Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoclast-mediated bone resorption plays a crucial role in osseous remodeling. Osteoblasts are important regulators of this activity, in part through their ability to produce osteoclast-regulating soluble factors such as interleukin-6 (IL-6). IL-11 is a newly appreciated pleotropic cytokine whose spectrum of biological activities overlaps with that of IL-6. As a result, we hypothesized that osteoblasts are an important skeletal source of this cytokine. To test this hypothesis, we characterized the IL-11 production of unstimulated and stimulated SaOS-2 human osteosarcoma cells. Unstimulated cells produced modest amounts of IL-11. The osteotropic agents recombinant IL-1 (0.25-5 ng/ml), transforming growth factor-beta 1 (0.1-10 ng/ml), PTH (10(-8)-10(-11) M), and PTH-related peptide ((10(-8)-10-11 M) further increased SaOS-2 cell IL-11 protein production and messenger RNA accumulation. These stimulatory effects were dose and time dependent, and the IL-11 that was produced was bioactive, as demonstrated by its ability to stimulate the proliferation of T10D plasmacytoma cells. The protein kinase-C activator, 12-O-Tetra-decanoylphorbol 13-acetate, and a variety of cAMP agonists [forskolin, prostaglandin E1, prostaglandin E2, and (Bu)2AMP] also stimulated osteoblast IL-11 protein production and messenger RNA accumulation. In contrast, recombinant IL-4, recombinant interferon-gamma, and endotoxin did not stimulate SaOS-2 cells in a similar fashion. Importantly, the ability to produce IL-11 was not a unique property of SaOS-2 cells, because primary human trabecular bone osteoblasts also produced significant amounts of bioactive IL-11 when stimulated with transforming growth factor-beta 1. These studies demonstrate that appropriately stimulated human osteoblasts and osteoblast-like cells are potent producers of IL-11 and suggest that osteoblast-derived IL-11 may be an important component of the cytokine network mediating osteoblast-osteoclast communication in normal and pathological bone remodeling.
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PMID:Cytokine and hormonal stimulation of human osteosarcoma interleukin-11 production. 783 81

The pleckstrin homology (PH) domain is extended in the Btk kinase family by a region designated the TH (Tec homology) domain, which consists of about 80 residues preceding the SH3 domain. The TH domain contains a conserved 27 amino acid stretch designated the Btk motif and a proline-rich region. Sequence similarity was found to a putative Ras GTPase activating protein and a human interferon-gamma binding protein both in the PH domain and the Btk motif region. SLK1/SSP31 protein kinase and a non-catalytic p85 subunit of PI-3 kinase had similarity only with the proline rich region. The identification of a PH domain extension in some signal transduction proteins in different species suggests that this region is involved in protein-protein interactions.
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PMID:Tec homology (TH) adjacent to the PH domain. 807 May 76

The signal pathways by which interferon-gamma (IFN-gamma) is able to up-regulate major histocompatibility complex (MHC) class I transcription were studied in two human hematopoietic tumor cell lines, K562 and Ramos. These studies suggest that the IFN-gamma signal is transduced via an H7- and staurosporine-sensitive kinase that is distinct from protein kinase C (PKC) and protein kinase A (PKA) in both cell types. Ramos cells appear to utilize an additional pathway involving double-stranded RNA-dependent protein kinase. PKC and possibly PKA appear to be involved in one or more intersecting pathways by which agonists of these kinases are able to act synergistically with IFN-gamma, but activation of these latter pathways is neither necessary nor sufficient for induction of MHC class I transcription. Modulation of G-protein- and Ca2+-calmodulin-associated pathways and arachidonic acid metabolism had no effect on constitutive or IFN-gamma-stimulated class I transcription. The class I stimulatory factor produced in response to IFN-gamma treatment appears to have a short t1/2. The identity of this factor is unknown, but is likely to be distinct from known mediators of IFN-stimulated transcription. Gene and cell-type specificity in the signal transduction pathways utilized by IFN-gamma implies that such pathways may be useful targets for experimental and therapeutic manipulation.
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PMID:Stimulation of MHC class I transcription by interferon-gamma involves a non-A, non-C kinase in addition to protein kinase C. 809 99

We studied the effect of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interferon-gamma (IFN-gamma) on the function of thyroid cells and pituitary thyrotrophs. In FRTL-5 rat thyroid cells, both human and murine TNF-alpha inhibited basal and TSH-stimulated [125I]iodide transport. IL-1 shared this action with TNF-alpha, but was less potent. IL-1 and IFN-gamma did not cause a further reduction of TNF-alpha-induced inhibition of [125I]iodide transport. TNF-alpha, phorbol ester 12-myristate 13-acetate (PMA), and calcium ionophore (CI) A23817 all inhibited [125I]iodide transport, but high doses of PMA and CI also blocked the inhibitory action of TNF-alpha on [125I]iodide transport. Inhibition of protein kinase A and protein kinase C by H7 or HA inhibited TSH-stimulated iodide transport, but did not block the TNF-alpha action, suggesting that the mechanism of TNF-alpha action on thyroid cells is independent of protein kinase A and C. In pituitary cells, both human and murine TNF-alpha did not affect basal TSH secretion, but TNF-alpha reduced TRH-stimulated TSH secretion. This study provides further in vitro evidence that TNF-alpha inhibits the function of the hypothalamus-pituitary-thyroid axis acting directly on both the pituitary and thyroid glands.
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PMID:Suppression of rat thyrotroph and thyroid cell function by tumor necrosis factor-alpha. 811 27

The effects of interferon-gamma (IFN-gamma) were investigated on cytoplasmic motility of alveolar macrophages (AM) from rat lungs in vitro. Cytoplasmic motility was examined by measuring remnant field strength from the cell surface of AM containing Fe3O4 particles, and the relaxation rate (lambda 0; min-1), which is related to cytoplasmic motility, was determined. IFN-gamma caused an increase in lambda 0 in a concentration-dependent fashion with the maximal effect at 1,000 U. Dibutyryl cyclic GMP (db cyclic GMP; 10(-3) M) mimicked IFN-gamma-induced effects, but db cyclic AMP (10(-3) M) decreased lambda 0. IFN-gamma (1,000 U)-induced increases in lambda 0 were concentration-dependently inhibited by NG-monomethyl-L-arginine (L-NMMA) with complete inhibition of a concentration of 10(-4) M and were also completely inhibited by either methylene blue (10(-5) M) or KT 5823 (10(-5) M), a specific inhibitor of protein kinase G. IFN-gamma (1,000 U) caused significant nitrite (NO2-) production from the control values of 0.2 +/- 0.1 to 10.0 +/- 0.2 microM/24 h per 10(6) cells (P < 0.001, n = 10), and this increase in NO2- production by IFN-gamma (1,000 U) was completely inhibited by L-NMMA (10(-4) M). IFN-gamma caused a concentration-dependent increase in a filamentous-actin (F-actin) content with the maximal effect at 1,000 U. db cyclic GMP (10(-3) M) mimicked IFN-gamma induced effects on F-actin formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interferon-gamma increases cytoplasmic motility of alveolar macrophages via nitric oxide-dependent signaling pathways. 829 82

Trypanosoma brucei brucei releases a lymphocyte-triggering factor (TLTF) that activates CD8+ T cells. We here study second messenger mechanisms in this activation, i.e. the effects of protein kinase C (PKC), protein kinase A (PKA) and tyrosine kinases (TPK) inhibitors on TLTF-induced interferon-gamma (IFN-gamma) secretion and proliferation in lymphoid cell cultures. The effects were compared to those obtained by phytohemagglutinin (PHA) stimulation. Rat spleen mononuclear cells (MNC) and spleen MNC from a mutant mouse strain possessing CD8+ T cells but lacking CD4+ T cells were used as responder cells. Although both the PKC and the PKA inhibitors suppressed PHA-induced IFN-gamma secretion and proliferation of rat MNC and mouse CD8+ CD4- MNC, they had no effect on the same TLTF-induced responses. The TPK inhibitor genistein, however, strongly suppressed TLTF-induced activation of both types of responder cells to IFN-gamma secretion and the TLTF-induced proliferation of mouse CD8+ CD4- MNC. The suppressive effects of the drugs could be overcome by ionomycin and tetradecanoylphorbol acetate, which show that the effects were not due to drug nonspecific cellular toxicity of the drugs. We conclude that TLTF activates CD8+ T cells through pathways other than the PKC- or PKA-dependent signal transduction, and that TPK may be involved in the triggering.
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PMID:T cell activation by a Trypanosoma brucei brucei-derived lymphocyte triggering factor is dependent on tyrosine protein kinases but not on protein kinase C and A. 832 29

The methylxanthines, pentoxifylline (PTX) and caffeine, modulated major histocompatibility complex class I expression on three constitutively class I-positive murine T cell lymphoma lines. On two cell lines, PTX or caffeine treatment enhanced H-2K and H-2D expression. Treatment with PTX and either interferon-gamma, interferon-alpha/beta, tumor necrosis factor, or lymphotoxin increased the levels of K and D expression above those observed following treatment with either PTX or cytokines alone. On the third cell line, PTX or caffeine treatment enhanced D expression and reduced K expression. Treatment with PTX and any of the cytokines resulted in a level of D expression greater than that seen following treatment with either PTX or cytokines alone. However, PTX inhibited the cytokine-induced enhancement of K expression. PTX and caffeine did not induce class I expression on three constitutively class I-negative murine T cell lymphoma lines. Dibutyryl cAMP modulated class I expression in the same manner as PTX and caffeine. The PTX- and caffeine-mediated enhancement of class I expression was at least partially blocked by an inhibitor of cAMP-dependent protein kinase A. These results demonstrate that PTX and caffeine are able to regulate class I expression and that this regulation involves a cAMP-dependent mechanism.
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PMID:Pentoxifylline- and caffeine-induced modulation of major histocompatibility complex class I expression on murine tumor cell lines. 838 69

Several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) are expressed by astrocytes, the predominant glial cell of the central nervous system (CNS). Such molecules are important in the trafficking of leukocytes to sites of inflammation, and in lymphocyte activation. ICAM-1 is constitutively expressed by neonatal rat astrocytes, and expression is enhanced by the proinflammatory cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma), with IL-1 beta and TNF-alpha being the strongest inducers. In this study, we have examined the nature of the second messengers involved in ICAM-1 gene expression induced by the cytokines IL-1 beta and TNF-alpha. Our results indicate that stimuli related to protein kinase C (PKC) such as the phorbol ester phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 increase ICAM-1 mRNA expression, whereas cyclic nucleotide analogs and PKA agonists have no effect. Pharmacologic inhibitors of PKC such as H7, H8, and calphostin C inhibit ICAM-1 gene expression inducible by IL-1 beta and TNF-alpha. Prolonged treatment of astrocytes with PMA results in a time-dependent downregulation of the PKC isoforms alpha, delta, and epsilon, and a concomitant diminution of ICAM-1 mRNA expression induced by IL-1 beta, TNF-alpha, and PMA itself at specific time points post-PMA treatment. These data, collectively, demonstrate a role for various PKC isoforms in IL-1 beta and TNF-alpha enhancement of ICAM-1 gene expression in rat astrocytes.
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PMID:Interleukin 1-beta- and tumor necrosis factor-alpha-mediated regulation of ICAM-1 gene expression in astrocytes requires protein kinase C activity. 853 Jan 84

L-Thyroxine (T4) and 3,3',5-L-triiodothyronine (T3) potentiate the antiviral state induced by interferon-gamma(IFN-gamma) in homologous cells by a mechanism that is dependent upon calcium/phospholipid-dependent protein kinase (PKC). L-T4 and T3 also potentiate induction by IFN-gamma of MHC class II HLA-DR antigen expression in HeLa cells. In the present studies of HLA-DR expression, the PKC inhibitor staurosporine (0.1-1 nM) enhanced the expression of HLA-DR when the inhibitor was added simultaneously with IFN-gamma, 100 IU/ml. In the presence of IFN-gamma and 10(-7) M T4, the same concentrations of staurosporine inhibited potentiation of HLA-DR expression by thyroid hormone. A more specific PKC inhibitor, CGP41251 (0.5-5 nM), similarly enhanced HLA-DR expression in the presence of IFN-gamma but inhibited thyroid hormone potentiation of antigen expression. Both actions of CGP41251 were suppressed when cells were also treated with phorbol 12-myristate 13-acetate (PMA). A phospholipase C inhibitor, U73122 (1-1000 nM), did not alter the potentiating ability of T4, although it inhibited in a concentration-dependent manner the expression of HLA-DR induced by IFN-gamma. The potentiating effect of T4 was much more sensitive to a cyclic AMP-dependent protein kinase (PKA) inhibitor,KT5720 (1-1000nM), than was the induction of HLA-DR by IFN-gamma. The inhibitory effects of KT5720 were reversed by concurrent 8-bromo-cAMP treatment. The calmodulin antagonist W-7 (5-50 microM) did not alter IFN-gamma induction of HLA-DR in either the presence or absence of T4. HLA-DR expression in HeLa cells appears to be under PKC-associated inhibition; IFN-gamma reverses this inhibition to promote the appearance of the DR antigen. In contrast, potentiation by T4 of induction of HLA-DR by IFN-gamma requires activation of PKC. PKA is involved both in DR induction by IFN-gamma and in potentiation of the latter by T4. Thus, PKA and PKC have discrete roles in IFN-gamma-induced MHC class II antigen expression and its modulation by thyroid hormone.
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PMID:Potentiation by thyroxine of interferon-gamma-induced HLA-DR expression is protein kinase A- and C-dependent. 864 Apr 46

The specific signal transduction pathway(s) involved in the induction of the expression of the MHC class II molecule, Ia, on macrophages by interferon-gamma (IFN-gamma) is unclear. In this paper, we assessed the role of several signal transduction pathways including calcium mobilization, phospholipase C, protein kinase C and cyclic nucleotide-dependent protein kinase, and the tyrosine kinase pathways. IFN-gamma was unable to mobilize intracellular calcium, unlike platelet-activating factor, which stimulated a threefold increase in cytosolic Ca2+ concentration in macrophages. Inhibition of the phospholipase C pathway by U73122 or ET-180CH3 and of phosphatidic acid phosphohydrolase by propranolol did not suppress IFN-gamma-induced Ia expression. In addition, inhibition of protein kinase C by calphostin C or cyclic nucleotide-dependent protein kinase by HA1004 did not suppress Ia expression. However, IFN-gamma-induced Ia expression was significantly suppressed when the tyrosine kinase pathway was inhibited with herbimycin A and genestein. In addition, those two inhibitors suppressed tyrosine phosphorylation of several proteins in macrophages that may or may not be involved in the induction of Ia expression. Thus, IFN-gamma used only the tyrosine kinase signaling pathway, but not the phospholipid/Ca2+ signaling pathways, to induce Ia expression in macrophages.
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PMID:Tyrosine kinase but not phospholipid/Ca2+ signaling pathway is involved in interferon-gamma stimulation of Ia expression in macrophages. 865 34


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