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)

Macrophage colony-stimulating factor (CSF-1) binds to a receptor (CSF-1R) encoded by the c-fms proto-oncogene and activates transcription of the urokinase plasminogen activator (uPA) gene in murine bone-marrow-derived macrophages. This article demonstrates that the murine macrophage cell line RAW264 responds to CSF-1 with inducible phosphorylation of cytoplasmic proteins on tyrosine residues but fails to induce transcription of uPA. The defect was correlated with a selective failure to maintain CSF-1Rs on the cell surface, whereas all RAW264 cells contained abundant CSF-1Rs within the presumptive Golgi/endoplasmic reticulum compartment. Transfection with a CSF-1R expression plasmid permitted CSF-1-dependent activation of the signalling pathway targeting an Ets/AP1 (activator protein 1) element in the uPA promoter that has been shown previously to be a target of oncogenic ras and protein kinase C pathways. Mutation of the expressed CSF-1R at either Y807 or Y559, sites of receptor tyrosine phosphorylation implicated in signal transduction, reduced but did not abolish uPA promoter activation by CSF-1. Activation by mutant CSF-1R plasmids was additive; there was no evidence of mutual complementation. The results indicate that maintenance of elevated uPA transcription by CSF-1 requires new receptors emerging continuously on the cell surface. Parallel, partly redundant, signalling pathways arising from phosphorylated tyrosines on the CSF-1R activate multiple cis-acting elements on the complex uPA promoter.
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PMID:Regulation of urokinase plasminogen activator gene transcription in the RAW264 murine macrophage cell line by macrophage colony-stimulating factor (CSF-1) is dependent upon the level of cell-surface receptor. 1072 33

Membrane-bound macrophage colony-stimulating factor (m-M-CSF) is the membrane form M-CSF by alternative splicing. J6-1 leukemic cell line spontaneously forms cell clusters, whose growth depends on the auto-juxtacrine mediated by m-M-CSF and its receptor (M-CSFR). In this study, M-CSFR isolated from J6-1 cells and recombinant human M-CSF soluble receptor (rh-M-CSFsR) were used to study their effects on J6-1 cells. Both receptors inhibited cell proliferation. Use of M-CSFR monoclonal antibodies, M-CSFR or rh-M-CSFsR to block either M-CSFR or m-M-CSF on cell surface inhibited the cluster forming process, while both receptors stimulated cells adhering to culture plate. Furthermore, M-CSFR and/or rh-M-CSFsR caused multiple cellular changes including cytoplasmic pH, multinuclear cell ratio, antigen expression and cell diameter. A [Ca(2+)] rise was induced within 90 s by both receptors. Western blot experiments showed that rh-M-CSFsR caused tyrosine phosphorylation on multiple cytoplasmic proteins of 45 kDa and 55-90 kDa, which could be blocked by H7. These observations suggested that m-M-CSF and M-CSFR mediate J6-1 cell intercellular adhesion with bi-directional signal transduction, and Ca(2+), protein tyrosine kinases, PKC and/or other H7 sensitive kinase(s) involve in the counter-directional signal transduction.
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PMID:Membrane-bound macrophage colony-stimulating factor and its receptor play adhesion molecule-like roles in leukemic cells. 1078 59

Using mouse osteoclast-like cells (OCs), we have shown that short exposure to calcitonin (CT) resulted in prolonged reduction of CT binding by inhibiting de novo CT receptor (CTR) synthesis. Additionally, CT-treated OCs demonstrated resistance to CT rechallenge on the inhibitory effect of CT in osteoclastic bone resorption. There is, however, scant information on CT effects on human osteoclasts. In this study, we examined the features of CTR down-regulation and its recovery after short exposure to CT of human OCs. OCs were prepared by treatment of peripheral blood mononuclear cells in vitro with osteoclast differentiation factor and macrophage colony-stimulating factor. Treatment of OCs with salmon CT (sCT) and human CT (hCT) resulted in a dose-dependent reduction in [125I]sCT binding capacity. Continued receptor occupancy by ligand was excluded by using a glycine-acid washing procedure. Treatment with sCT reduced CTR messenger RNA expression, suggesting that CTR down-regulation is, at least partly, attributable to an inhibition of de novo CTR synthesis. To investigate the intracellular signal transduction pathways that mediate these effects, we examined the effects of activation of the protein kinase (PK)A, PKC, and Ca2+-calmodulin-dependent kinases. Treatment with PKC activators mimicked CT, whereas neither activation of PKA nor elevation of intracellular Ca2+ did so. We further investigated the intracellular signaling pathways responsible for the inhibitory effects of CT on bone resorption, which showed that treatment with PKC activators reproduced the effects of CT. These data suggest that the PKC pathway plays an important role in homologous CTR down-regulation, as well as inhibition of bone-resorbing activity by CT, in human OCs. Short exposure of OCs to CT (10(-9) M, 1 h) reduced [125I]sCT-specific binding for a prolonged period, as we have shown previously in mouse OCs. The reduced specific binding, CTR messenger RNA levels, and CT-sensitive adenylate cyclase responsiveness returned to the control levels by 96 h after removal of CT. These results strongly support the notion that escape from CT inhibition of osteoclastic bone resorption in humans is attributable to the development of resistance by OCs to CT. This study also showed that even short exposure to CT induced prolonged desensitization to CT rechallenge, although the OCs eventually regained responsiveness to sCT rechallenge.
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PMID:Calcitonin receptor regulation and responsiveness to calcitonin in human osteoclast-like cells prepared in vitro using receptor activator of nuclear factor-kappaB ligand and macrophage colony-stimulating factor. 1101 33

Osteoclast differentiation factor (ODF), a recently identified cytokine of the TNF family, is expressed as a membrane-associated protein in osteoblasts and stromal cells. ODF stimulates the differentiation of osteoclast precursors into osteoclasts in the presence of M-CSF. Here we investigated the effects of LPS on the gene expression of ODF in mouse osteoblasts and an osteoblast cell line and found that LPS increased the ODF mRNA level. A specific inhibitor of extracellular signal-regulated kinase or protein kinase C inhibited this up-regulation, indicating that extracellular signal-regulated kinase and protein kinase C activation was involved. A protein synthesis inhibitor, cycloheximide, rather enhanced the LPS-mediated increase of ODF mRNA, and both a neutralizing Ab of TNF-alpha and a specific inhibitor of PGE synthesis failed to block the ODF mRNA increase by native LPS. Thus, LPS directly induced ODF mRNA. Mouse osteoblasts and an osteoblast cell line constitutively expressed Toll-like receptor (TLR) 2 and 4, which are known as putative LPS receptors. ODF mRNA increases in response to synthetic lipid A were defective in primary osteoblasts from C3H/HeJ mice that contain a nonfunctional mutation in the TLR4 gene, suggesting that TLR4 plays an essential role in the process. Altogether, our results indicate that ODF gene expression is directly increased in osteoblasts by LPS treatment via TLR, and this pathway may play an important role in the pathogenesis of LPS-mediated bone disorders, such as periodontitis.
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PMID:Gene expression of osteoclast differentiation factor is induced by lipopolysaccharide in mouse osteoblasts via Toll-like receptors. 1120 18

We and other groups have recently demonstrated that oxidized low density lipoprotein (Ox-LDL) induces proliferation of macrophages in vitro. Since previous immunohistochemical studies demonstrated that macrophages and macrophage derived foam cells proliferated in situ in atherosclerotic lesions, it seems reasonable to expect that the Ox-LDL-induced macrophage proliferation might be linked to the development of atherosclerotic lesions. Thus, clarification of the molecular cascades of Ox-LDL-induced macrophage proliferation is expected to enhance our knowledge of the pathogenesis of atherosclerosis. Recently, we demonstrated that the activation of PKC leads to release into the culture medium of granulocyte/macrophage colony-stimulating factor (GM-CSF) which plays an important role in Ox-LDL-induced macrophage proliferation. In this review article, we mainly show the role of GM-CSF in the Ox-LDL-induced macrophage proliferation. Moreover, based on our recent findings, we summarize the Ox-LDL-induced signaling pathway for macrophage proliferation.
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PMID:Granulocyte/macrophage colony-stimulating factor plays an essential role in oxidized low density lipoprotein-induced macrophage proliferation. 1142 39

Epidemiological, clinical and experimental evidence suggests that fatty acids have a modulatory effect on bone metabolism in animals and humans. To investigate this hypothesis, we evaluated the effects of three different fatty acids, arachidonic acid (AA), eicosapentaenoic acid (EPA) and oleic acid (OA), on the expression of cytokines involved in bone remodelling. Cytokine mRNAs in the human osteoblast-like cell line MG-63 were quantified by reverse transcription-PCR. AA induced increased expression of interleukin-1alpha, interleukin-1beta, tumour necrosis factor-alpha and macrophage colony-stimulating factor mRNAs in a time- and dose-dependent manner. EPA and OA had no stimulatory effects, but instead caused a significant inhibition of AA-induced cytokine mRNA expression. Cell treatment with calphostin C, an inhibitor of protein kinase C (PKC), and cellular PKC down-regulation experiments independently resulted in significant inhibition of AA-induced cytokine expression, suggesting that a PKC-dependent mechanism accounts for the effects of AA on cytokine production. In conclusion, our study demonstrates specific effects of fatty acids on cytokine gene expression in human osteoblast-like cells. The clinical relevance of our findings requires further investigation.
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PMID:Fatty acids and cytokine mRNA expression in human osteoblastic cells: a specific effect of arachidonic acid. 1191 2

Parathyroid hormone (PTH) is a major regulator of osteoclast formation and activation, effects that are associated with reciprocal up- and down-regulation of RANKL and osteoprotegerin (OPG), respectively. The roles of specific downstream signals generated by the activated PTH/PTH-related protein (PTHrP) receptor (PTH1R), such as cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) and phospholipase C/protein kinase C (PLC/PKC), in controlling RANKL and OPG expression and osteoclastogenesis remain uncertain. In MS1 conditionally transformed clonal murine marrow stromal cells, which support PTH-induced osteoclast formation from cocultured normal spleen cells, PTH(1-34) increased RANKL and macrophage colony-stimulating factor (M-CSF) mRNA expression and decreased that of OPG when present continuously for 7-20 days at 37 degrees C in the presence of dexamethasone (Dex). In cells precultured for 7 days and then treated with PTH(1-34), similar reciprocal regulation of RANKL and OPG occurred, maximally at 6-24 h, that was of greater amplitude than the changes induced by chronic (7-10 days) PTH exposure. These acute effects of PTH(1-34) were mimicked by PKA stimulators (8-bromoadenosine [8Br]-cAMP or forskolin [FSK]), blocked by the PKA inhibitor Rp-cAMPs but unaffected by the PKC inhibitor GF109203X. Amino-truncated PTH(1-34) analogs PTH(5-34) and PTH(7-34) neither increased cAMP production in MS1 cells nor regulated RANKL or OPG mRNA. Reciprocal RANKL/OPG mRNA regulation was induced in MS1 cells by PTH(3-34) but only at high concentrations that also increased cAMP. The highly PKA-selective PTH analog [Gly1,Arg19]human PTH(1-28) exerted effects similar to PTH(1-34) on RANKL and OPG mRNAs and on osteoclast formation, both in MS1/spleen cell cocultures and in normal murine bone marrow cultures. The direct PKC stimulator 12-O-tetradecanoylphorbol-13-acetate (PMA) did not induce RANKL mRNA in MS1 cells, but it did up-regulate OPG mRNA and also antagonized osteoclast formation induced by PTH(1-34) in both MS1/spleen cocultures and normal bone marrow cultures. Thus, cAMP/PKA signaling via the PTH1R is the primary mechanism for controlling RANKL-dependent osteoclastogenesis, although direct PKC activation may negatively regulate this effect of PTH by inducing expression of OPG.
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PMID:Cyclic adenosine monophosphate/protein kinase A mediates parathyroid hormone/parathyroid hormone-related protein receptor regulation of osteoclastogenesis and expression of RANKL and osteoprotegerin mRNAs by marrow stromal cells. 1221 38

Colony-stimulating factor-one (CSF-1) and parathyroid-hormone-related protein (PTHrP) down-regulate osteoprotegerin (OPG) gene expression in the dental follicle of the rat first mandibular molar. To examine this regulation at the signal transduction level, we treated cultured dental follicle cells with either phorbolmyristate acetate (PMA) or dibutyryl cyclic AMP (dbcAMP) to activate either protein kinase C (PKC) or protein kinase A (PKA). Our results demonstrate that PMA up-regulates OPG gene expression and down-regulates the expression of CSF-1 and the PTHrP receptor (PTHrP-R). Conversely, dbcAMP down-regulates OPG expression and up-regulates CSF-1 and PTHrP-R expression. Immunostaining shows that PMA also increases the steady-state levels of protein. Thus, treatment with agents that affect protein kinase activity also enhance the steady-state mRNA and protein levels of OPG, as well as decreasing the mRNA levels of CSF-1 and PTHrP-R. The PKC-alpha isoform may be critical in OPG regulation because PKC-alpha gene expression is enhanced by PMA and reduced by either CSF-1 or PTHrP.
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PMID:Regulation of osteoprotegerin gene expression in dental follicle cells. 1265 35

Our previous study has shown that lipophilic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors of statins can inhibit interferon-gamma-induced inducible nitric oxide synthase gene expression in RAW264.7 macrophages. In this study, we showed that lovastatin and fluvastatin are able to upregulate the mRNA expression of the suppressor of cytokine signaling-3 (SOCS-3) gene. This effect is specific for SOCS-3 and could be blocked by mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, while it was not affected by inhibitors of protein kinase C and A, mitogen-activated protein/extracellular signal-regulated kinase kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, Src, Raf and Rho kinase. SOCS-3 expression results in the inhibition of interferon-gamma-, interleukin-6- and macrophage colony-stimulating factor-elicited signal transducer and activator of transcription phosphorylation, suggesting a novel anti-inflammatory mechanism of statins to down-modulate the functions of interferon-gamma-activated macrophages.
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PMID:Statins induce suppressor of cytokine signaling-3 in macrophages. 1464 48

Tooth eruption requires the presence of the dental follicle to recruit mononuclear cells, which fuse to form osteoclasts that resorb the alveolar bone such that the tooth can erupt. In the rat first mandibular molar, there is a major burst of osteoclastogenesis at day 3 postnatally and a lesser burst at day 10. Eruption molecules, such as CSF-1, are maximally expressed at day 3 in the dental follicle to promote this maximal osteoclast formation, but by the time of the secondary burst of osteoclastogenesis their expression is dramatically reduced. Because vascular endothelial growth factor (VEGF) can substitute for CSF-1 to promote osteoclastogenesis, we examined its gene expression in vivo in the dental follicle and found that it and its two major isoforms (VEGF 120 and 164) were all maximally expressed at days 9-11, the time of the secondary burst. Treatment of the cells with phorbolmyristate acetate (PMA), a protein kinase C (PKC) activator, enhanced expression of the 2 major VEGF isoforms in the cultured dental follicle cells, whereas adding a specific PKC inhibitor prevented this. Treatment with PMA also increased the protein level of VEGF. Thus, VEGF may be involved in promoting the secondary burst of osteoclastogenesis, and activation of PKC may upregulate its expression.
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PMID:Expression of vascular endothelial growth factor in the dental follicle. 1469 65


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