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)

Human T lymphocytes possess both the type I and II isozymes of protein kinase A (PKA). The type I (PKA-I) isozyme is predominantly associated with the plasma membrane, whereas the type II (PKA-II) isozyme is primarily localized to the cytosol. Because the functions of both PKA-I and PKA-II isozymes in the biochemical events of T lymphocyte activation have not been clearly elucidated, we tested the hypothesis that very early events of normal human T lymphocyte activation are mediated by the PKA-I and/or PKA-II isozyme(s). Fresh normal human T cells and a normal human CD4+ T cell line (GK606) activated with anti-CD3-epsilon and recombinant interleukin 1 alpha (rIL-1 alpha) exhibited a peak six- to sevenfold increase of PKA phosphotransferase activity at 5 min that returned to baseline by 60 min. Similarly, both fresh T cells and the T cell line activated by phorbol myristate acetate and ionomycin demonstrated a peak eightfold increase of PKA activity by 15 min that returned toward baseline by 60 min. Chromatographic separation of the PKA isozymes and quantification of phosphotransferase activities after T cell activation by either agonist pair showed preferential activation of the PKA-I isozyme, resulting in a significant reduction in the ratio of PKA-I to PKA-II isozyme activity from 3.1:1-6.2:1 to 1.1:1-3.2:1. PKA-I isozyme activation resulted in the release of free catalytic (C) subunit, an increase in C subunit phosphotransferase activity, and the phosphorylation of T cell plasma membrane-associated proteins, p14, p17, p20, p21, p38, and p48. However, activation of the PKA-I isozyme did not appear to be required for the transcription of IL-2 mRNA, an event necessary for mitosis. These data indicate that ligand-induced T cell activation is associated with rapid activation of the PKA-I, but not PKA-II, isozyme that results in phosphorylation of plasma membrane-associated proteins. The involvement of the PKA-I isozyme during the very early events of T cell activation suggests that this isozyme may be an antigen- or mitogen-stimulated protein kinase.
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PMID:Early events of human T lymphocyte activation are associated with type I protein kinase A activity. 822 35

Bacterial LPS induce production of cytokines such as IL-1, IL-6, and TNF in mononuclear phagocytes, and this represents a central component in the pathogenesis of septic shock syndrome. However, the mechanisms by which LPS activates these cells to express cytokines are not completely characterized. The present study addressed the role of different protein kinases in the LPS induction of cytokines. It is shown that LPS induced a 12- to 16-fold increase in IL-1 beta, IL-6, and TNF-alpha mRNA levels, and this was completely or more than 80% blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1.7 and 37 microM, respectively. Protein kinase C inhibition by staurosporine reduced LPS induction of TNF-alpha, whereas it had no effects on IL-6 and IL-1 beta. Inhibition of protein kinase A by H89 reduced IL-6 mRNA levels but did not detectably change IL-1 beta or TNF-alpha mRNA levels. In contrast, LPS did not increase leukemia inhibitory factor mRNA, which was constitutively expressed and not significantly reduced by these inhibitors. In addition to cytokine mRNA levels, LPS-induced IL-6 protein synthesis and IL-6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein. Both PTK inhibitors also reduced the LPS activation of nuclear factor-kappa B (NF-kappa B), which is a transcription factor involved in the expression of cytokine genes such as IL-6 and TNF-alpha. The activation of NF-kappa B was also reduced by H89, whereas staurosporine had no effect on this response. In summary, these findings suggest that protein kinase C and protein kinase A appear to have selective effects in the LPS induction of cytokines, whereas PTK is required for LPS induction of a broad spectrum of cytokines and NF-kappa B activation in monocytes.
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PMID:Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. 825 85

Several protein kinase inhibitors (PKIs) were investigated for their effects on IL-1 beta, TNF alpha and PMA-induced IL-8 production from human umbilical vein endothelial cells (HUVEC). IL-1 beta (ED50 0.07 ng/ml), TNF alpha (ED50 100 ng/ml) and PMA (ED50 20 ng/ml) induced IL-8 production that could be detected as early as 2 h following stimulation. Staurosporine, a potent but non-specific inhibitor of protein kinases, inhibited PMA-induced (IC50 2 nM) but not IL-1 beta or TNF alpha (IC50 > 200 nM) induced IL-8 production. Neither the cAMP-dependent PKI, KT5720, nor the tyrosine PKIs, genistein, tyrphostin (1-100 microM) or lavendustin A (0.0001-1 microM), inhibited IL-8 production elicited by IL-1 beta. However, the macrolide protein kinase inhibitor geldanamycin (IC50 = 30 nM), but not the closely related analog herbimycin A (5-500 nM), inhibited IL-8 production by 60%. Northern blot analysis of IL-8 mRNA revealed that staurosporine suppressed mRNA increase following stimulation by PMA but not by IL-1. It is proposed that a novel protein kinase susceptible to geldanamycin inhibition may be involved in IL-1-mediated signal transduction.
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PMID:Effect of protein kinase inhibitors on IL-8/NAP-1 release from human umbilical vein endothelial cells. 827 91

Rapamycin (RAP) inhibits several biologic responses in the YAC-1 T cell lymphoma, including the serum-driven proliferation and cyclin A mRNA expression, the induction of Ly-6E Ag expression by IFN, and the induction of IFN-gamma production by IL-1. RAP also suppresses the enzymatic activity of the 70 kDa S6 protein kinase (pp70s6k). To define the mechanistic relationship between these multiple effects of RAP, we have generated stable somatic mutants with altered sensitivities to this drug. A first series of mutants, represented by the R19, 4R16, and 10R13 clones, showed markedly reduced sensitivity to the inhibitory effect of RAP on all biologic responses tested and on pp70s6k activity. Two other mutant types, R103 and R125, were both highly sensitive to RAP-mediated suppression of proliferation, of IL-1-induced IFN-gamma production, and of pp70s6k activity but differed in their Ly-6E response. This response was not affected by RAP in the R125 clone and was enhanced in the R103 clone. Therefore, the inhibitory effects of RAP on proliferation and IL-1-mediated IFN-gamma induction both appear associated with the inhibition of pp70s6k activity, whereas the modulation of Ly-6E induction is independent from the latter. Moreover, the cellular binding of [3H]dihydro-FK-506 was found to be blocked by RAP in all mutant types to the same extent as in wild-type YAC-1 cells, suggesting that the altered sensitivity to the effects of RAP in these mutants is not due to an inability of the drug to enter the cells or to interact with FKBP. Further biochemical characterization of the mutant cells described here is expected to help clarify the mechanisms of RAP action.
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PMID:Relationship between multiple biologic effects of rapamycin and the inhibition of pp70S6 protein kinase activity. Analysis in mutant clones of a T cell lymphoma. 830 Nov 50

AP-1 is a transcriptional activator composed of homo- and heterodimers of Jun and Fos proteins. It is involved in activation of genes, such as collagenase, stromelysin, IL-2 and TGF beta 1, by tumour promoters, growth factors and cytokines. AP-1 activity is also elevated in response to transforming oncogenes and is required for cell proliferation. AP-1 activity is subject to complex regulation both transcriptionally and post-transcriptionally. Transcriptional control of jun and fos gene expression determines the amount and composition of the AP-1 complex. The jun and fos genes are regulated both positively and negatively and are highly inducible in response to extracellular stimuli. Post translational control is also important. Both cJun and cFos are subject to regulated phosphorylation. In the case of cJun, phosphorylation of sites near the DNA-binding domain inhibits DNA-binding, while dephosphorylation reverses this inhibition. Phosphorylation of cJun on sites within the N-terminal activation domain increases its ability to activate transcription. The protein kinase phosphorylating these sites is stimulated by cytokines and growth factors. Another mechanism modulating AP-1 activity is transcriptional interference by members of the nuclear receptor family and is relevant for the pathophysiology of rheumatoid arthritis (RA). In RA, chronic inflammation leads to increased AP-1 activity in T cells,macrophages and synoviocytes as a response to secretion of cytokines such as IL-1 and TNF alpha. While the IL-2 gene plays a major role in T cell activation, another AP-1 target gene encodes an enzyme, collagenase, responsible for destruction of bone and tendon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Various modes of gene regulation by nuclear receptors for steroid and thyroid hormones. 831 34

IL-1 activates human lung fibroblasts via IL-1-specific membrane receptors. The numbers of IL-1 binding sites on fibroblasts are increased after exposure to prostaglandin E2 (PGE2) or IL-1. Increases in binding sites are associated with changes in functional responses to IL-1. In these studies, we determined if alterations in numbers of IL-1 binding sites on human lung fibroblasts were associated with parallel changes in IL-1R mRNA. In addition, since IL-1 and PGE2 can activate protein kinase C (PKC) and protein kinase A (PKA), we exposed human lung fibroblasts to 1-(5-Isoquinoline sulfonyl)-2-methylpiperafine (H7) or staurosporine, which are relatively specific inhibitors of PKC, and N-[2-(methylamino)ethyl]-5-isoquinolinesulfomamide (H8), an inhibitor of PKA, to determine whether the IL-1 and PGE2 stimulated increases in binding sites were mediated by activation of PKC or PKA. H7 decreased the base line and PGE2-stimulated increases in numbers of IL-1 binding sites. Exposure of the fibroblasts to phorbol-12-myristate-13-acetate (PMA) for 24 h, which is known to deplete PKC, also decreased the numbers of base line IL-1 binding sites. These changes were paralleled by changes in amounts of IL-1R mRNA. H7 and staurosporine also blocked IL-1 and PGE2 stimulated increases in IL-1R mRNA. In contrast, H8 had no effect on the base line or PGE2-stimulated increases in numbers of IL-1 binding sites nor did it change the amounts of IL-1R mRNA. These studies show that changes in the numbers of IL-1 binding sites on human lung fibroblasts are paralleled by changes in IL-1R mRNA. In addition, PKC activity is necessary for the expression of both base line and stimulated increases in IL-1 binding sites and IL-1R mRNA. These studies suggest that PKC activity plays an important role in the modulation of IL-1R expression.
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PMID:Protein kinase C modulates the amounts of IL-1 receptor mRNA in human lung fibroblasts. 832 29

Human chorionic cells in culture synthesized and secreted a large amount of hyaluronate as well as tissue collagenase. When these cells were treated with human recombinant interleukin 1 alpha (hrIL-1), the biosynthesis and secretion of hyaluronate were predominantly accelerated, but those of sulfated glycosaminoglycans were not modulated. This promotive effect of hrIL-1 was not due to the increase in endogenous prostaglandins including prostaglandin E2 since cyclooxygenase inhibitors, indomethacin and diclofenac did not modulate the IL-1-mediated production of hyaluronate. On the other hand, the cotreatment of chorionic cells with hrIL-1 and cycloheximide suppressed the IL-1-mediated hyaluronate production, suggesting that protein, de novo, synthesis required for the enhancement of hyaluronate synthesis. Upon treatment with hrIL-1, the membrane bound-hyaluronate synthase activity was increased up to 5-fold in a time-dependent manner. On the other hand, when chorionic cells were treated with hrIL-1 and/or protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methyl-pyperadine hydrochloride (H7), the IL-1-mediated production of hyaluronate was effectively suppressed. Similarly, H7 effectively suppressed the protein kinase activator, 12-O-tetradecanoyl-phorbol-13-acetate-enhanced production of glycosaminoglycans with a similar extent. These results indicate that IL-1-induced acceleration of hyaluronate production was reflected on the increase in hyaluronate synthase activity, and that protein kinase C participates positively in the IL-1-signal transduction for the increased synthesis of hyaluronate in human chorionic cells.
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PMID:Regulation of hyaluronate production by interleukin 1 in cultured human chorionic cells. 835 36

T2, an extract of Tripterygium wilfordii Hook F, has been reported to be effective in the treatment of a variety of autoimmune diseases, including rheumatoid arthritis. Previous studies have shown that T2 inhibited mitogen- or antigen-induced proliferation of human peripheral blood T cells and B cells, IL-2 production by T cells and Ig production by B cells. In contrast, T2 did not affect monocyte functions, such as IL-1 production and antigen presentation. The current studies sought to localize the immunosuppressive action of T2 more precisely. Results show that T2 prevented [3H]-uridine uptake by mitogen-stimulated T cells and arrested them in the early GI phase of the cell cycle. The inhibitory effects of T2 could be partially overcome by costimulating PHA activated T cells with PMA and completely nullified by costimulation with PMA plus a monoclonal antibody to CD28. Moreover, T2 had no effect on expression of IL-2R or the transferrin receptor (CD71), but inhibited production of a number of cytokines, including IL-2 and IFN-gamma by activated T cells. T2 suppressed IL-2 mRNA levels, but not IL-2R mRNA levels, in activated T cells. T2-mediated inhibition reflected suppression of IL-2 gene transcription as indicated by suppression of the expression of a reporter gene driven by the IL-2 promoter. T2 had little inhibitory effect on either IL-2 gene expression or cell cycle progression when added after initial mitogenic stimulation, indicating that an early step in the cascade of activation events was inhibited. However, initial activation events including protein tyrosine phosphorylation, the generation of diacylglycerol, IP3, and the translocation of protein kinase C were not inhibited by T2. Moreover, T2 did not inhibit the phosphatase activity of calcineurin. These results have localized the effect of T2 to a step in the T cell activation cascade after initial second messenger generation, tyrosine phosphorylation and protein kinase activation, but before IL-2 gene transcription.
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PMID:The Chinese herbal remedy, T2, inhibits mitogen-induced cytokine gene transcription by T cells, but not initial signal transduction. 855 49

Bone-resorbing osteoclasts are of hemopoietic cell origin, probably of the CFU-M-derived monocyte-macrophage family. Bone marrow-derived osteoblastic stromal cells play an important role in modulating the differentiation of osteoclast progenitors in two different ways: one is the production of soluble factors, and the other is cell-to-cell recognition between osteoclast progenitors and osteoblastic stromal cells. M-CSF is probably the most important soluble factor, which appears to be necessary for not only proliferation of osteoclast progenitors, but also differentiation into mature osteoclasts and their survival. A number of local factors as well as systemic hormones induce osteoclast differentiation. They are classified into three categories in terms of the signal transduction: vitamin D receptor-mediated signals [1 alpha,25(OH)2D3]; protein kinase A-mediated signals (PTH, PTHrP, PGE2, and IL-1); and gp130-mediated signals (IL-6, IL-11, oncostatin M, and leukemia inhibitory factor). All of these osteoclast-inducing factors appear to act on osteoblastic cells to commonly induce osteoclast differentiation factor (ODF), which recognizes osteoclast progenitors and prepares them to differentiate into mature osteoclasts. This line of approach will undoubtedly produce new ways to treat several metabolic bone diseases caused by abnormal osteoclast recruitment such as osteoporosis, osteopetrosis, Paget's disease, rheumatoid arthritis, and periodontal disease.
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PMID:Modulation of osteoclast differentiation by local factors. 857 4

The present study was conducted to determine whether endogenous IL-1 is involved as a potent mediator of PGE2-stimulated osteoclast formation in 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3)-primed calvarial cells from mouse embryos. PGE2 induced IL-1 beta gene expression in the primed calvarial cells. IL-1 beta gene expression was also induced in a dose-dependent manner by forskolin and dibutyryl cAMP. PGE2-induced IL-1 beta gene expression was markedly inhibited by H-89, a potent inhibitor of protein kinase A. On the other hand, osteoclast formation in 1 alpha,25-(OH)2D3-primed calvarial cells was also stimulated by forskolin and dibutyryl cAMP, and their stimulatory effects were dose dependent. H-89 also inhibited PGE2-stimulated osteoclast formation. The presence of the IL-1 beta gene product in the conditioned medium of 1 alpha,25-(OH)2D3-primed calvarial cells treated with PGE2 was proved by the results of an immunoprecipitation assay using anti-mouse IL-1 beta Ab. The addition of anti-mouse IL-1 beta Ab to 1 alpha,25-(OH)2D3 primed calvarial cell cultures markedly inhibited PGE2-stimulated osteoclast formation. The stimulatory effect of conditioned medium of primed calvarial cells treated with PGE2 on osteoclast formation was also inhibited by anti-IL-1 beta Ab pretreatment. Furthermore, we found that endogenous IL-6 is partially involved in PGE2-stimulated osteoclast formation.
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PMID:Prostaglandin E2 stimulates osteoclast formation via endogenous IL-1 beta expressed through protein kinase A. 859 46


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