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)

The stimulation through TCR-CD3 complexes by immobilized anti-CD3 antibody induced the production of IL-2 and activation-induced cell death (ACD) in the majority of T cell hybridomas. However, some hybridomas produced IL-2 without showing any signs of ACD by the same stimulation, indicating that TCR-CD3-mediated signaling pathways of IL-2 production and of ACD are different. These pathways were discriminated from each other by protein kinase inhibitors and cAMP-elevating reagents such as forskolin. The pathway of IL-2 production but not of ACD was inhibited by protein kinase inhibitors. On the other hand, various cAMP-elevating reagents prevented the T cell hybridomas from TCR-mediated ACD with minimal inhibition of IL-2 production. The elevated cytoplasmic cAMP did not block dexamethasone-induced apoptosis. This indicates that apoptosis is regulated by multiple pathways. Furthermore, the inhibitory effect of cAMP is specific for the TCR-mediated signaling pathway of ACD. Messenger RNA for bcl-2 was detected after treatment with forskolin.
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PMID:Prevention of TCR-mediated apoptosis by the elevation of cAMP. 794 59

IL-2 stimulates the proliferative response of various lymphoid cells. Previous studies showed an increase in intracellular levels of cAMP concomitant with an increase in phosphorylation of discrete proteins by protein kinase A at late G1 phase in mitogen-stimulated lymphocytes. Thus, experiments were undertaken to study nuclear proteins that bind to the cAMP-responsive enhancer (CRE) in cloned T lymphocytes stimulated with IL-2. With the use of a 32P-labeled CRE consensus sequence in a DNA binding gel mobility shift assay, we showed that IL-2 stimulation resulted in the induction of two major DNA-protein complexes at late G1/S during the cell cycle. This binding was competed in a dose-dependent manner by a nonlabeled CRE oligonucleotide but was not competed by a nonlabeled AP-1 oligonucleotide. Rapamycin, a potent immunosuppressant, which arrests IL-2-stimulated T lymphocytes at G1/S, inhibited the IL-2-induced CRE binding activities concomitantly with inhibition of DNA synthesis. By using specific Abs in a gel mobility shift assay, we identified two known CREB/ATF transcription factors in the IL-2-induced CRE complexes: the CRE binding factor (CREB), and ATF1. The induction of CREB binding by IL-2 was not associated with an increase in its abundance but was associated with a major increase in CREB phosphorylation that was particularly prominent at late G1/S. However, we found that G1/S progression induced by IL-2 was not associated with an increase in the intracellular levels of cAMP. These results suggest that 1) the transcription factors CREB and ATF1 and possibly other CRE binding proteins may have an important role in the modulation of specific gene expression at G1/S during cell cycle progression induced by IL-2. 2) The involvement of these CRE binding transcription factors in IL-2-stimulated cells is regulated via a mechanism that is not cAMP dependent.
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PMID:Regulation of cAMP-responsive enhancer binding proteins during cell cycle progression in T lymphocytes stimulated by IL-2. 799 60

Approximately 2 wk after birth, mice having a TGF-beta 1 null mutation (TGF-beta 1(-/-)) exhibit a progressive wasting syndrome and death. Associated with this phenotype is a multifocal infiltration of lymphocytes and macrophages into target organs, especially the heart, lungs, and salivary glands. To explore the consequences of TGF-beta 1 deficiency on the immune system, lymphocyte phenotype and function were analyzed. Initially, lymphoid organ architecture seemed to be normal and, as symptoms developed, the thymus decreased in size, whereas lymph nodes were enlarged. Phenotypically, the TGF-beta 1(-/-) lymphoid cells seemed to be more differentiated in the thymus and activated in the lymph nodes, but remarkably unaffected in the spleen. Moreover, TGF-beta 1(-/-) spleen and lymph nodes displayed enhanced numbers of proliferating cells, as measured by proliferating cell nuclear Ag and/or cyclin-dependent kinase levels. Consistent with this hyperproliferative response, constitutive levels of IL-2 mRNA were elevated in the thymus and both IL-2 and IL-2R mRNA were increased in the lymph nodes. In contrast with the activation profile of TGF-beta 1(-/-) lymphoid cells in vivo, mitogen challenge of these cells in vitro revealed suppressed proliferation that was associated with a defect in inducible IL-2 mRNA expression and IL-2 secretion. Moreover, the addition of rIL-2 restored the deficient mitogen-induced proliferation. The mechanism leading to T cell anergy remains unclear; however, these data confirm the essential role for TGF-beta 1 in maintaining normal immune function.
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PMID:Immune dysregulation in TGF-beta 1-deficient mice. 805 99

The expression and/or up-regulation of several early T cell activation genes is dependent on signals transmitted through the interaction of IL-2 and IL-2R well before entry of the cells into S phase. In these studies, murine G0 T cells activated by immobilized anti-CD3 and subsequently blocked in late G1 expressed normal surface levels and mRNA for IL-2R alpha, IL-2R beta, and transferrin receptor (TfR). However, there was no expression of p34cdc2, and cyclin-dependent kinase (cdk)-2 was not up-regulated even in the presence of exogenous rIL-2. In addition the accumulation of c-myc-specific mRNA and protein was significantly reduced. Pretreatment of G0 T cells with c-myc antisense oligonucleotide effectively reduced the level of specific c-myc protein induced by activation of the cells by immobilized anti-CD3. The presence of antisense c-myc oligonucleotide inhibited the expression of cdc2 and cdk2 without affecting the expression of IL-2R alpha and blocked the activated T cells in the G1 phase. Together these studies demonstrate that c-myc regulates the expression of these cdk and suggest a role for c-myc in the G1/S transition.
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PMID:Up-regulation of c-myc induces the gene expression of the murine homologues of p34cdc2 and cyclin-dependent kinase-2 in T lymphocytes. 815 56

The immunosuppressant rapamycin (RAP) is a potent inhibitor of the entry of interleukin (IL)-2-stimulated T cells into S-phase. Earlier results indicated that RAP treatment arrested the growth of the murine IL-2-dependent T cell line CTLL-2 in late G1-phase. To explore further the interactions of RAP with the cell cycle control machinery in T cells, we examined the effects of RAP treatment on the activation of the cyclin-dependent kinases p34cdc2 and p33cdk2 in G1-phase CTLL-2 cells. Stimulation of factor-deprived cells with IL-2 led to the assembly of high molecular weight complexes containing active p34cdc2 and p33cdk2. The appearance of these complexes was explained, at least in part, by the association of both cyclin-dependent kinases with IL-2-induced cyclin A. RAP treatment profoundly inhibited both cyclin A expression and the appearance of active cyclin A-cyclin-dependent kinase complexes in IL-2-stimulated, late G1-phase CTLL-2 cells. Although p34cdc2 activation was largely dependent on association with cyclin A, a significant proportion of the active p33cdk2 pool was complexed with cyclin E. In contrast to cyclin A, the IL-2-induced accumulation of cyclin E in G1-phase cells was only partially suppressed by RAP, and cyclin E-p33cdk2 complexes were readily detected in drug-treated cells. These cyclin E-cyclin-dependent kinase complexes were nonetheless devoid of histone H1 kinase activity. The inhibitory effects of RAP on the activation of cyclin E- and cyclin A-associated cyclin-dependent kinases suggest that one or both events participate in the regulation of T cell entry into S-phase.
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PMID:Rapamycin inhibition of interleukin-2-dependent p33cdk2 and p34cdc2 kinase activation in T lymphocytes. 822 84

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

For successful allogenic pregnancy to occur, suppression of maternal defense responses toward the fetus are vital. Suppressor factors elaborated by decidual cells or immune cells may facilitate this suppression. In order for appropriate cellular responses to occur an intact signal transduction/second messenger system must be present. The calcium/phospholipid-dependent protein kinase, Pk-C, plays an important role in regulating immune responses, and may also be important in regulating uterine cell responses and implantation events. Pk-C activation is necessary for IL-2 synthesis and IL-2 receptor synthesis through activation of the proto-oncogenes c-jun and c-fos. These proto-oncogene gene products combine to form the heterodimer AP-1 which then activates IL-2 gene transcription for both peptide and receptor. If Pk-C activity becomes abrogated then appropriate cell responsiveness is diminished. We have shown that Pk-C activity is decreased in the particulate fraction of 4-7 day pregnant spleen, thymus and draining lymph node (DLN) cells. Spleen cells did not exhibit any change in cytosolic Pk-C activity, the thymus was found to have a decrease in both cytosol and particulate fractions, and the DLN cells exhibited a translocation effect whereby particulate Pk-C decreased and cytosolic Pk-C activity increased. Supernatant from 3-day cultures of DLN cells from pregnant animals was shown to inhibit proliferation of spleen cells. In addition, the supernatant was able to directly lower Pk-C activity. We hypothesize that DLN cells secrete a factor(s) that is able to suppress immune response through abrogation of Pk-C activity, thereby decreasing AP-1 formation resulting in decreased IL-2 synthesis and IL-2 receptor synthesis.
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PMID:Pregnancy-associated, lymphocyte-derived suppressor factor inhibits protein kinase C activity. 822 96

Expression of the IL-5 gene in T cells is induced in response to Ag stimulation; however, functional analysis of the IL-5 gene has been limited by lack of an appropriate transfection assay to facilitate measurement of the IL-5 promoter activity in response to T cell activation signals. Here, we describe a transient transfection system with which the IL-5 promoter activity can be assayed quantitatively. Using mouse thymoma line EL-4 cells, which produce several lymphokines including IL-2, IL-3, IL-4, IL-10, and GM-CSF in response to PMA, the effect of cAMP on IL-5 production was examined. These cells produce a low level of IL-5 when stimulated with PMA alone; however, N6, O2-dibutyryl cAMP (Bt2cAMP), in combination with PMA, augmented by more than tenfold the IL-5 production at the mRNA and the protein levels. Likewise, a transient transfection assay revealed that Bt2cAMP activated the IL-5 promoter more than tenfold, in a PMA-dependent manner, thereby indicating that two signals, PMA and cAMP, are required for optimal activation of the IL-5 promoter. Activation of the IL-5 promoter in response to Bt2cAMP and PMA depends on the region spanning from nucleotide position -1,200 to +33 relative to the transcription initiation site. Action of cAMP on the IL-5 promoter is mimicked by cotransfection of the expression plasmid containing cDNA encoding the catalytic subunit of protein kinase A, hence, cAMP probably exerts its action through the signaling pathway that involves protein kinase A. In contrast, Bt2cAMP almost completely inhibited the PMA-dependent activation of the endogenous IL-2 gene as well as the transfected IL-2 promoter. These results indicate that the IL-5 gene in EL-4 cells is positively regulated by cAMP in a manner opposite that for the IL-2 gene.
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PMID:cAMP activates the IL-5 promoter synergistically with phorbol ester through the signaling pathway involving protein kinase A in mouse thymoma line EL-4. 824 56

The product of the c-raf-1 proto-oncogene, Raf-1, is known to encode a 74-kDa ubiquitously expressed cytoplasmic serine/threonine kinase. Various growth factors such as epidermal growth factor, acidic fibroblast growth factor, platelet-derived growth factor, insulin, granulocyte-macrophage colony-stimulating factor, interleukin (IL)-2, IL-3 and erythropoietin have been shown to induce phosphorylation of Raf-1, thereby activating Raf-1 kinase. Raf-1 is, thus, believed to play a role in coupling growth factor receptors to proliferation. We have examined the role of Raf-1 in the mitogenic response of human peripheral blood-derived IL-2 receptor expressing T cells to human recombinant IL-2 employing c-raf antisense (AS) oligodeoxyribonucleotide. Uptake studies of oligonucleotides indicated that incorporation of oligomers was maximal at 4 h and oligodeoxynucleotides remained stable in these cells for up to 24 h. Treatment of T cells with the AS oligodeoxyribonucleotide in intracellular duplex formation followed by efficient translation blockade of c-raf-1. In contrast, sense (S) and nonsense (NS) oligodeoxynucleotides failed to form intracellular duplexes and did not interfere with translation of c-raf-1, suggesting specific elimination of c-raf-1 by the AS oligomer. Proliferation of T cells ([3H]thymidine incorporation) following exposure to IL-2 was substantially reduced when the c-raf-1 AS oligodeoxyribonucleotide was added to cultures, while the mitogenic response to this factor remained almost unaffected in the presence of S and NS oligodeoxyribonucleotides.
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PMID:The mitogenic response of T cells to interleukin-2 requires Raf-1. 825 28

After the binding of IL-2, IL-4, or IL-6 to their respective receptors on activated human B cells, a multistep cascade of intracellular events is initiated that results in the secretion of Ig. However, it is not known whether these different cytokine receptors use common or divergent signal transduction pathways to stimulate Ig secretion. Therefore, we examined the signaling mechanisms used by a human lymphoblastoid cell line arrested at a late stage of differentiation, SKW6.4, that secretes IgM following stimulation with IL-2, IL-4, or IL-6 alone. Our study demonstrated that IL-2, IL-4, and IL-6-stimulation of IgM secretion by SKW6.4 cells was inhibited by either the serine/threonine kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperizine dihydrochloride (H7) or the tyrosine kinase inhibitor, genistein. To investigate the early phosphorylation events initiated by these cytokines, a membrane-enriched preparation from SKW6.4 cells was isolated in a manner that minimized the disruption of membrane protein complexes and then incubated with IL-2, IL-4, or IL-6 in the presence of [gamma-32P]ATP. IL-2, IL-4, and IL-6 stimulated the rapid serine/threonine phosphorylation of 47-, 49-, and 91-kDa proteins. However, in contrast to the 47- and 49-kDa proteins that remained phosphorylated for up to 30 min poststimulation, the 91-kDa protein was rapidly dephosphorylated within 15 min of stimulation. The observation that serine/threonine phosphorylation of the same proteins was stimulated by IL-2, IL-4, and IL-6 suggested that the cytokines activated either different protein kinases with the same substrate specificity or the same protein kinase. In addition, stimulation of intact SKW6.4 cells with either IL-2, IL-4, or IL-6 induced the phosphorylation of two proteins with molecular masses of 45- to 50-kDa and 85 to 90-kDa. Taken together, our data demonstrate that activation of both a serine/threonine kinase and a tyrosine kinase is involved in the IL-2, IL-4, and IL-6-stimulation of IgM secretion by SKW6.4 cells and activation of the same or a similar serine/threonine protein kinase is an early step in the signal transduction pathway used by these cytokines.
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PMID:Immunoglobulin secretion and phosphorylation of common proteins are induced by IL-2, IL-4, and IL-6 in the factor responsive human B cell line, SKW6.4. 825 86


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