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)

We have reported recently that colchicine and other microtubule-disrupting agents stimulated interleukin-1 (IL-1) alpha and beta synthesis in human monocytes. In this study we found that unexpectedly colchicine failed to stimulate the expression of two other potent immune mediators, namely tumor necrosis factor-alpha and interleukin-6. Remarkably, taxol which induces stable microtubule bundles, antagonized the colchicine but not the LPS-induced IL-1 synthesis. These results suggested that the colchicine-mediated IL-1 induction was generated by microtubule disassembly. We next demonstrated that microtubule disruption triggered an elevation of intracellular levels of cAMP and a subsequent stimulation of protein kinase A. The use of different protein kinase inhibitors supported a role of the PKA, but not the PKC, in the colchicine-induced IL-1 production. Furthermore, elevation of intracellular cAMP levels by 8-bromo-cAMP, forskolin, or cholera toxin potentiated the effect of suboptimal concentration of colchicine on IL-1 synthesis. However, these agents alone were unable to induce IL-1 synthesis. Therefore, our data indicate that the cAMP/protein kinase A-signaling pathway is necessary but not sufficient to generate IL-1 synthesis by microtubule disruption. Thus, microtubule-disrupting drugs appear as useful tools to further characterize the molecular events which regulate IL-1 production in human monocytes.
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PMID:Disruption of microtubule network in human monocytes induces expression of interleukin-1 but not that of interleukin-6 nor tumor necrosis factor-alpha. Involvement of protein kinase A stimulation. 809 11

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

Experiments conducted on STS-50 indicated that space flight significantly inhibited tumor necrosis factor (TNF)-mediated killing of LM929 cells compared to ground controls. In ground-based studies, activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate (PMA) also inhibited TNF-mediated killing of LM929 cells. Therefore, we used PKC inhibitors to determine if the inhibitory effects of spaceflight on TNF-mediated cytotoxicity involved the activation of PKC. In experiments conducted onboard space shuttle mission STS-54, we saw that in the presence of the protein kinase C inhibitors H7 and H8, TNF-mediated cytotoxicity was restored to levels of those observed in the ground controls. Subsequent experiments done during the STS-57 mission tested the dose response of two protein kinase inhibitors, H7 and HA1004. We again saw that killing was restored in a dose-dependent manner, with inhibitor concentrations known to inhibit PKC being most effective. These data suggest that space flight ameliorates the action of TNF by affecting PKC in target cells.
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PMID:Abrogation of TNF-mediated cytotoxicity by space flight involves protein kinase C. 812 55

Two separate tumor necrosis factor (TNF) receptors of approximately 55 kDa (TNF-R55) and 75 kDa (TNF-R75) have been identified. The role of protein kinase A activation by dibutyryl cAMP (dbcAMP) and of protein kinase C activation with phorbol myristate acetate (PMA) for transcriptional and posttranscriptional regulation of the two receptors was investigated in promyelocytic HL-60 cells. Incubation with dbcAMP or the adenylate cyclase agonist forskolin caused an increase in the level of TNF-R75 mRNA while TNF-R55 mRNA was unaffected. The half-life of transcripts for both TNF-R55 and TNF-R75 was unaffected as judged by disappearance of mRNA after inhibition of transcription with actinomycin D. Thus the transcription of the TNF-R75 gene seemed to be enhanced by activation of protein kinase A. This enhancement was not dependent on de novo protein synthesis. Incubation with PMA did not affect the mRNA level of any of the TNF receptors. Both TNF-R55 and TNF-R75 mRNA showed a prolonged half-life after incubation with the inhibitor of protein synthesis cycloheximide, indicating superinduction of the genes. Our results demonstrate that the two TNF receptors can be regulated differently at the transcriptional level and that both transcriptional and posttranscriptional regulation occurs.
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PMID:Independent transcriptional and posttranscriptional regulation of the two tumor necrosis factor receptors in promyelocytic HL-60 cells. 821 93

Recent investigations identified a new signal transduction pathway, termed the sphingomyelin pathway, which may mediate the action of tumor necrosis factor (TNF) alpha and interleukin-1 beta (Mathias, S., Younes, A., Kan, C., Orlow, I., Joseph, C., and Kolesnick, R. N. (1993) Science 259, 519-522). This pathway is initiated by hydrolysis of sphingomyelin to ceramide by a neutral sphingomyelinase and stimulation of a ceramide-activated Ser/Thr protein kinase. Recent investigations demonstrated that kinase activity is proline-directed, recognizing substrates in which the phosphoacceptor site is followed by a proline residue. Until now, the kinase has been defined only as a membrane-bound activity capable of phosphorylating a peptide derived from the sequence surrounding Thr669 of the epidermal growth factor receptor. In the present studies, the kinase was quantitatively extracted from membrane with detergent and separated from protein kinase C by anion-exchange chromatography and isoelectric focusing. Ceramide-activated protein kinase was resolved as an exclusively membrane-bound, 97-kDa protein with a pI of 7.05. Kinase activity toward the epidermal growth factor receptor peptide co-purified with activity toward a generic proline-directed substrate, myelin basic protein. Kinase activity was reconstituted by a denaturation-renaturation procedure and demonstrated activity toward self (autophosphorylation) and exogenous substrate (myelin basic protein). Autophosphorylation occurred exclusively on serine residues. These activities were enhanced to 7-fold of control by ceramide and TNF alpha. These investigations provide additional evidence for a role for ceramide-activated protein kinase in signal transduction for TNF alpha.
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PMID:Renaturation and tumor necrosis factor-alpha stimulation of a 97-kDa ceramide-activated protein kinase. 830 Jun 38

Signal transduction for tumor necrosis factor-alpha and interleukin-1 involves sphingomyelin hydrolysis to ceramide and stimulation of a ceramide-activated serine/threonine protein kinase (Mathias, S., Younes, A., Kan, C., Orlow, I., Joseph, C., and Kolesnick, R. (1993) Science 259, 519-522). Kinase activity is detected by phosphorylation of a 19-amino acid peptide derived from the sequence surrounding Thr669 of the epidermal growth factor receptor. Thr669 is contained within a -Pro-Leu-Thr-Pro- motif, which conforms to a known recognition sequence for the proline-directed class of serine/threonine protein kinases. The present studies used peptides with single-site amino acid substitutions within this sequence to assess substrate recognition by ceramide-activated protein kinase. Substitution of alanine for the C-terminal but not the N-terminal proline reduced kinase activity by 80%. Similarly, substitution of basic residues for the leucine residue reduced kinase activity by 90%. Substitution of acidic residues for leucine, or its removal, also markedly reduced kinase activity. Surprisingly, addition of a leucine residue between threonine and the C-terminal proline enhanced kinase activity 3-4 fold. The Vmax(app) of the enzyme toward the control peptide containing -Pro-Leu-Thr-Pro- (200 +/- 11 pmol of peptide phosphorylated/min/mg of membrane protein) was enhanced 2.3-fold by ceramide. However, ceramide had no effect on the Km (2.0 +/- 0.4 mM). Membranes containing ceramide-activated protein kinase showed minimal activity toward peptides derived from substrates for casein kinase II, S6 kinase, protein kinase C, and cAMP-dependent protein kinase, but possessed substantial activity toward a calmodulin kinase substrate. However, activities toward these substrates were not enhanced by ceramide. These results suggest that ceramide-activated protein kinase may be a member of the proline-directed class of protein kinases and display specificity for -Leu-Thr-Pro- as a minimal substrate recognition motif.
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PMID:Substrate recognition by ceramide-activated protein kinase. Evidence that kinase activity is proline-directed. 837 61

Recent investigations suggest that tumor necrosis factor (TNF)-alpha may utilize the sphingomyelin pathway for signal transduction. Signaling in this system involves hydrolysis of sphingomyelin to ceramide by action of a neutral sphingomyelinase and stimulation of a ceramide-activated protein kinase (Dressler, K. A., Mathias, S., and Kolesnick, R. N. (1992) Science 255, 1715-1718). To clarify the role of this pathway in TNF action, the present studies assessed the effect of the sphingomyelin pathway on activation of nuclear factor kappa B (NF-kappa B), an event considered integral to the transfer of the TNF message to the cell nucleus. As shown previously, TNF (1 nM) induced a marked increase in nuclear NF-kappa B binding in human leukemia (HL-60) cells within 5 min, and elevated binding was detected for as long as 1 h. Addition of a maximally effective concentration of sphingomyelinase, 0.1 units.ml-1, induced a 50% reduction in sphingomyelin content by 5 min from a basal level of 560 pmol.10(6) cells-1 and a quantitative increase in ceramide levels from 89 pmol.10(6) cells-1. Sphingomyelinase 0.1 units.ml-1 also induced an increase in nuclear NF-kappa B binding within 5 min, an effect measurable for as long as 1 h. As little as 1 x 10(-5) units.ml-1 sphingomyelinase was effective and a maximal effect occurred with 1 x 10(-3) units.ml-1. A cell-permeable ceramide analog, C8-ceramide, which mimics biologic effects of TNF-alpha, also enhanced nuclear NF-kappa B activation within minutes. In contrast, addition of a phospholipase C or a synthetic diacylglycerol (DG) analog, 1,2-dioctanoylglycerol, failed to enhance nuclear NF-kappa B binding despite large increases in cellular DG content. Further, TNF-alpha induced elevation in ceramide content by 2 min to 185% of control but did not affect DG levels. These studies provide evidence that stimulation of the sphingomyelin pathway leads to NF-kappa B activation in HL-60 cells.
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PMID:Tumor necrosis factor activation of the sphingomyelin pathway signals nuclear factor kappa B translocation in intact HL-60 cells. 837 8

Fibroblasts of the pulmonary interstitium are intimately involved in the response of the lung to inflammation as well as in repair of injured tissues. The response of fibroblasts within an inflammatory site appears to be directed, in part, by peptide mediators. Neutral endopeptidase (NEP), a metallopeptidase on the surface membrane of fibroblasts, can inactivate various vasoactive peptides, including kinins and tachykinins. Because lung fibroblasts both secrete cytokines and respond to mediators within the immediate environment, NEP might be regulated by locally generated cytokines. We found that several cytokines, including interleukin-1 alpha (IL-1), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor, interleukin-6, and granulocyte macrophage colony-stimulating factor, enhanced activity of NEP on the surface of intact fibroblasts. In contrast, cultured pleural mesothelial cells had much lower levels of NEP than fibroblasts, and the enzyme was not enhanced by either IL-1 or TNF-alpha. Further studies with IL-1 showed that the effect required at least 6 h of exposure to the cytokine and depended upon final cytokine concentration. Combinations of IL-1 with other cytokines increased NEP activity beyond that in cells treated with individual cytokines, but combinations had less than additive effects. Selected pharmacologic agents indicated that the mechanism involves second messenger pathways. The cytokine effect on NEP was attenuated by indomethacin, an inhibitor of cyclooxygenase, by N-[2-(methylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride, an inhibitor of protein kinase, and by adenosine 3',5' cyclic monophosphothionate, an analog of cyclic adenosine monophosphate (cAMP) that competitively inhibits the cAMP signal pathway. It was mimicked by dibutyryl cAMP and by forskolin, an activator of adenyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokines increase neutral endopeptidase activity in lung fibroblasts. 838 Feb 49

This study investigated the expression of HLA class I antigens on Huh6 and HB611 cells induced by interferon (IFN)-alpha, IFN-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta. All of these cytokines induced the antigens on both cells in a dose-dependent manner, with IFNs inducing much more expression than TNF-alpha or IL-1 beta. We have already reported that protein kinase C (PKC) is involved in the antigen expression induced by IFN-gamma on Huh6 cells. The antigen expression induced by IFN-alpha was also blocked by a PKC inhibitor, H-7. However, the antigen expression by TNF-alpha or IL-1 beta was not inhibited by H-7, by a protein kinase A inhibitor, HA1004, nor by a calmodulin antagonist, W-7. These results suggested that PKC, Ca(2+)-calmodulin, and cAMP are not involved in the induction of HLA class I antigens on both cells by TNF-alpha and IL-1 beta. We concluded that TNF-alpha and IL-1 beta induced much less expression of HLA class I antigens on both cells than IFNs and that this might be because the signaling pathway by TNF-alpha and IL-1 beta differed from that by IFNs.
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PMID:Effects of cytokines on HLA class I antigen expression on Huh6 and HB611 cells. 838 37

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


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