, applying a protein tyrosine phosphatase to the cytoplasmic face of the patch caused a decrease in probability of opening of NMDA channels. Conversely, open probability was increased by a protein tyrosine phosphatase inhibitor. These results indicate that NMDA channel activity is reduced by a protein tyrosine phosphatase associated with the channel complex.
138 citations
Journal Article•
TL;DR: Although AG 1478 inhibited cell growth, DNA synthesis, EGFR tyrosine kinase activity, and receptor autophosphorylation of each cell line in a dose-dependent manner, it was significantly more potent in U87MG.
Abstract: The effects of a new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, tyrphostin AG 1478, were tested on three related human glioma cell lines: U87MG, which expressed endogenous wild-type (wt) EGFR, and two retrovirally infected U87MG cell populations which over-expressed either wt (U87MG.wtEGFR) or truncated EGFR (U87MG. delta EGFR). Although AG 1478 inhibited cell growth, DNA synthesis, EGFR tyrosine kinase activity, and receptor autophosphorylation of each cell line in a dose-dependent manner, it was significantly more potent in U87MG. delta EGFR cells than in the other two cell lines. The increased inhibitory response of U87MG. delta EGFR cells was due to a greater sensitivity of the constitutively autophosphorylated Mr 140,000 and 155,000 delta EGFR species to AG 1478. These results suggest that AG 1478 is a relatively specific inhibitor of the delta EGFR, and this finding may have important therapeutic implications since the delta EGFR occurs frequently in glioblastomas and in breast, lung, and ovarian cancers.
134 citations
Journal Article•
TL;DR: Results indicate that tyrosine kinase activity is required for the chemoresistant phenotype of HER-2/neu-overexpressing NSCLC cells and that tyrose kinase inhibitors such as emodin can sensitize these cells to chemotherapeutic drugs.
Abstract: Overexpression of the HER-2/neu proto-oncogene which encodes tyrosine kinase receptor p185neu, has been observed frequently in many human cancers, including non-small cell lung cancer (NSCLC), and is correlated with poor patient survival in these cancers. In addition, HER-2/neu overexpression in NSCLC is known to induce chemoresistance. Recently, we demonstrated that emodin, a tyrosine kinase inhibitor, suppresses HER-2/neu tyrosine kinase activity in HER-2/neu-overexpressing breast cancer cells and preferentially represses proliferation of these cells. The work described here was carried out to examine (1) whether the tyrosine kinase activity of p185neu is required for resistance to chemotherapeutic drugs of HER-2/neu-overexpressing NSCLC cells and (2) whether the tyrosine kinase inhibitor emodin can sensitize these cells to chemotherapeutic drugs. We found that emodin decreased tyrosine phosphorylation of HER-2/neu and preferentially suppressed proliferation of HER-2/neu-overexpressing NSCLC cells. Furthermore, the combination of emodin with cisplatin, doxorubicin or etoposide (VP16) synergistically inhibited the proliferation of HER-2/neu-overexpressing lung cancer cells, whereas low doses of emodin, cisplatin, doxorubicin, or VP16 alone had only minimal antiproliferative effects on these cells. These results indicate that tyrosine kinase activity is required for the chemoresistant phenotype of HER-2/neu-overexpressing NSCLC cells and that tyrosine kinase inhibitors such as emodin can sensitize these cells to chemotherapeutic drugs. The results may have important implications in chemotherapy for HER-2/neu-overexpressing cancers.
130 citations
TL;DR: Tyrosine phosphorylation-dependent association of eNOS with the cytoskeleton may have a role in targeting NO production to specific subcellular locations.
121 citations
TL;DR: The results indicate the possibility of a pharmacological approach to HSP70 induction and cardiac protection, and suggest that herbimycin-A may induce 70-kD hsp's via a tyrosine kinase-independent mechanism.
Abstract: Heat shock protein (hsp) induction by stressful stimuli such as heat and ischemia is known to protect cardiac cells from severe stress. The ability to induce hsp's in the heart directly by "nonstressful" means would potentially have important clinical implications. In noncardiac cells, the tyrosine kinase inhibitor herbimycin-A has been shown to induce the 72-kD hsp. We therefore examined whether herbimycin-A and another tyrosine kinase inhibitor, genistein, could induce 70-kD hsp's in primary cultures of rat neonatal cardiomyocytes, and whether these treatments protect against severe stress. Primary cardiomyocytes were incubated with herbimycin-A or genistein. hsp induction was measured 16-20 h later by Western blotting. Cell survival after subsequent lethal heat stress or simulated ischemia was assessed using trypan blue exclusion and released lactate dehydrogenase activity. Our results indicate that, in cardiac cells, herbimycin-A induces 70-kD hsp's but not hsp90, -60, -25, or glucose-regulated protein 78, whereas genistein has no effect on hsp's. Moreover, hsp induction correlated with the ability of herbimycin-A to protect cells against severe stress, whereas genistein has no protective effects. This suggests that herbimycin-A may induce 70-kD hsp's via a tyrosine kinase-independent mechanism. These results indicate the possibility of a pharmacological approach to HSP70 induction and cardiac protection, which may ultimately be of clinical relevance.
107 citations
Journal Article•
TL;DR: Tyrphostin AG825 can enhance chemosensitivity in high- but not in low-p185(neu) expressing NSCLC cell lines, and this differential effect cannot be explained by the alterations of drug-induced cell cycle changes by AG825.
Abstract: The HER-2/neu gene product, p185neu, is a membrane-bound receptor with tyrosine kinase activity High levels of p185neu is correlated with intrinsic chemoresistance of non-small cell lung cancer (NSCLC) cell lines We investigated the effects of tyrphostin AG825, a selective tyrosine kinase inhibitor preferentially inhibiting HER-2/neu kinase, on the chemosensitivities and on the drug-induced cell cycle changes of NSCLC cell lines that expressed different levels of p185neu Compared to the low-p185neu expressing cell lines, we found that the high-p185neu expressing cell lines were more resistant to doxorubicin, etoposide, and cis -diamminedichloroplatinum(II) but more sensitive to AG825 AG825 was able to significantly enhance the chemosensitivities of the high-p185neu expressing cell lines, whereas it had little effect on the chemosensitivities of the low-p185neu expressing cells, with a few exceptions in which minor antagonistic effects were observed Although high concentrations of AG825 could reduce the drug-induced G2 arrest that was accompanied by the activation of phosphorylated p34cdc2, we failed to find any remarkably differential effects of AG825 on drug-induced G2 arrest and the accompanying phosphorylation status of p34cdc2 of the high- and the low-p185neu expressing cell lines In summary, tyrphostin AG825 can enhance chemosensitivity in high- but not in low-p185neu expressing NSCLC cell lines This differential effect cannot be explained by the alterations of drug-induced cell cycle changes by AG825 Our results provide a rationale to develop p185neu-specific tyrphostin and to test them in combination with anticancer agents in vivo and in clinical trials
99 citations
TL;DR: The effects of GM3 on cell growth and signaling are determined and it is suggested that this ganglioside does not act directly on the intracellular intermediates of EGF receptor signaling, and soluble small molecule tyrosine kinase inhibitors such as leflunomide can directly affect the activity of MAP kinases and possibly other signaling intermediates.
Abstract: Ganglioside GM3 is a membrane component that has been described to modulate cell growth through inhibition of EGF receptor associated tyrosine kinase. In order to determine if the inhibition of cell growth by this ganglioside is specifically mediated through EGF receptor signaling, the effects of GM3 on key enzymes implicated in EGF signaling were determined and compared to another inhibitor of the EGF receptor kinase. Treatment of A IS cells in culture by GM3 or a tyrosine kinase inhibitor, leflunomide, led to the inhibition of MAP kinase and PI3 kinase activities. There was no detectable effect on phosphotyrosi ne phosphatases. In a cell free system, however, GM3 had no effect on the activity of these signaling intermediates. Leflunomide was able to directly inhibit MAP kinase activity. GM3 and leflunomide were also found to act differently on the expression of the early immediate genes. The expression of c-fos and c-jun was inhibited by both GM3 and leflunomide. The expression of c-myc, however, was only inhibited by leflunomide. These findings suggest that the action of GM3 on cell growth and signaling is specifically mediated by EGF receptor and that this ganglioside does not act directly on the intracellular intermediates of EGF receptor signaling. In addition, soluble small molecule tyrosine kinase inhibitors such as leflunomide can directly affect the activity of MAP kinases and possibly other signaling intermediates. The direct effects of leflunomide on signaling intermediates may explain the differential effects of leflunomide and GM3 on gene expression and cell growth.
TL;DR: A non‐hematopoietic action of rHuEpo is demonstrated showing both mitogenic and enzymatic effect upon primary myocyte cell culture and on pNPPase activity of neonatal rat heart, indicating that in the r HuEpo mediated mitogenic action on cardiomyocytes involves the activation of the same enzymatics pathways that have been described by other cytokines in different tissues.
Abstract: The mitogenic effect of recombinant human erythropoietin (rHuEpo) on primary cultures of neonatal rat cardiac myocytes was observed. rHuEpo triggered a dose-dependent increase in myocyte proliferation. The hormone effect over optimally grown control culture 1 day after addition was maximum with 0.5 U/ml and was inhibited with anti-rHuEpo. Inhibitors of enzymatic pathways known to be involved in the cytokines intracellular mechanism such as genistein (tyrosine kinase inhibitor), 2-nitro-4-carboxiphenyl-N,N-diphenylcarbamate (phospholipase C [PLC] inhibitor), and 1-(5-isoquinolinylsufonyl)-2-methyl-piperazine (protein kinase C [PKC] inhibitor) prevented the mitogenic action of rHuEpo. Also the inhibition of Na+-K+-ATPase activity by ouabain blunted the stimulatory action of rHuEpo on cell proliferation. The mitogenic action of the hormone was correlated with cardiac membrane paranitrophenilphosphatase (pNPPase) and PKC activity, since concentrations of rHuEpo that stimulate DNA synthesis increased pNPPase and PKC activity. Moreover, the enzymatic inhibition of tyrosine kinase, PLC, and PKC attenuated the stimulatory action of rHuEpo upon cardiac pNPPase activity. In this paper we demonstrate a non-hematopoietic action of rHuEpo showing both mitogenic and enzymatic effect upon primary myocyte cell culture and on pNPPase activity of neonatal rat heart. These effects are related to the capacity of rHuEpo to stimulate Na+-K+-ATPase activity and appear to be secondary to the activation of tyrosine kinase and PKC, indicating that in the rHuEpo mediated mitogenic action on cardiomyocytes involves the activation of the same enzymatic pathways that have been described by other cytokines in different tissues. © 1996 Wiley-Liss, Inc.
TL;DR: It is concluded that EPO induces proliferation in EC initially via tyrosine phosphorylated of six distinct proteins, and that the phosphorylation and nuclear translocation of the transcription factor STAT-5 is important for the effects of EPO on EC.
TL;DR: Results indicate that antibody-induced engagement of beta 2 integrins on neutrophils triggers tyrosine phosphorylation of Vav and, possibly through its association, a downstream activation of p21ras.
Abstract: It is known that beta 2 integrins are crucial for leukocyte cell-cell and cell-matrix interactions, and accumulating evidence now suggests that integrins serve not only as a structural link but also as a signal-transducing unit that controls adhesion-induced changes in cell functions. In the present study, we plated human neutrophils on surface-bound anti-beta 2 (CD18) antibodies and found that the small GTP-binding protein p21ras is activated by beta 2 integrins. Pretreatment of the cells with genistein, a tyrosine kinase inhibitor, led to a complete block of p21ras activation, an effect that was not achieved with either U73122, which abolishes the beta 2 integrin-induced Ca2+ signal, or wortmannin, which totally inhibits the phosphatidylinositol 3-kinase activity. Western blot analysis revealed that antibody-induced engagement of beta 2 integrins causes tyrosine phosphorylation of several proteins in the cells. One of these tyrosine-phosphorylated proteins had an apparent molecular mass of 95 kDa and was identified as the protooncogene product Vav, a p21ras guanine nucleotide exchange factor that is specifically expressed in cells of hematopoietic lineage. A role for Vav in the activation of p21ras is supported by the observations that antibody-induced engagement of beta 2 integrins causes an association of Vav with p21ras and that the effect of genistein on p21ras activation coincided with its ability to inhibit both the tyrosine phosphorylation of Vav and the Vav-p21ras association. Taken together, these results indicate that antibody-induced engagement of beta 2 integrins on neutrophils triggers tyrosine phosphorylation of Vav and, possibly through its association, a downstream activation of p21ras.
TL;DR: It is demonstrated that tyrosine kinase activation may partially mediate contractility to 5-HT in arterial smooth muscle, and tyrphostin 23 is somewhat nonselective and5-HT stimulates tyrosin kinase as documented by increased tyrosyl phosphorylation of proteins in cultured aortic smooth muscle cells and aorti tissue in active contraction of 5- HT.
Abstract: Serotonin (5-HT, 5-hydroxytryptamine) is a mitogen in vascular smooth muscle and vascular reactivity to 5-HT is significantly enhanced in hypertension and atherosclerosis. We have tested the hypothesis that tyrosine kinases, enzymes important for mitogenesis, may play a role in 5-HT-induced vascular smooth muscle contractility. Helical strips of rat carotid artery and aorta denuded of endothelium were mounted in tissue baths for measurement of contractile force. The tyrosine kinase inhibitor genistein (5 × 10-6M) decreased the potency of 5-HT approximately 4-fold and reduced maximal contraction to 5-HT in carotid arterial strips denuded of endothelium (58% control). Genistein’s inactive congener daidzein (5 × 10-6M) did not reduce maximal contraction to 5-HT in carotid arteries but did shift the 5-HT concentration response curve 3-fold to the right. Tyrphostin 23 (5 × 10–5M), another tyrosine kinase inhibitor, decreased the potency of 5-HT 4-fold and reduced the maximal contraction to 5-HT in the carotid artery (10% control). Contractions induced by phorbol-12,13-dibutyrate (10-9 to 10-5M) were not reduced or shifted by either tyrosine kinase inhibitor, indicating that phorbol-ester-sensitive protein kinase C isoforms were not affected. KCl-induced contraction was shifted 2-fold and the maximum significantly inhibited by tyrphostin 23 (38.6% control) but not genistein or daidzein, indicating that tyrphostin 23 but not genistein may inhibit voltage-gated calcium channels to reduce contractility. Western blot analysis using antiphosphotyrosine antibody confirmed that 5-HT produced a time- and concentration-dependent increase in the phosphotyrosine immunoreactivity of a 42-kD protein in cultured aortic smooth muscle cells. Lysate immunoprecipitation with an anti-mitogen-activated-protein (MAP)-kinase antibody indicated that the 42-kD protein was most likely a MAP kinase. 5-HT (10-5M) stimulated contraction and increased antiphosphotyrosine immunoreactivity in whole aorta mounted in tissue baths. Importantly, aortic contraction to 5-HT was shifted (5-fold rightward) and reduced (69% control) by genistein but not daidzein. These findings demonstrate that (1) tyrosine kinase activation may partially mediate contractility to 5-HT in arterial smooth muscle, (2) tyrphostin 23 is somewhat nonselective and (3) 5-HT stimulates tyrosine kinase as documented by increased tyrosyl phosphorylation of proteins in cultured aortic smooth muscle cells and aortic tissue in active contraction of 5-HT. These findings have significant implications not only in understanding a novel pathway of 5-HT signal transduction but also in vascular diseases in which growth and/or contractility to 5-HT is increased (e.g. hypertension, atherosclerosis).
TL;DR: These studies identify SAPK as a target for NO which may be critical for the NO‐induced apoptosis of glomerular mesangial and endothelial cells.
Journal Article•
TL;DR: In vivo administration of lavendustin A, a natural tyrosine kinase inhibitor, protected endothelial cells from TNFα-dependent vascular leakage in mouse liver, and it is proposed that the involvement of PECAM1 in TNF α-mediated effects on vascular permeability may depend on a dynamically regulated cytoskeletal association, related to the degree of P ECAM1 phosphorylation.
Abstract: Herein we show that exposure of human umbilical vein endothelial cells to tumor necrosis factor α (TNFα) led to platelet endothelial cell adhesion molecule-1 (PECAM1) surface redistribution, disruption of cytoskeleton connections, and increased PECAM1 phosphorylation, accompanied by increased permeability to macromolecules. The in vitro use of inhibitors of tyrosine or serine-threonine kinases could prevent both PECAM1 surface redistribution and the increase in permeability induced by the cytokine. In vivo administration of lavendustin A, a natural tyrosine kinase inhibitor, protected endothelial cells from TNFα-dependent vascular leakage in mouse liver. We propose that the involvement of PECAM1 in TNFα-mediated effects on vascular permeability may depend on a dynamically regulated cytoskeletal association, related to the degree of PECAM1 phosphorylation.
TL;DR: It is demonstrated that NaB induces both dose and time-dependent tyrosine phosphorylation of several proteins, the effects of which were blocked by the tyrosin kinase inhibitor genistein.
Patent•
16 Feb 1996TL;DR: A conjugate formed of epidermal growth factor covalently linked to a tyrosine kinase inhibitor, such as genistein, was used to kill cancer cells in vivo and in vitro as discussed by the authors.
Abstract: A conjugate formed of epidermal growth factor covalently linked to a tyrosine kinase inhibitor, such as genistein, and a method for killing cancer cells, in vivo and in vitro, by administering a cytotoxic dose of an epidermal growth factor tyrosine kinase inhibitor conjugate.
TL;DR: Tyrphostin AG556, which is more lipophilic than those of the AG126 family, was effective in preventing LPS-induced lethal toxicity when administered 2 h after LPS, and may block a critical step downstream of the signaling pathway induced by LPS after TNF-alpha production.
Abstract: Septic shock induced by gram-negative bacteria results primarily from excessive stimulation by lipopolysaccharide (LPS) of macrophages to produce tumor necrosis factor (TNF)-alpha and interleukin (IL)-1. The cellular effects of LPS, TNF-alpha, and IL-1 are mediated via tyrosine phosphorylation pathways. A recent report indicated that selective inhibitors of tyrosine kinases, tyrphostins of the AG126 family, protect mice against LPS-induced lethal toxicity in mice. Protection was most effective when the tyrphostin was injected before the LPS. In the present study, tyrphostin AG556, which is more lipophilic than those of the AG126 family, was effective in preventing LPS-induced lethal toxicity when administered 2 h after LPS. AG556 also prevented viable Escherichia coli-induced lethal toxicity when given 2 h before and, to a lesser extent, 2 h after the bacterial inoculation. AG556 may block a critical step downstream of the signaling pathway induced by LPS after TNF-alpha production.
TL;DR: The results suggest that the anti-arachidonic acid metabolism properties of quinacrine and chloroquine may be responsible for their ability to inhibit Tat-mediated LTR-regulated gene expression.
TL;DR: It is shown that lavendustin A, a potent, specific inhibitor of tyrosine kinase activity, strongly inhibits the P-initiated human AR and the essential P-mediated Cl- efflux.
Abstract: Previous studies showed that progesterone (P) can initiate the mammalian sperm acrosome reaction (AR) in vitro and that a sperm GABA A -like receptor/Cl - channel is involved in an essential Cl - efflux mediated by P during the AR. Here, we show that lavendustin A, a potent, specific inhibitor of tyrosine kinase activity, strongly inhibits the P-initiated human AR and the essential P-mediated Cl - efflux. Lavendustin B, a weak tyrosine kinase inhibitor, had no significant effect. These results suggest that, as part of AR initiation, P mediates tyrosine phosphorylation of the sperm GABA A -like receptor/Cl - channel.
TL;DR: IL-4 stimulates the proliferation of keratinocytes in vitro by promoting a transition from G0/G1 to S phase of the cell cycle, which suggests that tyrosine kinases may be involved in IL-4-induced proliferation.
Patent•
11 Sep 1996
TL;DR: In this article, a method of treating an individual or animal with osteoarthritis is described, which comprises administering to the individual or an animal a therapeutically effective amount of a protein tyrosine kinase inhibitor.
Abstract: Disclosed is a method of treating an individual or animal with osteoarthritis. The method comprises administering to the individual or animal a therapeutically effective amount of a protein tyrosine kinase inhibitor.
TL;DR: It is concluded that protein tyrosine kinase and Ca2+/calmodulin-dependent protein kinase II play a role in modulating release of glutamate in hippocampus and that the age-related decrease in glutamate release may be partly due to an age- related decrease in kinase activities.
TL;DR: It is suggested that TGF-β1 inhibits the human keratinocyte proliferation in vitro, possibly through induction of R-PTP-κ gene expression.
TL;DR: The results suggest that the interferon-gamma-induced inducible NO synthase induction involves activation of Jak2-STAT1 alpha pathway in both glial cells and macrophages.
TL;DR: The results indicate that a tyrosine kinase-regulated phospholipase D plays a critical role in alpha-adrenoceptor-induced contractions of the rat aorta and that stimulation of both alpha 1- and alpha 2- adrenoceptors is essential to allow phospholIPase activation.
TL;DR: It was found that genistein was able to inhibit EGF-induced EGF receptor degradation and tyrosine phosphorylation in human hepatoma HepG2 cells, and the amount of internalized EGF was remarkably decreased.
TL;DR: It is concluded that proliferative signal transduction in glioma cells occurs through a predominantly PKC-dependent pathway and that selectively targeting this enzyme provides an approach toglioma therapy.