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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analyzed the effect of overexpression of bcl-2 gene on cell cycle progression, using the growth factor dependent cell line, TF-1, derived from an erythroleukemia patient. TF-1 (bcl-2) cells, which were transfected with bcl-2 cDNA by the retrovirus vector system, survived and arrested in the G0-1 phase on GM-CSF removal. Centrifugal elutriation studies showed that G0-1-arrested subfraction of TF-1 (bcl-2) reentered the cell cycle with time delay upon GM-CSF re-addition, when compared with TF-1 (mock). A similar delay in cell cycle progression was observed during the recovery phase after 24h-exposure to staurosporine, a protein kinase C(PKC) inhibitor. These results imply functional involvement of bcl-2, both in the GM-CSF and the PKC signal transduction pathway and in G0-1 progression.
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PMID:[Overexpression of bcl-2 suppresses apoptotic cell death of the human leukemic cell line TF-1]. 874 72

The hematopoietic cytokine receptors rapidly activate tyrosine phosphorylation after ligand engagement. In addition, however, serine/threonine phosphorylation of important effector molecules also icreases. Interleukins 2-5 and granulocyte-macrophage colony stimulating factor all activate protein kinase C. This results in serine/threonine phosphorylation of such important regulatory molecules as Raf-1 kinase, myristoylated alanine-rich C kinase substrate, and SOS. These phosphorylated effector molecules are regulators of important genes related to cell survival and proliferation. In addition, as yet uncharacterized serine/threonine kinases associate directly with the hematopoietic receptor subunits themselves. These kinases may contribute to the phosphorylation of the STAT family of transcription factors that is important in regulating cytokine-specific gene inductions. Thus, it is time to begin integrating serine/threonine kinases into the postulated signaling pathways activated by hematopoietic cytokine receptors.
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PMID:The role of serine/threonine phosphorylation in hematopoietic cytokine receptor signal transduction. 903 64

The effect of fibronectin (FN) on IL-1 alpha, IL-1 beta, TNF-alpha, and IL-6 production was investigated with cultured monocytes isolated from human peripheral blood. Monokine concentrations were determined by ELISA. FN markedly stimulated the secretion of IL-1 alpha, IL-1 beta, TNF-alpha, and IL-6 from cultured monocytes. Northern blot analysis revealed the up-regulated expression of mRNA specific for each monokine on exposure of monocytes to FN. GM-CSF, IFN-gamma, and LPS synergistically enhanced FN-induced IL-1 alpha production. We further investigated the signal transduction pathways involved in FN-stimulated monokine secretion. FN-stimulated TNF-alpha secretion was markedly inhibited by either herbimycin A or genistein, inhibitors of protein tyrosine kinase (PTK), but was not affected by staurosporin, a inhibitor of protein kinase C (PKC). The results suggest that PTK is required for FN-stimulated TNF-alpha secretion. In contrast, LPS-stimulated TNF-alpha secretion was markedly inhibited by not only herbimycin A or genistein, but also staurosporin. Therefore, both PTK and PKC may be involved in LPS-stimulated TNF-alpha secretion. We also demonstrated that, in monocytes, cytoplasmic proteins of about 70 and 240 kDa were phosphorylated after FN stimulation. Our results indicate that FN may contribute to the inflammatory response of monocyte by inducing monokine production.
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PMID:[Effects of fibronectin on the monokine production by cultured-human monocytes]. 917 68

It is generally recognized that bcl-2 gene strongly protects cells from apoptosis in various situations. But its function is still to be examined. We analyzed the effect of bcl-2 gene using growth factor dependent cell line, TF-1, derived from an erythroleukemia patient. On GM-CSF removal TF-1 (bcl-2) cells which were transfected with bcl-2 cDNA by retrovirus vector system survived and arrested in G0-1 phase of the cell cycle, while TF-1 (mock) cells which were transfected with vector only also arrested in G0-1 but decreased in number in several days and showed typical apoptosis. N-acetylcysteine, one of antioxidants, did not show such anti-apoptotic effect as bcl-2 in the preincubation experiment. By centrifugal elutriation system the G0-1 arrested subfraction of TF-1 (bcl-2) showed time delay at the re-entry into cell after GM-CSF re-addition when compared with the G0-1 arrested subfraction of TF-1 (mock). Similar delay in cell cycle progression was observed after 24hs-exposure of staurosporine, a protein kinase C (PKC) inhibitor. The expression of cell cycle genes including cyclin A, C, D1, E, cdk2, 4, c-myc, bax and bcl-x showed no difference between these two cell lines upon growth factor removal. These results imply that the functional commitment of bcl-2 into cell cycle progression under the situation of apoptosis especially at the restriction point of G1-S transition.
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PMID:[Overexpression of bcl-2 suppresses apoptosis in the human leukemia cell line TF-1]. 925 8

Recent data have indicated that resident mouse peritoneal macrophages (PMo) transcribed the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes in response to stimulation with the monocyte-macrophage colony-stimulating factor (CSF-1) but only Il6 mRNA was translated into secreted protein. In this paper, we extend these observations. It is shown that resident PMo incubated with protein kinase (PK)C inhibitors, staurosporine (SP) and its derivative GF109203-X, showed a several fold increase in the levels of Il6 mRNA in control and CSF-1-primed PMo and a parallel release of large amounts of protein. In contrast, SP was shown to have no effect on the release of GM-CSF from control or CSF-1-primed PMo, although it increased by approximately twofold the amount of Csfgm mRNA in CSF-1-primed Mo. When SP was added 4 h after CSF-1 priming to block CSF-1-induced protein kinase pathways, an increased amount of IL-6 release was again seen but without any increase in Il6 mRNA levels. Under these conditions, Csfgm gene expression was relatively unaffected. Activation of PKC by phorbol myristate acetate (PMA) also resulted in increased Il6 gene expression by control and CSF-1-primed PMo. PMA had no apparent effect on Csfgm transcription but appeared to influence translation at a low level, as measured by the release of small amounts of GM-CSF protein. The addition of lipopolysaccharide (LPS) to CSF-1-primed PMo resulted in a synergistic increase in the expression of both genes at the levels of transcription and protein release. The addition of SP to CSF-1-primed Mo before LPS, however, further enhanced IL-6 release but not GM-CSF release from the cells. The data indicate that CSF-1-priming drives a number of pathways involved in the regulation of expression of both genes and renders PMo highly susceptible to appropriate secondary stimulatory agents that transform the PMo into secretory inflammatory cells.
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PMID:Priming of mouse macrophages with the macrophage colony-stimulating factor (CSF-1) induces a variety of pathways that regulate expression of the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes. 928 58

Interferon-tau (oIFNtau), the major secretory product of ovine conceptuses between days 13 and 21 (day 0=day of estrus) of pregnancy, is implicated in the process of maternal recognition of pregnancy. Culturing of day-14 and day-16 conceptus tissues in the presence of human granulocyte macrophage-colony stimulating factor (hGM-CSF) or interleukin-3 (IL-3) produces a marked increase in oIFNtau mRNA and protein expression. Since GM-CSF and IL-3 are localized at the luminal and glandular epithelia of the ovine endometrium, maternally derived GM-CSF and IL-3 may affect conceptus production of oIFNtau in a paracrine manner. However, the molecular mechanisms by which endometrial GM-CSF and IL-3 up-regulate oIFNtau production have not been defined. As an initial investigation of the signaling pathway regulating the GM-CSF induction of the oIFNtau gene, day-16 conceptuses were treated with an inducer, phorbol 12-myristate 13-acetate (PMA) and an inhibitor, calphostin C of the protein kinase C (PKC) pathway. Treatment with either 150 units/ml hGM-CSF (P<0.01) or 10 nM PMA (P<0.05) resulted in a significant increase in oIFNtau mRNA expression. Pretreatment of conceptuses with 1 microM PMA for 12 h to produce PKC-deficient tissues or treatment with 50 mM calphostin C abolished the hGM-CSF-induced increase in oIFNtau mRNA. An in vitro expression system was established for the analysis of oIFNtau gene regulatory sequences. The oIFNtau010 gene has been isolated previously and found to be the principal oIFNtau gene up-regulated during the preimplantation period. 5'-Flanking regions of the oIFNtau010 gene, 2 kb and 0.8 kb, were cloned into a basic chloramphenicol acetyltransferase reporter plasmid. These oIFNtau010 promoter constructs, along with expression controls, were transfected into human choriocarcinoma cells (JAR and JEG3) and their responsiveness to hGM-CSF and second messenger system activators including PMA, calcium ionophore (A23187) and 8-bromo-cAMP were characterized. The oIFNtau010 promoter constructs were up-regulated by hGM-CSF and PMA treatments (P<0.01). Combined treatment with PMA and A23187 prevented the promoter activation seen with PMA alone. The conceptus culture data, along with the results from the transfection experiments, suggest that the stimulatory effect of GM-CSF on oIFNtau is mediated through the PKC second messenger system.
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PMID:Enhancement of ovine trophoblast interferon by granulocyte macrophage-colony stimulating factor: possible involvement of protein kinase C. 934 4

Leukaemia inhibitory factor (LIF) acts on the growth and differentiation of haematopoietic cells. By using a specific enzyme-linked immunosorbent assay for human LIF, we demonstrate that human bone marrow stromal cells produce LIF. LIF synthesis is enhanced in a dose-dependent manner after stimulation with lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMAS). LIF production in response to PMA is PKC-dependent since the two PKC inhibitors sphingosine and staurosporine markedly diminished it. Interleukin 1alpha (IL-1alpha), IL-1beta, IL-3, IL-6, IL-8, tumour necrosis factor (TNF-alpha) and SCF (both at 10 ng/ml) stimulate LIF production. By contrast macrophage colony-stimulating factor (M-CSF), granulocyte (G)-CSF, GM-CSF, basic fibroblast growth factor (bFGF), platelet-activating factor (PAF), protaglandin E2 (PGE2), leukotriene B4 (LTB4), and leukotriene C4 (LTC4) did not. These results suggest that bone marrow stromal cells might represent a major source for the cytokine-regulated local production of LIF inside human bone marrow.
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PMID:Spontaneous and inducible production of leukaemia inhibitory factor by human bone marrow stromal cells. 934 7

During the development of allergic inflammation of asthma, eosinophils (EOS) are likely to interact with endothelial adhesion molecules, such as VCAM-1 and inflammatory cytokines, such as GM-CSF. To determine whether VCAM-1 and GM-CSF can interact to modify EOS superoxide anion (O2-) generation, peripheral blood EOS were incubated in either recombinant human (rh)-VCAM-1 or buffer (control)-coated 96-well plates in the presence or absence of 100 pM GM-CSF. VCAM-1 and GM-CSF acted synergistically to stimulate O2- generation which was significantly inhibited by either genistein, a tyrosine kinase inhibitor, or staurosporine, a protein kinase C inhibitor. These results indicate that interaction between VCAM-1 and GM-CSF can stimulate EOS function and its eventual contribution to the allergic inflammation process. Furthermore, our results demonstrate the involvement of tyrosine kinase and protein kinase C in this specific EOS activation.
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PMID:Synergistic activation of eosinophil superoxide anion generation by VCAM-1 and GM-CSF. Involvement of tyrosine kinase and protein kinase C. 936 33

Hematopoietic progenitor cells die by apoptosis after removal of the appropriate colony-stimulating factor (CSF). Recent pharmacologic data have implicated protein kinase C (PKC) in the suppression of apoptosis in interleukin-3 (IL-3) and granulocyte-macrophage (GM)-CSF-dependent human myeloid cells. Because IL-3 and GM-CSF induce increases in diacylglycerol without mobilizing intracellular Ca++, it seemed that one of the novel Ca++ independent isoforms of PKC was involved. We report here that overexpression of PKC epsilon in factor-dependent human TF-1 cells extends cell survival in the absence of cytokine. Overexpression of PKC delta does not have this effect. By 72 to 96 hours after cytokine withdrawal, the PKC epsilon transfectants remain distributed in all phases of the cell cycle, as shown by fluorescence-activated cell sorting (FACS) analysis, while little intact cellular DNA is detectable in vector or PKC delta transfectants. PKC epsilon induces bcl-2 protein expression fivefold to sixfold over the levels in empty vector transfectants, whereas the levels in PKC delta transfectants are similar to those in vector controls.
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PMID:Overexpression of protein kinase C isoform epsilon but not delta in human interleukin-3-dependent cells suppresses apoptosis and induces bcl-2 expression. 944 42

Mycobacterial cell wall contains various lipids (glycolipids and phospholipids) to contribute to its hydrophobic property or acid-fastness and these surface molecules contact with host cells in the early step of infection. Among them, cord factor (trehalose 6,6'-dimycolate, TDM or CF) is the most ubiquitous component, which may be a key molecule for pathogenesis and immunity. Initially, cord factor was isolated from a highly virulent strain of M. tuberculosis which grows in the form of serpentine cords, and showed a marked toxicity for mice when it was administrated intravenously. These observations led to the early hypothesis that cell wall components are related to virulence. However, later studies revealed that cord factors were also found in other non-cord-forming mycobacterial species and other mycolic acid-containing bacteria. Structural studies demonstrated that there were various mycoloyl glycolipids differing in carbohydrate moiety such as glucose mycolate, mannose mycolate, arabinose mycolate and fructose mycolate besides trehalose mycolate in acid-fast bacteria. Therefore, the interest has been focused to the structure-activity relationships of mycoloyl glycolipid and to the mechanism of virulence for host animals. So far, it has been demonstrated that cord factor showed lethal toxicity, granuloma forming activity, adjuvant activity, tumor regressing activity and non-specific infection prevention activity in experimental animals. We have extended investigations further on the structure analysis and immunomodifying activities of cord factor and related mycoloyl glycolipids from various species of mycobacteria, nocardia, rhodococci and gordona, and demonstrated that the most activities were shown in trehalose or glucose esters, but not in mannose, arabinose or fructose esters. Furthermore, it was shown that the longer chain-mycoloyl glycolipids showed the higher toxicity and immunomodifying activities. In mice, in vivo, cytokine inducing activities such as IL-1, IFN-gamma, TNF-alpha, GM-CSF and chemotactic factor were observed and in vitro, TNF-alpha, GM-CSF, chemotactic factor, complement, NO, PGE2 inductions and protein kinase C activation were demonstrated. Furthermore, recently, we have demonstrated that cord factor induced a marked thymic atrophy due to the cortical lymphocyte apoptosis before granuloma formation in mice. It was also established that cord factor showed antigenicity in mice and rabbits and human tuberculous patient sera contained specific antibody (IgG) reactive against cord factor. From above results, cord factor seems to be one of the most potent immunomodulators in the mycobacterial cell wall components pathologically and beneficially.
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PMID:[The 72nd Annual Meeting Education Lecture. Cord factor]. 949 42


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