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)

Jun homodimers and Fos/Jun heterodimers bind to the gene for phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) at three sites within the first 350 base pairs of the promoter. These include CRE-1 (-82 to -90), and P3(II) and P4 (-252 to -258 and -268 to -285, respectively). Over-expression of Jun in HepG2 cells resulted in a 10-15-fold increase in the level of transcription of a chimeric PEPCK (-490 to +73)-CAT gene, while expression of Fos decreased transcription and blocked the induction of transcription from the PEPCK promoter by Jun. The action of Fos and Jun on PEPCK gene transcription involved each of the Fos/Jun-binding sites and was modulated by additional transcriptional regulatory elements within the PEPCK promoter. The ability of Fos to inhibit PEPCK transcription was dependent upon P3(I), a region of the promoter which does not bind Fos/Jun heterodimers, but does bind members of the C/EBP family of transcription factors. Stimulation of PEPCK transcription by 8-Br-cAMP or by overexpression of the catalytic subunit of protein kinase A was inhibited by Fos expression. The inhibitory effects of phorbol esters and protein kinase C on PEPCK gene expression may be mediated through the action of Fos and Jun.
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PMID:Opposing actions of Fos and Jun on transcription of the phosphoenolpyruvate carboxykinase (GTP) gene. Dominant negative regulation by Fos. 132 59

Recently, it was shown that lipoprotein lipase (LPL) was produced in neonatal but not in adult rat liver. In an attempt to further define the mechanism involved in liver LPL expression, we identified a neonatal mouse hepatoma cell line, BWTG3, capable of producing LPL. The regulation of LPL expression by various extracellular stimuli was investigated in this cell line. Progesterone caused a rise in LPL production by BWTG3 cells. Other hormones tested, such as insulin, glucagon, adrenalin, testosterone, and thyroid hormone, had no effect on LPL production. The effects of progesterone on LPL production showed slow kinetics reaching a maximum 24 h after addition. Cotransfection of a progesterone receptor expression vector with a 5'-LPL-CAT reporter construct resulted in an induction of CAT activity, suggesting that the increase in LPL accumulation after progesterone was linked to transcriptional induction of the LPL gene. Stimuli causing an elevation of protein kinase A activity in the cells also increased LPL production. Three agents capable of elevating intracellular cAMP levels, i.e., forskolin, dBcAMP, and choleratoxin, caused an elevation of LPL production. The increase in LPL activity caused by forskolin and choleratoxin was paralleled by an elevation of LPL mRNA levels, while dBcAMP only induced a small elevation of LPL mRNA levels. The increase in LPL production was shown to be linked to the stimulation of the PKA signal transduction pathway and was apparently transmitted via the transcription factor CREB. No effect of the stimulation of protein kinase C or calcium/calmodulin-dependent kinase on LPL production was detected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipoprotein lipase expression in undifferentiated hepatoma cells is regulated by progesterone and protein kinase A. 132 33

To examine the molecular mechanisms by which mechanical stimuli induce protooncogene expression, we cultured rat neonatal cardiocytes in deformable dishes and imposed an in vitro mechanical load by stretching the adherent cells. Myocyte stretching increased total cell RNA content and mRNA levels of c-fos and skeletal alpha-actin followed by activation of protein synthesis. CAT assay indicated that sequences containing a serum response element were required for efficient transcription of c-fos gene by stretching. This accumulation of c-fos mRNA was suppressed by protein kinase C inhibitors at the transcriptional level and was inhibited markedly by down-regulation of protein kinase C. Moreover, myocyte stretching increased inositol phosphate levels. These findings suggest that mechanical stimuli might directly induce protooncogene expression, possibly, via protein kinase C activation. Furthermore, we observed the activation of mitogen activated protein (MAP) kinase by myocyte stretching. This result suggest that MAP kinase activation might increase the efficiency of protein synthesis in ribosomes induced by mechanical stimuli.
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PMID:Role of protein kinase system in the signal transduction of stretch-mediated myocyte growth. 133 62

We have previously shown that the phorbol ester, TPA, which activates protein kinase C, causes, in PC12 cells, a transcriptional activation of tyrosine hydroxylase (TH), the key enzyme in catecholamine synthesis. The study has now been extended to examine the processes that underlie this transcriptional stimulation and, in addition, to seek whether similar mechanisms are involved in long-term trans-synaptic induction of the TH gene in adrenal medullae of rats that have been given a single injection of reserpine. In both systems, it was found that the induction of c-fos gene transcription was associated with that of the TH gene but with different kinetics. The promoter of the TH gene contains (at position -207/-200) a sequence (TGATTCA) which differs from the consensus TRE or AP-1 site (TGACTCA) by one nucleotide. Experiments were carried out to investigate whether the AP-1 protein complex which is known to contain Fos and Jun binds to the putative TRE region of the TH promoter. In the gel shift assays, the nuclear protein extracts derived from TPA-treated PC12 cells and from AM of reserpine injected rats displayed a higher magnitude of binding to a 25-mer TRE-TH oligonucleotide as compared to controls. The results showed that the behaviour of TRE-TH was atypical in that two retarded complexes (A and B) were observed, which were displaced by specific competitors. Trans-activation experiments with plasmids TRE-TH/TK/CAT and -754/-19 TH/pUC18-CAT in PC12 cells showed an increase in CAT activity in response to TPA that correlates with the previously observed increase in TH transcriptional activity by TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:AP-1 complex and c-fos transcription are involved in TPA provoked and trans-synaptic inductions of the tyrosine hydroxylase gene: insights into long-term regulatory mechanisms. 138 60

1. Cultured aortic endothelial cells of the pig respond to the endothelium-derived relaxing factor (EDRF) they release with an increase in cyclic GMP content. This response is inhibited by haemoglobin or by L-NG-monomethyl-arginine (L-NMMA), and has been used to investigate the effects of phorbol esters on EDRF release. 2. Pretreatment with phorbol-12,13-dibutyrate (PDB) but not the inactive 4 alpha-phorbol-12,13,-didecanoate (PDD), inhibited increases in cyclic GMP induced by substance P (10(-8) M) in a time and concentration-dependent manner. PDB did not affect basal cyclic GMP levels. 3. PDB (3 x 10(-7) M), but not PDD (3 x 10(-7) M), also inhibited ATP (10(-5) M)-induced increases in cyclic GMP, but did not affect those induced by bradykinin (10(-7) M). 4. Increases in cyclic GMP induced by low (10(-7) M) but not high (10(-6) M) concentrations of the calcium ionophore A23187 were inhibited by PDB (3 x 10(-7) M). This inhibitory effect was due to enhanced destruction of EDRF by superoxide anions rather than inhibition of EDRF release, as the inhibition was abolished in the presence of superoxide dismutase (SOD, 30 mu ml-1) and catalase (CAT, 100 mu ml-1). 5. SOD and CAT did not affect the inhibitory action of PDB on substance P or ATP-induced increases in cyclic GMP. 6. Increases in endothelial cell cyclic GMP content induced by sodium nitroprusside (10(-5) M) were unaffected by PDB pretreatment. 7. The inhibitory effects of PDB are probably a result of an action of protein kinase C on the steps between receptor occupation and phospholipase C activation.
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PMID:Release of endothelium-derived relaxing factor from pig cultured aortic endothelial cells, as assessed by changes in endothelial cell cyclic GMP content, is inhibited by a phorbol ester. 169 49

IL-8 is produced by a wide variety of cells in response to polyclonal mitogens and cytokines. Northern blotting analysis revealed that IL-1, TNF and PMA could induce rapid expression of IL-8 mRNA in the absence of new protein synthesis. Nuclear run-off assays using different cell types demonstrated that IL-8 mRNA expression could at least be partly due to the activation of transcription. Cloning and determination of the entire sequence of IL-8 genomic DNA enabled us to explore the functional significance of the 5'-flanking enhancer region of the IL-8 gene by employing CAT assays. The results indicated that the region spanning from -94 to -71 bp is minimally sufficient for conferring responsiveness to IL-1, TNF and PMA. Further analysis using point-mutations revealed that this region consisted of two distinct cis-elements; one being the potential binding site for NFkB-like and the other for a C/EBP-like factor. These results suggested that all three stimuli, IL-1/TNF/PMA, modulate the identical combination of nuclear factors possibly by phosphorylation. We previously reported that these three stimuli activated the same serine protein kinase which phosphorylates identical 65 kDa and 74 kDa cytosol proteins in human PBMC. This IL-1/TNF/PMA-activated protein kinase is distinct from protein kinase A, protein kinase C or casein kinase in substrate specificity; in Ca and phospholipid dependency; in cyclic nucleotide dependency; and sensitivity to protein kinase inhibitors. Taken collectively, IL-1/TNF/PMA may activate a common serine protein kinase and this protein kinase may in turn directly or indirectly modulate several nuclear factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of human interleukin 8 gene expression and binding of several other members of the intercrine family to receptors for interleukin-8. 175 77

Mediation by Ca2+ of TRH action on the PRL promoter was investigated by both additivity and pharmacological studies and by techniques that probe more gene-proximal events. TRH required the presence of Ca2+ in the medium for stimulation of transient expression in GH3 cells of a PRL-chloramphenicol acetyltransferase (PRL-CAT) construct containing proximal PRL promoter sequences [(-187)PRL-CAT]. Chronic 12-O-tetradecanoyl phorbol-13-acetate down-regulation of cellular protein kinase C did not block induction of expression of (-187)PRL-CAT by either Ca2+ or TRH. In studies with Ca2+ blockers, the Ca2+ flux inhibitors cobalt ion and nimodipine blocked induction of (-187)PRL-CAT expression by either Ca2+ or TRH. On the other hand, the Ca2+ immobilizers 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyltetraester and 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate blocked induction of expression of this construct by Ca2+ but not by TRH, suggesting that TRH regulation of the PRL promoter may be dependent on Ca2+ fluxes but insensitive to Ca2+ immobilization. We have shown previously that the PRL promoter pit-1 binding site 1P is a TRH response element. In the present studies, Ca2+ regulation studies with 5'-deletion mutants of (-204)PRL-CAT showed that (-75)PRL-CAT, containing the single pit-1 binding site 1P, also contains a Ca2+ response element. The observation that two copies of a site 1P oligomer transferred a Ca2+ response to either of the two minimal constructs (-39)PRL-CAT or (-39)mouse metallothionein-CAT showed that site 1P is an independent Ca2+ response element. Analysis of site 1P mutants yielded a strong correlation between the ability to bind pit-1 and to transfer a Ca2+ response. In addition, coexpression of a mutant pit-1 possessing reduced trans-activational activity strongly inhibited TRH regulation of (-187)PRL-CAT and partially blocked Ca2+ regulation of this construct. We conclude that Ca2+ mediates TRH action on the PRL promoter, and that pit-1 represents a gene-proximal mediator in this signalling pathway.
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PMID:Mediation by calcium of thyrotropin--releasing hormone action on the prolactin promoter via transcription factor pit-1. 177 32

The expression of human immunodeficiency virus type 1 (HIV) is enhanced after T cell activation due to the interaction of cell-encoded nuclear factors with binding sites in the viral long terminal repeats (LTR). We studied the minimal signal transduction requirements for induction of HIV transcription during T cell activation. Monoclonal antibodies (mAb) against the T cell receptor/CD3 complex induced interleukin (IL) 2 production as well as HIV-LTR-directed gene expression in Jurkat T cells. Addition of cyclosporin A or buffering of intracellular Ca2+ changes did not abolish this LTR-directed gene expression but did block IL 2 production. In contrast, interference with protein kinase C (PKC) activation did inhibit both IL 2 production and LTR-driven gene expression. Under all conditions HIV-LTR-directed gene expression correlated with gene expression induced by the NF-kB binding enhancer, but not by the NF-AT or OCT-1 binding sites. In accordance with observations by Verweij, Geerts and Aarden on the CD28 co-stimulatory activation of IL2 transcription via an NF-kB-like activity, stimulation of the CD2, CD28 and CD44 accessory molecules was tested to mimick physiological activation signals independent of T cell receptor triggering. mAb directed against CD2 and CD44 only marginally induced the LTR. Next, non-mitogenic stimulation by mAb against CD28 clearly induced the HIV-LTR- and NF-kB- but not NF-AT- and OCT-1-driven chloramphenicol acetyltransferase CAT expression, showing a direct effect on gene expression via this receptor. Taken together, this report shows that non-mitogenic T cell activation signals are sufficient to induce HIV transcription. The finding that these signals may be delivered by receptors that are not dependent on antigen-specific activation may have important implications for our understanding of HIV pathogenesis.
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PMID:Non-mitogenic T cell activation signals are sufficient for induction of human immunodeficiency virus transcription. 184 14

EGR2 is a human zinc finger encoding gene whose expression is induced with fos-like kinetics by diverse mitogens in several cell types. Since its cDNA sequence predicts a protein which contains zinc finger motifs, EGR2 may play a transcriptional regulatory role in cellular proliferation. The present study was undertaken to: 1) examine the genomic organization and 5' flanking sequence of EGR2 so as to identify upstream regulatory elements; 2) test whether these elements are functional in gel shift assays and by transient expression; and 3) examine whether pathways other than protein kinase C lead to serum induction of EGR2, and if they do, ask whether the different pathways converge on a serum response element. The EGR2 gene spans 4.3 kb and has one intron. The translation initiation site is located within the first exon. The transcription start site of EGR2 was determined by S1 nuclease and primer extension analysis and a TATA box was identified 28 bp upstream. Two putative serum response elements, designated CArG-1 and CArG-2 were identified in the 5' flanking sequence. By deletion analyses and mutagenesis, serum and PMA responsiveness of the cloned EGR2 promoter region was traced to the CArG-1 region in transient CAT assays performed in NIH 3T3 cells. Both protein kinase C dependent and independent pathways were found to converge on the CArG-1 box to induce the expression of EGR2.
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PMID:The serum and TPA responsive promoter and intron-exon structure of EGR2, a human early growth response gene encoding a zinc finger protein. 211 Oct 9

IL-1, like other agents that have been shown a capacity to induce protein kinase C, is a potent transcriptional activator of the metalloproteinase, stromelysin, in synovial and other fibroblasts. cAMP has been shown to inhibit stromelysin transcription in fibroblasts of nonsynovial origin, and is regarded as an important second messenger for IL-1. In addition to stimulating metalloproteinase transcription, IL-1 also induces PGE2 production in synoviocytes. We determined that rIL-1 alpha led to the time-dependent accumulation of intracellular cAMP in serum-starved rheumatoid synovial fibroblasts, and that the effect was blocked by indomethacin. The cAMP agonists forskolin, 3-isobutyl-1-methylxanthine, and PGE2 suppressed the IL-1 induction of stromelysin; conversely, indomethacin superinduced IL-1-elicited stromelysin mRNA. These results were recapitulated on the transcriptional level in cells transfected with the rat transin/stromelysin promoter in a reporter (CAT) construct. 2',5'-Dideoxyadenosine, an inhibitor of adenylate cyclase, also augmented the IL-1 induction of stromeylsin mRNA, as did H-8, a specific inhibitor of the cAMP-dependent protein kinase A. Staurosporine and H-7, inhibitors of protein kinase C, blocked the IL-1 induction of stromelysin mRNA. We conclude that IL-1 appears to stimulate at least two transduction pathways in synovial fibroblasts from patients with rheumatoid arthritis, and that these have antagonistic effects on the regulation of stromelysin transcription.
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PMID:IL-1 regulation of transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway. 217 73


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