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 examined the effect of agents which augment intracellular levels of cyclic adenosine monophosphate on the expression of adhesion molecules on human umbilical vein endothelial cells. Surface protein expression of vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecule-1, or intercellular adhesion molecule-1, which is induced by tumor necrosis factor, interleukin-1, and lipopolysaccharide, was not induced by pentoxyfilline, a phosphodiesterase inhibitor, nor by dibutyryl cyclic adenosine monophosphate. Furthermore, neither of these two cyclic adenosine monophosphate elevating agents nor HA 1004, an inhibitor of the cyclic adenosine monophosphate-dependent protein kinase, had any effect on tumor necrosis factor-alpha-induced surface expression of these adhesion molecules. Likewise, cyclic adenosine monophosphate elevating agents were without effect on leukocyte adherence to endothelium stimulated either with these agents alone or in combination with tumor necrosis factor-alpha. Additionally, activators of the stimulatory or inhibitory guanine nucleotide-dependent binding proteins did not affect TNF-alpha-induced surface expression of endothelial leukocyte adhesion molecule-1 or vascular cell adhesion molecule-1.
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PMID:Cytokine-induced adhesion molecule expression on human umbilical vein endothelial cells is not regulated by cyclic adenosine monophosphate accumulation. 839 31

Previous studies have demonstrated that treatment of human U-937 myeloid leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with growth arrest and induction of monocytic differentiation. The present work describes the isolation of a U-937 cell variant, designated TUR, which is unresponsive to the growth-inhibitory effects of this agent. The results demonstrate that, in contrast to U-937 cells, the TUR line fails to respond to TPA with induction of the c-jun, junB, c-fos, and EGR-1 early response genes. The finding that these cells also fail to exhibit adherence or induction of the tumor necrosis factor and c-fms genes further supports their resistance to TPA-induced differentiation. In contrast, TUR cells responded to 1,25-dihydroxyvitamin D3, another inducer of monocytic differentiation, with growth arrest and induction of early response gene and c-fms transcripts. TUR cells also responded to okadaic acid, an inhibitor of type 1 and 2A protein phosphatases, with similar changes in gene expression. Further characterization of TUR cells has demonstrated decreased expression of protein kinase C as compared to wild-type U-937 cells. We also demonstrate that although treatment of U-937 cells with TPA is associated with activation of the Raf-1 serine/threonine kinase, there was no detectable decrease in electrophoretic mobility of this protein in TPA-treated TUR cells. Taken together, these findings indicate that the TUR variant is defective in TPA-induced signaling events upstream to activation of Raf-1 kinase.
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PMID:Resistance to phorbol ester-induced differentiation of a U-937 myeloid leukemia cell variant with a signaling defect upstream to Raf-1 kinase. 839 7

In this study, we characterized the molecular events involved in the activation of the ubiquitous transcription factor NF-kappa B by the viral transactivator pX. pX expression in HeLa cells determines a manyfold increase in NF-kappa B-dependent transcription, which is associated with an increase in p50/p65 heterodimer DNA-binding activity. Since the I kappa B-alpha inhibitory subunit proteolytic degradation, which follows its phosphorylation/modification, is a key event in NF-kappa B activation by different stimuli (such as growth factors, phorbol esters, tumor necrosis factor, UV irradiation, and oxygen radicals), we investigated pX effects on I kappa B-alpha, as well as the possible involvement of known signalling pathways in pX-induced NF-kappa B-dependent transcription. We observed that although pX had no direct effect on p50 or p65, it was able to restore the I kappa B-alpha-suppressed p50/p65 activity. More directly, the stable expression of pX in HeLa cells resulted in reduced levels of I kappa B-alpha in the cytoplasm. Pretreatment of the cells with H7, calphostin C, tyrphostin 25, or N-acetylcysteine did not impair the effects of pX on NF-kappa B, thus ruling out the involvement of protein kinase C, tyrosine kinases, and oxygen radicals. Finally, while most of the known NF-kappa B-activating agents converge on Raf-1 protein kinase, when Raf-1 activity is blocked by overexpression of a dominant negative mutant, the effects of pX on NF-kappa B are not impaired. Thus, we suggest that although pX is able to activate the Ras/Raf-1-signalling pathway, it triggers NF-kappa B activation by an as yet unidentified Raf-1-independent pathway.
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PMID:Hepatitis B virus pX activates NF-kappa B-dependent transcription through a Raf-independent pathway. 852 86

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

This study compared the effects of intracellular pathway inhibitors on tumor necrosis factor-alpha (TNF-alpha) release from human monocytes. Cells were stimulated with peptidoglycan (PG) from Staphylococcus epidermidis or with Escherichia coli lipopolysaccharide (LPS), both in the presence of 10% human serum. Of 10 substances tested, only the protein tyrosine kinase inhibitor tyrphostin AG 126 discriminated significantly between PG and LPS: TNF-alpha release induced by PG, but not by LPS, was dose-dependently suppressed. The results obtained with other modulatory substances, including different protein kinase and G protein inhibitors, suggest that calmodulin-dependent protein kinase, protein tyrosine kinase, and a cholera-toxin-sensitive G protein are involved in both PG- and LPS-induced TNF-alpha release. Further, drugs such as pentoxifylline, chloroquine, and the antioxidant apocynin similarly inhibited TNF-alpha release by PG- as well as LPS-stimulated cells.
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PMID:Intracellular pathways involved in tumor necrosis factor-alpha release by human monocytes on stimulation with lipopolysaccharide or staphylococcal peptidoglycan are partly similar. 853 61

To explore the role of glomerular endothelial cells (GEN) in the pathogenesis of glomerulonephritis, the in vitro production of monocyte chemoattractant protein-1 (MCP-1) by bovine GEN was determined by chemotaxis assay, and Western blot analysis, and immunocytochemistry. Monocyte chemotactic activity of GEN-conditioned media was detectable by a chemotaxis assay using human peripheral blood monocytes. Exposure to human recombinant interleukin-1 beta (IL-1 beta) and phorbol myristate acetate (PMA) significantly increased the chemotactic activity of GEN-conditioned media. A checkerboard analysis showed that the response of monocytes to GEN-conditioned media was truly chemotactic. Immunoadsorption with a monoclonal antibody to human MCP-1 reduced the chemotactic activity of GEN-conditioned media by 85%. Northern blot analysis revealed that MCP-1 mRNA was constitutively expressed by GEN and that IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) increased MCP-1 mRNA levels in a dose- and time-dependent manner. Furthermore, PMA induced an increase in MCP-1 mRNA levels, whereas dibutyryl cyclic AMP and forskolin had minimal effects. Inhibition study using protein kinase inhibitors revealed that MCP-1 mRNA expression induced by IL-1 beta and TNF-alpha was suppressed by the tyrosine kinase inhibitor genistein, not by the protein kinase C inhibitors staurosporine or H-7, or the protein kinase A inhibitor H-89, suggesting an important role of tyrosine kinase in the cytokine-induced MCP-1 gene expression. Dexamethasone had a small inhibitory effect on constitutive MCP-1 mRNA expression, but no effect on the induction by TNF-alpha. By immunoperoxidase staining and Western blot analysis using an anti-MCP-1 monoclonal antibody. MCP-1 protein was detected in untreated GEN and increased by exposure to TNF-alpha. These results demonstrate the cytokine-induced production of MCP-1 by GEN at gene and protein levels as well as bioactivity, and suggest that GEN may participate in the development of glomerulonephritis through the production of MCP-1.
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PMID:Production of monocyte chemoattractant protein-1 by bovine glomerular endothelial cells. 858 46

A new member of the mitogen-activated protein kinase family, alternatively termed CSBP, p38, or RK, has been identified independently by several laboratories recently. Activation of this novel protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of stimuli, such as physicochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as interleukin-1 and tumor necrosis factor. Furthermore, CSAID cytokine biosynthesis inhibitors have now been determined to be potent and selective inhibitors of CSBP/p38/RK kinase activity. These inhibitors will help to dissect signaling pathways involved in inflammatory responses. In particular, for the first time a definitive signal transduction pathway can be prescribed to the action of lipopolysaccharide in cytokine production in macrophages.
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PMID:Role of CSB/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. 860 87

The type I cGMP-dependent protein kinase (cGK) is one of the major pathways for the cGMP cascade and has been demonstrated to inhibit platelet aggregation, relax smooth muscle cells, and control cardiocyte contractility. There are two subtypes of the type I cGK, cGKIalpha and cGKIbeta. The former is more sensitive to cGMP than the latter. In humans, cGKIbeta cDNA was isolated, but the full structure and tissue-specific gene expression of cGKIalpha have not been determined. The significance of cGK in human cardiovascular diseases has not been investigated at the molecular level. In the present study, we isolated the full-length human CGKIalpha cDNA (-36 to +2177; the translation start site: +1) enclosing the 671-amino acid protein. Nucleotides +267 to +2177 of the isolated cDNA were identical to the corresponding nucleotides of human cGKIbeta cDNA. Southern blot analysis suggested that human cGKIalpha and cGKIbeta are generated by alternative splicing of a single gene assigned to chromosome 10. By Northern blot analysis, we detected abundant human cGKIalpha mRNA (7.0 kb) in the aorta, heart, kidneys, and adrenals. In contrast, human cGKIbeta mRNA (7.0 kb) was detected abundantly only in the uterus. In cultured vascular smooth muscle cells, the type I cGK mRNA concentration was reduced to 10% of the basal level by 4 x 10(-10) mol/L platelet-derived growth factor. Angiotensin II (10(-8) mol/L), transforming growth factor-beta (4 x 10(-11) mol/L), and tumor necrosis factor-alpha (6 x 10(-6) mol/L) also exhibited an inhibitory effect on type I cGK gene expression. These findings suggest a pathophysiological implication of the type I cGK in cardiovascular diseases, including hypertension and atherosclerosis.
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PMID:cDNA cloning and gene expression of human type Ialpha cGMP-dependent protein kinase. 861 2

CSBP p38 is a mitogen-activated protein kinase that is activated in response to stress, endotoxin, interleukin 1, and tumor necrosis factor. Using a catalytically inactive mutant (D168A) of human CSBP2 as the bait in a yeast two-hybrid screen, we have identified and cloned a novel kinase which shares approximately 70% amino acid identity to mitogen-activated protein kinase-activated protein kinase (MAPKAP kinase)-2, and thus was designated MAPKAP kinase-3. The binding of CSBP to MAPKAP kinase-3 was confirmed in vitro by the precipitation of epitope-tagged CSBP1, CSBP2, and CSBP2(D168A) and endogenous CSBP from mammalian cells by a bacterially expressed GST-MAPKAP kinase-3 fusion protein and in vivo by co-precipitation of the epitope-tagged proteins co-expressed in HeLa cells. MAPKAP kinase-3 was phosphorylated by both CSBP1 and CSBP2 and was then able to phosphorylate HSP27 in vitro. Treatment of HeLa cells with sorbitol or TNF resulted in activation of CSBP and MAPKAP kinase-3 and activation of MAPKAP kinase-3 could be blocked by preincubation of cells with SB203580, a specific inhibitor of CSBP kinase activity. These data suggest that MAPKAP kinase-3 is activated by stress and cytokines and is a novel substrate of CSBP both in vitro and in vivo.
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PMID:Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. 862 50

The NF-kappaB/Rel transcription factors participate in the activation of immune system regulatory genes and viral early genes including the human immunodeficiency virus type 1 long terminal repeat. NF-kappaB/Rel proteins are coupled to inhibitory molecules, collectively termed IkappaB, which are responsible for cytoplasmic retention of NF-kappaB. Cell activation leads to the phosphorylation and degradation of IkappaBalpha, permitting NG-kappaB/Rel translocation to the nucleus and target gene activation. To further characterize the signaling events that contribute to IkappaBalpha phosphorylation, a kinase activity was isolated from Jurkat T cells that specifically interacted with IkappaBalpha in an affinity chromatography step and phosphorylated IkappaBalpha with high specificity in vitro. By using an in-gel kinase assay with recombinant IkappaBalpha as substrate, two forms of the kinase (43 and 38 kDa) were identified. Biochemical criteria and immunological cross-reactivity identified the kinase activity as the alpha catalytic subunit of casein kinase II (CKII). Deletion mutants of IkappaBalpha delta1 to delta4) localized phosphorylation to the C-terminal PEST domain of IkappaBalpha. Point mutation of residues T-291, S-283, and T-299 dramatically reduced phosphorylation of IkappaBalpha by the kinase in vitro. NIH-3T3 cells that stably expressed wild-type IkappaBalpha (wtIkappaB), double-point-mutated IkappaBalpha (T291A, S283A), or triple-point-mutated IkappaBalpha (T291A, S283A, T299A) under the control of the tetracycline-responsive promoter were generated. Constitutive phosphorylation of the triple point mutant was eliminated in vivo, although tumor necrosis factor-inducible IkappaBalpha degradation was unaffected. In cell lines and in transiently transfected cells, mutation of the CKII sites in IkappaBalpha resulted in a protein with increased intrinsic stability. Together with results demonstrating a role for N-terminal sites in inducer-mediated phosphorylation and degradation of IkappaBalpha, these studies indicate that CKII sites in the C-terminal PEST domain are important for constitutive phosphorylation and intrinsic stability of IkappaBalpha.
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PMID:Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein kinase II affects intrinsic protein stability. 865 13


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