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)

Many of the concepts presented in this paper are summarized in Fig. 7. Some aspects are well supported while others are speculative. The operation of PLC in VSM is well established, and in some hypertensive models (AHR, SHRSP) PLC assays exhibited altered activation. Currently this pathway leading to the production of IP3 and DAG is considered to be the major regulator of Ca release from sarcoplasmic reticulum (SR) and Ca entry by channels (CaC). Regulation of PKC by [Ca]i and DAG is thought to play a major role in controlling Ca entry. PKC has also been proposed to regulate PLA2 as well as PLD in conjunction with elevated [Ca]i. An important issue to be resolved is whether receptor regulation of other lipases occurs independently of the PLC-[Ca]i-PKC axis. Currently information supporting receptor regulation is lacking for VSM, but few studies have been conducted. Our observation that NE stimulation of PLD activity occurs in VSM indicates that the control of VSM by biochemical messengers is much more complicated than previously proposed. This seemingly redundant pathway may allow VSM to use alternate substrates for producing PA and DAG than are readily available to PLC. It also allows PA to be produced directly without phosphorylation of DAG. Although the role of PA in the regulation of Ca entry was proposed earlier, definitive studies establishing this linkage are still required. Any PLD activity on PIP2 would produce biochemical messengers (PA, DAG) which could stimulate Ca entry without producing the messenger, IP3, associated with Ca release (inactive IP2 would be produced). If PLC and PLD were independently regulated by receptor-guanine nucleotide-regulatory protein (G-protein) complexes, this would offer the potential for some agonists to excite VSM by Ca release and Ca entry mechanisms while others may excite by Ca entry alone. This system would also circumvent the problem of limited substrate for cellular regulation of [Ca]i if PIP2 were the primary substrate. This limitation does not exist with other phospholipids such as phosphatidylcholine which is a preferred substrate for PLD. The presence of multiple phospholipases under separate receptor regulation allows for a wider range of tissue responses to various agonists, than a system which is linked only through the PLC-[Ca]i-PKC axis. The presence of a PLD pathway also reopens the interpretation of previous studies which demonstrated a resetting between receptor occupancy and production of second messengers by PLC.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Altered phospholipase activities related to alpha 1-adrenergic receptor supersensitivity of aortas from aldosterone-salt hypertensive rats. 166 67

Previous studies in this laboratory have shown that benzo(a)pyrene (BaP) modulates protein kinase C (PKC)-mediated phosphorylation of aortic smooth muscle cell (SMC) proteins. This observation is consistent with the ability of other aromatic hydrocarbons (AHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), to modulate kinase activities in cells of hepatic, testicular, and thymic origin. Because all these chemicals share the ability to bind the aryl hydrocarbon receptor (AhR), the present studies were conducted to determine if changes in PKC activity by AHs conform with established structure-activity relationships. Experiments were conducted to examine the effects of TCDD, 2,3,7,8-tetrachlorodibenzofuran (TCDF), and 2,8-dichlorodibenzodioxin (DCDD) on the phosphorylation of exogenous histone type-III under basal and PKC-activating conditions. These congeners exhibit both high (TCDD and TCDF) and low (DCDD) AhR agonist activities. Measurements of kinase activity were conducted in the cytosolic and particulate fractions of growth-arrested (i.e., serum-deprived) cultured rat aortic SMCs incubated with 10 nM TCDD, TCDF, and DCDD for 0.5, 12, or 24 hours. No changes in basal kinase activity were induced by these chemicals at any of the times tested. Significant decreases in cytosolic and particulate PKC activity relative to controls were observed upon exposure of SMCs for 0.5 hours to 10 nM TCDD, TCDF, and DCDD. In contrast, SMCs exposed to TCDD and TCDF for 12 hours exhibited a significant increase in PKC activity in both cytosolic and particulate fractions. The PKC activity in cells exposed to DCDD for 12 hours was not altered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biphasic modulation of protein kinase C (PKC) activity by polychlorinated dibenzo-p-dioxins (PCDDs) in serum-deprived rat aortic smooth muscle cells. 798 76

Transcriptional activation of the human CYP1A1 gene by halogenated and polycyclic aromatic hydrocarbons is mediated by the aryl hydrocarbon receptor (AhR) complex, a ligand-dependent transcription factor. A competent AhR comprises at least two components following nuclear translocation and DNA binding, the AhR and the AhR nuclear translocator (Arnt) protein, whose combined action on human CYP1A1 gene transcription is shown to be dependent upon functional protein kinase C (PKC). In the present study, we examined the effects of phorbol 12-myristate 13-acetate, a potent PKC activator, on the ligand-induced transcriptional activation of the CYP1A1 gene and cellular function of the AhR in human HepG2 101L cells. The 101L cells carry a stable transgene consisting of 1800 bases of 5'-flanking DNA and the promoter of the human CYP1A1 gene linked to the firefly luciferase structural gene (Postlind, H., Vu, T. P., Tukey, R. H. & Quattrochi, L. C. (1993) Toxicol. Appl. Pharmacol. 118, 255-262). Pretreatment of cells with 12-myristate 13-acetate enhanced ligand-induced CYP1A1 gene expression 2-3-fold. Inhibition of PKC activity blocked directly the transcriptional activation and the transactivation of the CYP1A1 gene, indicating a role for PKC in the AhR-mediated transcriptional activation process. However, the DNA binding activities of the in vitro activated and the induced nuclear AhR as measured by electrophoretic mobility shift analysis were not affected when CYP1A1 transcription was inhibited, indicating the actions of PKC to be a nuclear event that works in concert with or precedes AhR binding to the gene. These results illustrate that PKC is absolutely essential for the cellular and molecular events that control induction of CYP1A1 gene transcription.
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PMID:Protein kinase C modulates regulation of the CYP1A1 gene by the aryl hydrocarbon receptor. 882 76

We have investigated mechanisms of omeprazole (OME)-mediated induction of CYP1A1 and CYP3A, using the rat hepatoma H4IIE cell line, in comparison with mechanisms exerted by traditional aryl hydrocarbon receptor (AhR) ligands such as benso(a)pyrene (B(a)P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). OME did not bind specifically to AhR, and it could not activate the AhR complex in rat cytosol to a xenobiotic-responsive element (XRE)-binding form in vitro. Genistein, a tyrosine kinase inhibitor, and daidzein, an inhibitor of casein kinase II, efficiently inhibited OME-mediated but not B(a)P- or TCDD-mediated induction of CYP1A1, as monitored at the transcriptional, mRNA, and protein levels as well as by analysis of activation of XRE-luciferase reporter constructs transfected into H4IIE cells. The protease inhibitor Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) and lavendustin A also had similar OME-specific effects. In addition, insulin pretreatment caused an almost complete inhibition of OME-dependent CYP1A1 induction but only partially affected TCDD and B(a)P-mediated induction of CYP1A1. Staurosporine, an inhibitor of protein kinase C, impaired the induction by both B(a)P and OME. OME caused an approximately 2-fold increase in the level of CYP3A expression, but all inhibitors used were ineffective in preventing this induction. Gel shift analysis with radiolabeled XRE and specific peptide antibodies toward AhR and aryl hydrocarbon receptor nuclear translocator protein (Arnt) revealed an OME-mediated translocation of the AhR.Arnt complex into the nuclei. Genistein inhibited the specific nuclear XRE binding caused by OME, but it potentiated the formation of the TCDD-induced XRE.AhR complex. Although daidzein was able to effectively inhibit the OME-stimulated CYP1A1 gene transcription, it did not influence the OME-dependent AhR.XRE complex formation. The data are consistent with a mechanism for OME-mediated induction of CYP1A1 that involves activation of the AhR complex via intracellular signal transduction systems and that is distinct from induction mediated by AhR ligands.
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PMID:Signal transduction-mediated activation of the aryl hydrocarbon receptor in rat hepatoma H4IIE cells. 939 20

The role of protein kinase C (PKC) in the human aryl hydrocarbon receptor (hAhR) signal transduction pathway was examined in cell lines stably transfected with pGUDLUC6.1, in which luc+ is solely controlled by four dioxin-responsive elements (DREs). These cell lines, P5A11 and HG40/6, were derived from HeLa and HepG2 cells respectively. Simultaneous treatment of these cells with 2,3,7,8, -tetrachlorodibenzo-p-dioxin (TCDD) and phorbol-12-myristate-13-acetate (PMA) enhanced trans-activation of the reporter construct several-fold relative to cells treated with TCDD alone. PKC inhibitors block the PMA effect and hAhR-mediated signal transduction, demonstrating these processes require PKC activity. Examination of other independently generated, HeLa-derived cell lines stably transfected with pGUDLUC6.1 demonstrates the PMA effect in P5A11 cells is not a clonal artifact. Transient transfections indicate the PMA effect is not due to a luciferase message/gene product stabilization mechanism or stimulation of the basal transcription machinery. Examination of cytosolic preparations demonstrates PKC stimulation or inhibition does not alter hAhR and hAhR nuclear translocator protein levels or TCDD-induced down-regulation of hAhR levels. Similarly, examination of nuclear extracts indicated PKC stimulation or inhibition does not alter nuclear AhR levels or hAhR/hAhR nuclear translocator protein heterodimer DRE-binding activity as assessed by electrophoretic mobility shift assay. These results demonstrate a PKC-mediated event is required for the hAhR to form a functional transcriptional complex that leads to trans-activation and that the DRE is the minimal DNA element required for PMA to enhance AhR-mediated trans-activation.
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PMID:Protein kinase C activity is required for aryl hydrocarbon receptor pathway-mediated signal transduction. 954 60

Polychlorinated biphenyls (PCBs) are persistent contaminants that exist as complex mixtures in the environment. One problem faced by risk assessors is that the possible interactive effects of specific PCB congeners and related chemicals found in environmental and biological samples have not been systematically investigated. Some PCBs perturb Ca2+ homeostasis and cause protein kinase C (PKC) translocation in neuronal cell cultures and in brain homogenate preparations at concentrations where no cytotoxicity is observed, and these systems are necessary for the growth and normal functioning of neurons. The changes in second messenger systems appear to be associated with the extent of noncoplanarity of the PCB molecule. We studied the interactive effects of selected PCB congeners, a PCB metabolite, and a dioxin on PKC translocation, as determined by [3H]phorbol ester binding in cerebellar granule cells. The binary combinations included coplanar and noncoplanar PCB congeners or PCB congeners with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/PCB metabolite. In addition, we tested the interactive effects of several PCB congeners (three or more) found in environmental samples such as human milk and blood, contaminated fish, and brain samples from PCB-treated animals. The results indicated that 1) the coplanar congener [3,3',4, 4'-tetrachlorobiphenyl (TeCB)] did not alter the in vitro activity of the noncoplanar (2,2',5,5'-TeCB) or coplanar [4, 4'-dichlorobiphenyl (DCB)] congeners; 2) binary mixtures of active PCB congeners (2,2',4,4'-TeCB and 2,2'-DCB; 2,2'-DCB and 3,5-DCB; 2,2',3,5',6-PeCB and 2,2',4,4',5-PeCB) interact in a dose-additive manner; 3) TCDD did not alter the activity of either coplanar (3,3', 4,4'-TeCB) or noncoplanar (2,2',5,5'-TeCB) congeners; 4) the interaction between the parent PCB congener and hydroxy metabolite of PCB is additive; 5) PCB congener mixtures at the ratios found in environmental samples are biologically active; and 6) there was no indication of synergism in any of the combinations studied. These results suggest that the biological effects of binary mixtures of PCB congeners fit a dose-additive model, indicating that there is a specific site of action for these PCB congeners which is independent of the aryl hydrocarbon receptor. Environmental mixtures contain mostly noncoplanar PCB congeners, and because they appear to be biologically active, the potential human health risk by this group of chemicals should be considered in the risk assessment of PCBs.
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PMID:Interactive effects of environmentally relevant polychlorinated biphenyls and dioxins on [3H]phorbol ester binding in rat cerebellar granule cells. 968 75

The scandal in Belgium last spring has drawn attention to the environmental hazards of dioxins. Previous production of pesticides and widespread combustion of organic material in the presence of chloride have lead to environmental accumulation of these toxicants, which more precisely are termed polychlorinated dibenzo-p-dioxins and dibenzofurans. Their very long biological half-lives in combination with detectable biological effects at very low concentrations have caused health concerns. Chloracne is the only well documented health effect in man, but there are experimental evidence for carcinogenic, teratogenic, reproductive and immunosuppressive effects. In this presentation we review current knowledge about the cellular effects of dioxins. Dioxins bind to and exert their effects through the cytoplasmic aryl hydrocarbon receptor, which acts as a transcription factor and regulates a number of cytokines and microsomal enzymes. Furthermore, dioxins interfere with hormonal signalling, and anti-oestrogenic effects, vitamin A inhibition and thyroxin mimicry have been reported. Recently, effects on intracellular growth factor signalling have been demonstrated. Dioxins inhibit epidermal growth factor receptor, activate protein kinase C and other intracellular signal transducers, and activate transcription factors. As overall understanding of their cellular mechanisms of toxicity is lacking, we do not possess a complete basis for estimating the adverse health effects of this group of environmental toxicants.
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PMID:[Why is dioxin harmful?]. 1066 31

Nine vitamin K3 analogs were compared with respect to the induction of the cytochrome P450 1A1 (CYP1A1) expression in mouse hepatoma Hepa-1c1c7 cells. 6-(4-Diethylamino)phenyl-7-chloro-5,8-quinolinedione (EA4) caused a significant induction of the CYP1A1-mediated ethoxyresorufin O-deethylase activity in a time- and concentration-dependent manner. The induction was accompanied by an increase of the Cyp1a1 mRNA transcription. The transient expression of the mouse Cyp1a1-CAT gene into cells showed that EA4 induced CAT activity. However, the aryl hydrocarbon receptor and its nuclear partner, aryl hydrocarbon receptor nuclear translocator mRNA transcription, were unaffected by the EA4 treatment. When the cells were incubated with EA4 in the presence of 1 nM TCDD, the ethoxyresorufin O-deethylase activity that was induced by TCDD was significantly suppressed by EA4. Inhibition of protein synthesis by cycloheximide strongly enhanced the EA4-dependent Cyp1a1 mRNA expression. Up-regulation of protein kinase C by a 2 h preincubation with phorbol 12-myristate 13-acetate increased the EA4-dependent expression of the Cyp1a1 gene. In human cells, such as HepG2 (human hepatocarcinoma), MCF-7 (human breast adenocarcinoma cell line), and HL-60 (human promyelocytic cell line), the expression of CYP1A1 mRNA was also induced by EA4 treatment. Moreover, CYP1B1 mRNA was increased by EA4 in MCF-7 cells. These results indicate that EA4 modulates CYP1A1 and CYP1B1 expressions by transcriptional activation. Also, protein kinase C may be involved in the induction mechanism of CYP1A1 by EA4.
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PMID:Induction of cytochrome P450 1A1 gene expression by a vitamin K3 analog in mouse hepatoma Hepa-1c1c7 cells. 1171 May 20

We delineate a mechanism by which dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD)-mediated formation of the aryl hydrocarbon receptor (AhR) DNA binding complex is disrupted by a single mutation at the conserved AhR tyrosine 9. Replacement of tyrosine 9 with the structurally conservative phenylalanine (AhRY9F) abolished binding to dioxin response element (DRE) D, E, and A and abrogated DRE-driven gene induction mediated by the AhR with no effect on TCDD binding, TCDD-induced nuclear localization, or ARNT heterodimerization. The speculated role for phosphorylation at tyrosine 9 was also examined. Anti-phosphotyrosine immunoblotting could not detect a major difference between the AhRY9F mutant and wild-type AhR, but a basic isoelectric point shift was detected by two-dimensional gel electrophoresis of AhRY9F. However, an antibody raised to recognize only phosphorylated tyrosine 9 (anti-AhRpY9) confirmed that AhR tyrosine 9 is not a phosphorylated residue required for DRE binding. Kinase assays using synthetic peptides corresponding to the wild-type and mutant AhR residues 1-23 demonstrated that a tyrosine at position 9 is important for substrate recognition at serine(s)/threonine(s) within this sequence by purified protein kinase C (PKC). Also, compared with AhRY9F, immunopurified full-length wild-type receptor was more rapidly phosphorylated by PKC. Furthermore, co-treatment of AhR-deficient cells that expressed AhRY9F and a DRE-driven luciferase construct with phorbol 12-myristate 13-acetate and TCDD resulted in a 30% increase in luciferase activity compared with AhRY9F treated with TCDD alone. Overall, AhR tyrosine 9, which is not a phosphorylated residue itself but is required for DNA binding, appears to play a crucial role in AhR activity by permitting proper phosphorylation of the AhR.
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PMID:The aryl hydrocarbon receptor (AhR) tyrosine 9, a residue that is essential for AhR DNA binding activity, is not a phosphoresidue but augments AhR phosphorylation. 1497 34

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor which plays a role as an intracellular mediator of the xenobiotic signaling pathway. We previously identified the minimum nuclear localization signal (NLS) of AhR(13-39): it is composed of two basic amino acid segments, AhR(13-16:RKRR) and AhR(37-39:KRH). In this study, we showed that the two protein kinase C (PKC) sites of Ser-12 and Ser-36 are located one amino acid upstream from each of the two segments, and that a ligand-dependent nuclear import of AhR is inhibited by substitution of aspartic acid for Ser-12 (S12D) or Ser-36 (S36D), which mimics the negative charge of phosphorylation. This observation was supported by microinjection analysis, an in vitro nuclear transport assay, and a luciferase reporter assay, suggesting a two-step mechanism in the ligand-dependent nuclear translocation of AhR.
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PMID:Phosphorylation of nuclear localization signal inhibits the ligand-dependent nuclear import of aryl hydrocarbon receptor. 1506 92


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