Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of anticancer agents on signal transduction for reactive oxygen generation was examined in polymorphonuclear leukocytes (PMN). Inositol 1,4,5-trisphosphate and diacyl glycerol levels in formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated PMN were decreased by cis-diammine-dichloroplatinum (CDDP), 5-fluorouracil (5-FU), 137Cs, and peplomycin (PLM, a bleomycin analog) in this order. Intracellular calcium ([Ca2+]i) level and protein kinase C (PKC) activity in the membrane after phorbol myristate acetate (PMA) stimulation were decreased by 5-FU and CDDP but not by 137Cs and, in contrast, were increased by PLM. The level of [Ca2+]i was decreased by 8 h treatment with 5-FU and CDDP. 5-FU and CDDP inhibited tyrosine phosphorylation of 83-kDa and 115-kDa proteins, however 137Cs did not inhibit their phosphorylation and PLM enhanced the tyrosine phosphorylation. Short term (< or = 4 h) treatment with PLM, 5-FU and CDDP enhanced respiratory burst of PMN, whereas long term (8 h) treatment, as well as radiation, suppressed reactive oxygen generation from PMN in a dose dependent manner. Genistein suppressed chemiluminescence in 5-FU-, CDDP-, and 137Cs-pretreated PMN to a greater extent than it did in PLM-pretreated PMN, however near suppression of chemiluminescence by staurosporine, 4-bromophenyl bromide and methionine was observed in PMN pretreated with these agents. In conclusion, these results indicate that long term treatment of PMN with 5-FU and CDDP inhibit respiratory burst, suppressing intracellular calcium mobilization, PKC translocation and tyrosine kinase activation, in adverse, short term treatment with PLM enhances PKC translocation and tyrosine kinase activation, but inhibits myeloperoxidase (MPO) activity, and radiation causes weak inhibition of signal transduction for respiratory burst.
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PMID:Suppression by anticancer agents of reactive oxygen generation from polymorphonuclear leukocytes. 874 91

Monocyte chemotactic protein-1 (MCP-1)/monocyte chemotactic activating factor has a potent histamine-releasing activity for basophils and is a major component of IgE-independent histamine-releasing factors (HRF). In this study, we examined the effect of a panel of kinase inhibitors on MCP-1-induced histamine release from human basophils to characterize the signaling pathway used by this chemokine. Genistein (3 micrograms/ml), an inhibitor of tyrosine kinase, inhibited MCP-1-induced histamine release by 44%. Wortmannin is a specific inhibitor of phosphatidylinositol 3 kinase (PI-3 kinase). It blocked MCP-1-induced histamine release with an IC50 of 3.3 x 10(-8) M indicating a role of PI-3 kinase in this reaction. KT5926, an inhibitor of myosin light chain kinase, also inhibited histamine release in response to MCP-1 with an IC50 of 10(-6) M. Staurosporine, a potent inhibitor of protein kinase C, although being not specific, augmented MCP-1-induced histamine release by 31.9% at 10(-6) M. These results indicate the possible involvement of a series of kinases, including PI-3 kinase, in the signal transduction pathway used by MCP-1.
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PMID:Pharmacologic study of basophil histamine release induced by monocyte chemotactic protein-1 with kinase inhibitors. 875 39

1. Endothelial cells can be stimulated by the pro-inflammatory cytokines interleukin (IL)-1 alpha and tumour necrosis factor (TNF) alpha to express the leukocyte adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 but the intracellular signalling mechanisms leading to this expression are incompletely understood. We have investigated the role of protein tyrosine kinases (PTK) in adhesion molecule expression by cytokine-activated human umbilical vein endothelial cells (HUVEC) using the PTK inhibitors genistein and herbimycin A, and the protein tyrosine phosphatase (PTP) inhibitor sodium orthovanadate. 2. Maximal E-selectin expression induced by incubation of HUVEC for 4 h with IL-1 alpha (100 u ml-1) and TNF alpha (100 u ml-1) was dose-dependently inhibited by genistein and herbimycin A. Although similar effects were seen on phorbol 12-myristate, 13-acetate (PMA)-induced expression, this was not due to inhibition of protein kinase C (PKC) activity as the selective inhibitors of PKC, bisindolylmaleimide (BIM), Ro31-7549 or Ro31-8220 did not affect IL-1 alpha- or TNF alpha-induced E-selectin expression at concentrations which maximally inhibited PMA-induced expression. 3. Genistein inhibited VCAM-1 expression induced by incubation of HUVEC for 24 h with TNF alpha or IL-1 alpha whereas it did not affect ICAM-1 expression induced by 24 h incubation with either of these cytokines. Herbimycin A inhibited both VCAM-1 and ICAM-1 expression induced by TNF alpha. 4. Basal expression of E-selectin, VCAM-1 and ICAM-1 was dose-dependently enhanced by sodium orthovanadate. In contrast, vanadate differentially affected TNF alpha-induced expression of these molecules with maximal E-selectin and ICAM-1 expression being slightly enhanced and VCAM-1 expression dose-dependently reduced. 5. We also studied the effects of PTK and PTP inhibitors on adhesion of the human pre-myeloid cell line U937 to TNF alpha-stimulated HUVEC. Adhesion of U937 cells to HUVEC pretreated for 4 or 24 h with TNF alpha was dose-dependently inhibited by genistein and herbimycin A but unaffected by daidzein. Adhesion of U937 cells after 4 h was partially inhibited by blocking antibodies against both E-selectin and VCAM-1 but after 24 h was only inhibited by anti-VCAM-1. 6. Sodium orthovanadate had no effect on TNF alpha-induced U937 adhesion but dose-dependently enhanced adhesion to unstimulated HUVEC. Vanadate-induced adhesion was inhibited by an antibody against VCAM-1. 7. These results demonstrate that PTK-mediated phosphorylation events are important for the regulation of adhesion molecule expression by human endothelial cells, and additionally show that PTK inhibitors differentially affect upregulation of different adhesion molecules, implicating divergent regulatory pathways for cytokine-induced adhesion molecule expression.
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PMID:Effects of protein tyrosine kinase inhibitors on cytokine-induced adhesion molecule expression by human umbilical vein endothelial cells. 884 42

Basic fibroblast growth factor (bFGF) is a potent mitogen for bone. In this study, we utilized the clonal rat osteoblastic cell line, Py1a, to examine signal transduction by bFGF and to determine the role of mitogen activated protein kinases (MAPK) and induction of c-fos mRNA in the mitogenic response to bFGF. Stimulation of [3H]thymidine incorporation (TDR) into DNA by bFGF was determined in the presence of phorbol myristate acetate of (PMA) to down-regulate the protein kinase C (PKC) pathway, genistein, an inhibitor of tyrosine kinase and H-7, a PKC inhibitor, bFGF 10(-8) M and PMA 10(-7) M increased TDR by 242 and 245%, respectively. Treatment with bFGF or PMA for 5 or 30 minutes increased tyrosine phosphorylation of multiple proteins, and immunoblotting with MAPK-specific antibody revealed that two of these bands were the 42 and 44 kD isoforms of MAPK. PMA and bFGF induced c-fos mRNA expression at 30 minutes. Genistein at 10 micrograms/ml blocked the mitogenic effect of bFGF and partially inhibited the mitogenic effect of PMA. Genistein at 100 micrograms/ml also blocked both bFGF- and PMA-induced increases in c-fos mRNA. A 24 h pretreatment with PMA at 10(-7) M inhibited the mitogenic response, tyrosine phosphorylation of MAPK, and induction of c-fos mRNA subsequent to the addition of PMA, but not bFGF. H-7 at 50 microM blocked bFGF-induced mitogenesis and c-fos induction, but did not inhibit bFGF-induced tyrosine phosphorylation of MAPK. In this study, we show that the signaling pathway of bFGF and PMA are similar in that they both induce tyrosine phosphorylation of MAP kinases and activate c-fos. However, the signaling pathways ultimately diverge in that once the PKC pathway is down-regulated by PMA pretreatment or blocked by the PKC inhibitor H-7, tyrosine phosphorylation of MAP kinase, c-fos induction, and the mitogenic effect of PMA is blocked. In contrast, down-regulation of the PKC pathway inhibits c-fos and the mitogenic response to bFGF, but not bFGF's effects on tyrosine phosphorylation of MAP kinase.
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PMID:Signal transduction by basic fibroblast growth factor in rat osteoblastic Py1a cells. 886

Collagen (10-90 micrograms/ml) and ionomycin (1 microM; a calcium ionophore) each evoked rises in intracellular free calcium, protein kinase C activity and arachidonic acid release in human platelets, and as previously demonstrated for collagen, ionomycin (1 microM) stimulated protein tyrosine phosphorylation. However, at lower concentrations (60 and 250 nM) ionomycin selectively mobilised calcium. Ro31-8220 (a selective inhibitor of protein kinase C) inhibited (by 50%) ionomycin-stimulated arachidonic acid release. Genistein (an inhibitor of protein tyrosine kinases) also reduced by 50% ionomycin-stimulated arachidonic acid release. In combination, genistein and Ro31-8220 abolished ionomycin-stimulated arachidonic acid release. These findings show 1) that a rise in calcium is not sufficient, and 2) the activation of both protein kinase C and protein tyrosine phosphorylation is necessary, for full ionomycin-stimulated arachidonic acid release in human platelets.
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PMID:Ionomycin-stimulated arachidonic acid release in human platelets: a role for protein kinase C and tyrosine phosphorylation. 886 40

Exposure of Farage, a human B-cell line, to interleukin 4 (IL4) reduced the amount of CD38 antigen on the surface of the cells and in cell lysates. No evidence was obtained for accelerated breakdown, shedding, or internalization of CD38 molecules following IL4 treatment, nor the accumulation of CD38 molecules in the cell interior. The inhibition of protein synthesis with cycloheximide (CXM) diminished the down-regulation of CD38 induced by IL4. CXM decreased the expression of CD38 in Farage cells with arrested mitosis, and IL4 failed to further reduce CD38 expression. Staurosporine, an inhibitor of serine/threonine protein kinases, and H7 (1-(5-isoquinolinylsulfonyl)-2-methylpiperazine), a preferential inhibitor of protein kinase C (PKC), abrogated the effect of IL4 on CD38, while inhibitors of other serine protein kinases W7 (N-(aminohexyl)-5-chloro-1-naphthalenesulfoamide) and H8 (N-(2-[methylamino]ethyl)-5-isoquinolinesulfonamide) failed to interfere with the effect of IL4. Phorbol 12-myristate 13-acetate (PMA), an activator of PKC, resembled IL4 in decreasing the expression of CD38, and either staurosporine or H7 abolished this effect. Genistein, an inhibitor of tyrosine kinases, increased the expression of CD38, but failed to abrogate the inhibitory effect of IL4 on CD38. It is concluded that serine/threonine protein kinases mediated the IL4-induced down-regulation of the expression of CD38 molecules in B cells.
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PMID:The mechanism of interleukin 4-induced down-regulation of CD38 on human B cells. 887 4

Acrosomal membranes isolated from the caput and cauda epididymal spermatozoa of hamster exhibited protein kinase activity and the endogenous protein substrates that were phosphorylated in the acrosomal membranes of caput and cauda spermatozoa were not all the same. The kinase activity was identified as a cAMP independent type and the use of specific stimulators and inhibitors indicated that the activity was not due to casein kinase, protein kinase A or protein kinase C but due to a tyrosine specific protein kinase that was not inhibited by Genistein. Phosphotyrosine was identified as the predominant phosphorylated residue in the proteins.
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PMID:Acrosome membrane associated protein kinase activity in hamster spermatozoa. 891 71

Effects of an inhibitor of tyrosine protein kinases, genistein, and anti-phosphotyrosine monoclonal antibody on mouse oocyte maturation in vitro were examined. Genistein inhibited germinal vesicle breakdown (GVBD) in a dose dependent manner (ED50:20 micrograms/ml), and the inhibitory effect was completely reversible. The level of oocyte cAMP just before GVBD was not affected by the addition of genistein to the culture medium. The addition of 30 micrograms/ml genistein to the medium after 45 min culture in the absence of dibutyryl cAMP (dbcAMP) resulted in 50% inhibition of GVBD. Activator of protein kinase C, 12-O-tetradecanoylphorbol-13-acetate (5 ng/ml) or dbcAMP (40 microM) inhibited GVBD synergistically with genistein (15 micrograms/ml). The meiotic maturation was significantly inhibited in the oocytes injected with anti-phosphotyrosine monoclonal antibody compared with the control oocytes injected with phosphate buffered saline. Genistein attenuated phosphorylation of the maturation-associated phosphoproteins which was demonstrated by means of one dimensional gel electrophoresis. Oocytes cultured with 30 micrograms/ml genistein showed a decreased rate of the first polar body emission (15 to 20%), and the inhibitory effect was dose dependent. The majority of oocytes (80 to 90%) inhibited from emitting the first polar body by genistein exhibited maturation arrest at metaphase 1. These data suggest that protein tyrosine phosphorylation may be implicated in the regulation of mouse oocyte maturation.
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PMID:[Studies on protein tyrosine phosphorylation in mouse oocyte maturation]. 896 Jun 88

Previous work has demonstrated that glioma cells have very high protein kinase C (PKC) enzyme activity when compared to non-malignant glia, and that their PKC activity correlates with their proliferation rate. The purpose of this study was to determine whether the elevated PKC activity in glioma is secondary to an autonomously active PKC isoform implying oncogenic transformation, or whether this activity is driven by upstream ligand-receptor tyrosine kinase interactions. We treated established human glioma cell lines A172, U563 or U251 with either the highly selective PKC inhibitor CGP 41 251, or with genistein, a tyrosine kinase inhibitor. The proliferation rate and PKC activity of all the glioma lines was reduced by CGP 41 251; the IC50 values for inhibiting cell proliferation corresponded to the IC50v values for inhibition of PKC activity. Genistein also inhibited cell proliferation, with IC50 proliferation values approximating those for inhibition of tyrosine kinase activity in cell free protein extracts. Importantly, in genistein-treated cells, downstream PKC enzyme activity was dose dependently reduced such that the correlation coefficient for effects of genistein on proliferation rate and PKC activity was 0.92. These findings suggest that upstream tyrosine kinase linked events, rather than an autonomously functioning PKC, result in the high PKC activity observed in glioma. Finally, fetal calf serum (FCS) evoked a strong mitogenic effect on glioma cell lines. This mitogenic activity was completely blocked by CGP 41 251, suggesting that although the many mitogens in FCS for glioma cells signal initially through genistein-inhibitable tyrosine kinases, they ultimately channel through a PKC-dependent pathway. We conclude that proliferative signal transduction in glioma cells occurs through a predominantly PKC-dependent pathway and that selectively targeting this enzyme provides an approach to glioma therapy.
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PMID:Signal transduction for proliferation of glioma cells in vitro occurs predominantly through a protein kinase C-mediated pathway. 896 53

The mechanisms by which T lymphocytes are transformed from passively transported cells during circulation in the vascular system to actively migrating cells during extravasation are unknown. Therefore, the possibility that lymphocyte receptors are capable of inducing motility was investigated using a modified Boyden chamber assay. Cross-linking of alphaL beta2 and alpha4 beta1 on human T lymphocytes (T cell line and peripheral blood T cells) with immobilized mAbs induced motile behavior on fibronectin, laminin, collagen type IV, and poly-L-lysine. This induction of T cell migration was very potent and in most cases more efficient than pretreatment of the cells with phorbol esters. In contrast, control Abs to several other integrin- and non-integrin molecules present on T lymphocytes did not induce T cell migration. Anti-CD3 Abs themselves did not trigger motile behavior. However, anti-CD3 promoted T cell migration in the Boyden chamber system if present simultaneously with 40-kDa alpha4 beta1 binding fibronectin fragments or alphaL beta2 binding intercellular adhesion molecule-1/hIgG1Fc fusion proteins on the upper side of the filter. Abs to other surface components on T cells did not trigger motility when presented together with the 40-kDa fibronectin fragments or the intercellular adhesion molecule-1/hIgG1Fc fusion proteins. The induction of motile behavior could be blocked if the T cells were pretreated with Genistein and Calphostin C, indicating the involvement of a protein tyrosine kinase and protein kinase C-dependent signaling pathway in triggering of T cell motility via integrins. These results indicate that alphaL beta2 and alpha4 beta1 on T lymphocytes can selectively trigger motile behavior when cross-linked by their endothelial or extracellular matrix ligands. Furthermore, these data indicate that cross-linking of CD3 facilitates ligand binding and subsequent triggering of a motile phenotype by alphaL beta2 and alpha4 beta1.
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PMID:Triggering of motile behavior in T lymphocytes via cross-linking of alpha 4 beta 1 and alpha L beta 2. 897 77


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