Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The autoimmune process leading to the destruction of pancreatic beta-cells is mediated by T lymphocytes. Peripheral T cells from subjects with preclinical and clinical type I diabetes respond weakly in vitro to lectin stimulation. We, therefore, investigated in a group of newly diagnosed diabetic patients the presence of a defect in the signal transduction pathway of the T cell receptor (TcR)/CD3 complex. Following stimulation with anti-CD3-coupled beads, the proliferative response in diabetic T cells was significantly decreased in comparison with that from normal T cells. Interestingly, addition of either recombinant interleukin (IL)-2 or phorbol 12-myristate 13-acetate to the cell culture was able to completely restore impaired anti-CD3-induced proliferation in diabetic T cells, suggesting the presence of a defect through the TcR/CD3 pathway, located upstream of protein kinase C (PKC) activation and resulting in low IL-2 production and proliferation. Intracellular Ca2+ measurements by Fluo-3 labeling and flow cytometry analysis on diabetic and control T cells after anti-CD3 stimulation gave comparable results, indicating that this defect does not involve events leading to intracellular Ca2+ mobilization. In contrast, anti-CD3 stimulation of diabetic T cells resulted in a marked impairment of PKC translocation and CD69 antigen expression, as assessed by peptide substrate phosphorylation and by flow cytometry analysis, respectively. Taken together, our data clearly show the presence in individuals at the onset of the disease of an in vitro defect in the signal transduction pathway of the TcR/CD3 complex, resulting in ineffective PKC activation which is not able to induce normal IL-2 production and proliferation of diabetic T cells.
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PMID:Defective T cell receptor/CD3 complex signaling in human type I diabetes. 814 68

G0S8 is a member of a set of putative G0/G1 switch regulatory genes (G0S genes) selected by screening cDNA libraries prepared from blood mononuclear cells cultured for 2 hr with lectin and cycloheximide. Comparison of a full-length cDNA sequence with the corresponding genomic sequence reveals an open reading frame of 211 amino acids, distributed across 5 exons. The 24-kD protein has a basic domain preceding a potential helix-loop-helix domain which contains a QTK motif found about 60 amino acids from the carboxyl terminus in the loop region of several helix-loop-helix proteins. There are potential phosphorylation sites for protein kinase C, creatine kinase II, and protein tyrosine kinases and regions of sequence similarity to helix-loop-helix proteins, tyrosine phosphatases, and RNA and DNA polymerases. The genomic sequence contains a CpG island, suggesting expression in the germ line. Potential binding sites for transcription factors are present in the 5' flank and introns; these include Zif268/NGFI-A/EGR1/G0S30, NGFI-B, Ap1, and factors that react with retroviral long terminal repeats (LTRs). There are several potential interferon response elements and a serum response element in the 3' flank overlapping a region of similarity to a cytomegalovirus immediate-early gene enhancer. Many of these motifs are found in immediate-early G0/G1 switch genes; however, we were unable to demonstrate an increase in G0S8 mRNA in response to lectin alone. Sequence similarities are noted between G0S8 and a variety of genes involved in the immune system, in the regulation of retroviruses, and in the cell cycle.
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PMID:A human gene encoding a putative basic helix-loop-helix phosphoprotein whose mRNA increases rapidly in cycloheximide-treated blood mononuclear cells. 817 20

The effects of cell differentiation and mitogen and phorbol ester stimulation on the formation of 8-methoxypsoralen (8-MOP)-DNA photoadducts in murine T lymphocytes were examined using 3H-8-MOP. While there were no significant differences in 8-MOP photoadduct formation among BALB/c thymocytes, splenocytes, splenic T cells and MRL/lpr lymph node cells, BALB/c bone marrow cells showed fewer photoadducts than did the lymphocytes. This suggested that proliferating progenitor cells may be resistant to 8-MOP photoadduct formation. Incubation of purified splenic T cells with lectin mitogens for 2 h or with phorbol 12-myristate 13-acetate (PMA) for 2-43 h resulted in reduction of 8-MOP photoadduct formation in the DNA, whereas 64 h cultivation with these agents augmented the photoadduct formation. The reduction of photoadduct formation induced by phytohemagglutinin was restored by the further addition of a protein kinase C (PKC) inhibitor, H-7, to the culture. Thus, it is assumed that the reduction of adduct formation evoked by mitogens and PMA is mediated in part by the activation of PKC in the cells. On the other hand, the augmentation of the adduct formation induced by the longer-period cultures with mitogens and PMA appeared to be caused by down-regulation of PKC. The present study showed that the stimulatory signals in which PKC is presumably involved affect the ability of cells to form 8-MOP-DNA photoadducts.
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PMID:Modulation of 8-methoxypsoralen-DNA photoadduct formation by cell differentiation, mitogenic stimulation and phorbol ester exposure in murine T lymphocytes. 831 3

Human T cells were studied with regard to the regulation of interleukin-4 (IL-4) and IL-3 gene expression. IL-4 and IL-3 mRNA were undetectable in unstimulated T cells. On activation with the lectin concanavalin A (Con A), both IL-4 and IL-3 mRNA were expressed. Accumulation of IL-4 mRNA peaked after 6 to 12 hours, whereas IL-3 mRNA levels peaked after 3 to 6 hours of stimulation with Con A. Nuclear run-on assays showed a low constitutive transcription for both genes. The transcription rates were increased by Con A resulting in a peak for IL-4 after 1 hour (30% increase) and for IL-3 after 3 hours (40% increase) of Con A treatment. mRNA stability studies demonstrated that on activation with Con A both messages decayed with a half-life of approximately 90 minutes. No IL-4 or IL-3 mRNA expression was induced by the protein kinase C activator phorbol myristate acetate (PMA). However, PMA augmented the Con A-induced IL-4 and IL-3 mRNA accumulation. This was shown to be mediated at posttranscriptional level by a large increase in the stability of both messages (t 1/2 > 3 hours). The transcription rate of both genes was also enhanced by Con A+PMA and reached peak levels for IL-4 after 1 hour (90% increase) and for IL-3 after 3 hours (70% increase) of stimulation. Furthermore, it appeared that the induction of IL-4 mRNA was dependent on protein synthesis because cycloheximide (CHX) blocked the Con A- and Con A+PMA-induced expression of IL-4 mRNA. In contrast, CHX inhibited, but failed to completely block, the Con A- and Con A+PMA-induced IL-3 mRNA expression, whereas the expression of both genes was completely blocked by cyclosporine A. With regard to the secretion of IL-4 protein it was shown that it closely follows the accumulation of IL-4 mRNA. Taken together, the data show that expression of the IL-4 and IL-3 genes in human T cells is controlled by different activation pathways that affect the gene regulation at transcriptional and posttranscriptional levels.
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PMID:Transcriptional and posttranscriptional regulation of the interleukin-4 and interleukin-3 genes in human T cells. 841

Investigations into the biological actions of nerve growth factor (NGF) have shown that dorsal root ganglion (DRG) neurons subserving nociception require NGF for survival and maintenance of phenotype. This discovery suggests that the signaling NGF receptor, TrkA, can be used as a marker for nociceptive neurons. In this study, we have used antibodies to TrkA, in conjunction with cell biological markers that show a restricted distribution in the DRG, to further characterize subsets of DRG neurons that are dependent upon NGF. Staining for TrkA labeled small and medium-sized neurons that composed 47% of all neurons in thoracic ganglia. Double-labeling with antibodies to the high molecular weight neurofilament protein (NFH), a marker for neurons with myelinated axons, demonstrated that TrkA staining is found in only a small subset of myelinated neurons. Surprisingly, many DRG neurons were not labeled by either TrkA or NFH. These neurons had small soma areas, contained the intermediate filament protein peripherin, and were labeled by the lectin BSI, identifying them as neurons likely to have unmyelinated axons. In addition, small TrkA-negative neurons were extensively labeled by antibodies to the intermediate filament protein alpha-internexin, the delta isoform of protein kinase C, and by the BSI isolectin BSI-B4. In order to assess the potential functions of TrkA-negative small neurons, we examined their projections to the dorsal horn of the spinal cord. TrkA-immunoreactivity in the spinal cord was restricted to lamina I and the outer region of lamina II (IIo), similar to staining for calcitonin gene-related peptide. In contrast, the central projections of TrkA-negative neurons, as visualized by BSI-B4 staining, were particularly dense in lamina IIi. Our results suggest that TrkA-expressing and non-TrkA-expressing small neurons compose functionally distinct populations of DRG neurons.
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PMID:Presence or absence of TrkA protein distinguishes subsets of small sensory neurons with unique cytochemical characteristics and dorsal horn projections. 855 Aug 88

In the present study we compared the effect of rapamycin to that of CsA on the in vitro responses of lectin (PHA), phorbol-ester (PMA) and CA2+ ionophore (ionomycin)-activated peripheral blood mononuclear cells by measuring the release of soluble IL-2R (sIL-2R), high levels of which have been detected in clinical syndromes characterized by an ongoing immune activation. PHA was the stimulant associated with high sIL-2R release, whereas ionomycin-induced sIL-2R release only exceeded the background response and the sensitivity of the ELISA kit. The highest sIL-2R release, however, was obtained when PMA was used in combination with either PHA or ionomycin. Rapamycin inhibited the release of sIL-2R in response to all activators, whereas CsA only abolished the ionomycin-induced sIL-2R release. In parallel experiments rapamycin inhibited cell proliferation in response to all stimulants with the exception of PMA/ionomycin, whereas CsA inhibited all proliferation. Our study clearly shows that for optimal sIL-2R release both Ca+ and protein kinase C-triggered signals are required and that rapamycin has a distinct advantage over CsA in inhibiting the release of sIL-2R, which has been shown to be a reliable marker of lymphocyte activation either in vivo or in vitro.
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PMID:Rapamycin inhibits the in vitro release of soluble interleukin-2 receptor by activated peripheral blood mononuclear cells (PBMC) independently of the mode of activation. 858 87

A bovine IL-2-dependent lymphoblastoid T-cell line (BLTC) was developed and established from peripheral blood mononuclear cells stimulated with Con A, and subpassaged in conditioned media prepared from Con A-activated bovine lymph node cells. The BLTC cell line is IL-2 dependent, requiring exogenous IL-2 either in the form of recombinant bovine or human IL-2 or conditioned media prepared from Con A-stimulated bovine lymph node cells. Conditioned media prepared from mononuclear cells from other species, such as dogs and rats, were without any stimulatory effects. The growth of these cells was lectin-independent, and monokines such as IL-1 beta and TNF-alpha, or conditioned media from LPS-stimulated macrophases failed to support their growth. Immunophenotyping showed that over 90% of the cells were CD2+, CD3+, and CD4+, 25% were CD5%, less than 2% were CD8+, and less than 2% were CD20+. The cells were negative for the gamma delta 215/300 kDa T-cell markers and the 75/110 kDa monocyte markers. The growth of these cells was inhibited by dibutyryl cAMP in the presence or absence of IL-2, and stimulated by the phorbol ester, PMA, in the absence but not in the presence of IL-2. The effects of IL-2 and PMA were blocked by the protein kinase C inhibitor, H-7, suggesting that IL-2 signaling is closely associated with the PKC activation pathway.
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PMID:Development and characterization of an IL-2-dependent bovine CD4+ lymphoblastoid T-cell line. 859 23

We investigated the presence of a galectin-like protein in rat mononuclear cells using a polyclonal antibody raised against a soluble lactose-binding lectin purified from adult chicken liver that immunoreacted strongly with a broad protein band of about 16 kd in Western blot assays. Immunochemical studies revealed a constitutive expression of this protein in mononuclear cells mainly in the macrophage (M phi) population. Subcellular localization was assessed by Western blot assays of the cytosolic and membrane fractions of different cell populations studied: (1) spleen mononuclear cells, (2) T cell-enriched, (3) B cell- and M phi-enriched populations, and (4) peritoneal cells, processed in the presence of lactose. In broad agreement with immunocytochemical studies of nonpermeabilized and permeabilized cells, Western blot assays suggest that this protein is localized mainly in the cytoplasmic compartment but also associated with the cell surface. By flow cytometric analyses we detected about a 14% of ED1 double-positive cells corresponding to macrophages that constitutively express this galectin-like protein associated with their cell surface. The cytosolic fraction obtained from the M phi-enriched cell population showed hemagglutinating activity specifically inhibited by beta-galactoside-related sugars. Moreover, this galectin-like protein was retained in a lactosyl-Sepharose matrix and specifically eluted with lactose. In this work, evidence is also provided to show that different stimuli are able to modulate the expression of the galectin-like protein. Expression was upregulated in inflammatory and activated macrophages, revealing a significant increase in phorbol ester- and formylmethionine oligopeptide-treated cells. Both stimuli involving protein kinase C activation pathway have been able not only to up-regulate the total expression of this protein but also to modulate its subcellular localization.
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PMID:Regulated expression of a 16-kd galectin-like protein in activated rat macrophages. 860 14

Glycosphingolipids (GSLs), cell type-specific markers which change dramatically during ontogenesis and oncogenesis, have been implicated as playing major roles in cellular interactions and control of cell proliferation in multicellular organisms. These functional roles have been partially clarified through two types of studies: (i) Studies of cell recognition mediated by (a) GSL-GSL interaction, (b) GSL-lectin interaction, and (c) GSL-dependent modulation of integrin receptor function. (ii) Studies on control of transmembrane signaling by GSLs and/or sphingosine (Sph) derivatives, with emphasis on effects of these compounds on: (a) signaling pathways initiated by tyrosine kinase-linked receptors; (b) signaling systems mediated by protein kinase C, MAP kinase, other kinases, or cytosolic Ca2+ concentration, leading to changes in cellular phenotypes such as motility, proliferation, differentiation, and apoptosis.
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PMID:Functional role of glycosphingolipids in cell recognition and signaling. 872 Jan 20

The effects of low level exposure of rats to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) on their immune system was investigated Dietary administration to young adult male Leeds strain rats of a total dose of 3 micrograms/kg body weight of TCDD resulted in an exposure duration-dependent reduction of in vitro lipopolysaccharide-induced production of interleukin (IL)-1 in cultures of their splenic macrophages. A 30-day exposure produced approximately 30% suppression and 180-day exposure produced approximately 52% suppression. This reduction did not negatively influence lipopolysaccharide- induced proliferation of B cells, instead an enhancement of B cell proliferation was observed after 30 days exposure. A 180 day exposure significantly suppressed the generation of IL-2 by either concanavalin A or phorbol myristate acetate/calcium ionophore stimulation, and reduced the lectin-induced proliferation of splenic T cells. The 30-day TCDD exposure showed no such immunotoxicity. TCDD at both exposure durations suppressed the expression of the alpha chain of the IL-2 receptor in concanavalin A-activated T cells, without affecting the CD4+/CD8+ ratio. The results suggest that exposure to a low dietary dose of TCDD suppresses the functions of several T cell subsets, some of the immunotoxic effects being produced early, while others require a longer exposure also down-regulates the IL-1 production function of macrophages. A common mechanism of TCDD immunotoxicity may be on the multifunctional signal transduction pathways downstream to the activation of protein kinase C and Ca2+ flux.
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PMID:Immunotoxic effects of prolonged dietary exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 874 96


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