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)

Our recent studies on rat pituitary tissue suggest that the annexin 1 (ANXA1)-dependent inhibitory actions of glucocorticoids on ACTH secretion are effected via a paracrine mechanism that involves protein kinase C (PKC)-dependent translocation of a serine-phosphorylated species of ANXA1 (Ser-P-ANXA1) to the plasma membrane of the nonsecretory folliculostellate cells. In the present study, we have used a human folliculostellate cell line (PDFS) to explore the signaling mechanisms that cause the translocation of Ser-P-ANXA1 to the membrane together with Western blot analysis and flow cytometry to detect the phosphorylated protein. Exposure of PDFS cells to dexamethasone caused time-dependent increases in the expression of ANXA1 mRNA and protein, which were first detected within 2 h of steroid contact. This genomic response was preceded by the appearance within 30 min of substantially increased amounts of Ser-P-ANXA1 and by translocation of the phosphorylated protein to the cell surface. The prompt membrane translocation of Ser-P-ANXA1 provoked by dexamethasone was inhibited by the glucocorticoid receptor, antagonist, mifepristone, but not by actinomycin D or cycloheximide, which effectively inhibit mRNA and protein synthesis respectively in our preparation. It was also inhibited by a nonselective PKC inhibitor (PKC(9-31)), by a selective inhibitor of Ca(2+)-dependent PKCs (Go 6976) and by annexin 5 (which sequesters PKC in other systems). In addition, blockade of phosphatidylinositiol 3-kinase (wortmannin) or MAPK pathways with PD 98059 or UO 126 (selective for MAPK kinse 1 and 2) prevented the steroid-induced translocation of Ser-P-ANXA1 to the cell surface. These results suggest that glucocorticoids induce rapid serine phosphorylation and membrane translocation of ANXA1 via a novel nongenomic, glucocorticoid receptor-dependent mechanism that requires MAPK, phosphatidylinositiol 3-kinase, and Ca(2+)-dependent PKC pathways.
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PMID:Dexamethasone induces rapid serine-phosphorylation and membrane translocation of annexin 1 in a human folliculostellate cell line via a novel nongenomic mechanism involving the glucocorticoid receptor, protein kinase C, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase. 1263 97

Pretreatment with glucocorticoids for 60 min depressed insulin-stimulated uptake of 2-[3H] deoxyglucose (2-DOG), an effect that neither cycloheximide, an inhibitor of protein synthesis, nor RU38486, a glucocorticoid receptor antagonist, could restore. Preincubation with conventional PKC inhibitors restored dexamethasone-induced insulin resistance. We also examined the dexamethasone-mediated inhibitory effect on insulin-induced 2-DOG uptake in adipocytes overexpressed with wild-type and dominant negative forms of PKCbeta. The dexamethasone-mediated inhibitory effect on insulin-induced 2-DOG uptake was abrogated in adipocytes overexpressed with dominant-negative PKCbeta. These results indicate that PKCbeta may play an important role in glucocorticoid-induced insulin resistance.
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PMID:Inhibition of PKCbeta improves glucocorticoid-induced insulin resistance in rat adipocytes. 1266 48

Cortisol and epinephrine released in response to stress are replenished via activation of the hypothalamic-pituitary-adrenal (HPA or stress) axis. Immobilization (IMMO) stress in rats stimulates epinephrine production in part via the gene encoding the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT). PNMT mRNA rose up to 7.0-fold with acute or chronic stress. Two transcription factors mediating stress induction of the PNMT gene are the glucocorticoid receptor (GR) and Egr-1, which interact with -533, -759, and -773 bp, and -165 bp binding sites in the rat PNMT promoter, respectively. To identify molecular mechanisms involved, effects of hypoxic stress on PNMT promoter activity were examined in PC12 cells transfected with the PNMT promoter-luciferase reporter gene construct pGL3RP893. Oxygen reduction to 5% increased PNMT promoter-driven luciferase expression, with maximum activity at 6 h. Pretreatment of the cells with protein kinase A (PKA) and protein kinase C (PKC) inhibitors, H-89 and GF109203X, respectively, attenuated the rise in luciferase. Similarly, PKA-deficient PC12 cells transfected with pGL3RP893 and exposed to hypoxia also showed attenuated PNMT promoter-driven luciferase expression. Mutation of the Egr-1 binding site completely prevented PNMT promoter activation, indicating that Egr-1 is essential to the stress response. Consistent with this result, hypoxia increased Egr-1 protein. Hypoxia also increased endogenous PNMT mRNA. However, a shift to intron-retaining mRNA from which truncated, nonfunctional protein is produced, occurred, suggesting that posttranscriptional regulation may be an important genetic mechanism controlling adrenergic expression and hence, epinephrine, during stress.
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PMID:Genetic mechanisms for adrenergic control during stress. 1524 Mar 94

Proliferation of vascular smooth muscle cells (VSMC) contributes to the progression of atherosclerotic plaques. Calcium channel blockers have been shown to reduce VSMC proliferation, but the underlying molecular mechanism remains unclear. p21(Waf1/Cip1) is a potent inhibitor of cell cycle progression. Here, we demonstrate that amlodipine (10(-6) to 10(-8) M) activates de novo synthesis of p21(Waf1/Cip1) in vitro. We show that amlodipine-dependent activation of p21(Waf1/Cip1) involves the action of the glucocorticoid receptor (GR) and C/EBP-alpha. The underlying pathway apparently involves the action of mitogen-activated protein kinase or protein kinase C, but not of extracellular signal-related kinase or changes of intracellular calcium. Amlodipine-induced p21(Waf1/Cip1) promoter activity and expression were abrogated by C/EBP-alpha antisense oligonucleotide or by the GR antagonist RU486. Amlodipine-dependent inhibition of cell proliferation was partially reversed by RU486 at 10(-8) M (58%+/-29%), antisense oligonucleotides targeting C/EBP-alpha (91%+/-26%), or antisense mRNAs targeting p21(Waf1/Cip1) (96%+/-32%, n=6); scrambled antisense oligonucleotides or those directed against C/EBP-beta were ineffective. The data suggest that the anti-proliferative action of amlodipine is achieved by induction of the p21 (Waf1/Cip1) gene, which may explain beneficial covert effects of this widely used cardiovascular therapeutic drug beyond a more limited role as a vascular relaxant.
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PMID:The calcium channel blocker amlodipine exerts its anti-proliferative action via p21(Waf1/Cip1) gene activation. 1546 60

The induction of hippocampal long-term synaptic plasticity is exquisitely sensitive to behavioral stress, but the underlying mechanisms are still unclear. We report here that hippocampal slices prepared from adult rats that had experienced unpredictable and inescapable restraint tail-shock stress showed marked impairments of long-term potentiation (LTP) in the CA1 region. The same stress promoted the induction of long-term depression (LTD). These effects were prevented when the animals were given the glucocorticoid receptor antagonist 11beta, 17beta-11[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-estra-4-9-dien-3-one before the stress. Immunoblotting analyses revealed that stress induced a profound and prolonged extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK1/2 MAPK) hyperphosphorylation through small GTPase Ras, Raf-1, and MAPK kinase 1/2 (MEK1/2). Furthermore, the stress effects were obviated by the intrahippocampal injection of specific inhibitors of MEK1/2 (U0126), protein kinase C (bisindolylmaleimide I), tyrosine kinase (K252a), and BDNF antisense oligonucleotides. These results suggest that the effects of stress on LTP and LTD originate from the corticosterone-induced sustained activation of ERK1/2-coupled signaling cascades.
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PMID:Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation. 1559 Sep 19

Dexamethasone induced the expression of 15-PGDH in a time- and concentration-dependent manner in A549 human lung adenocarcinoma cells. Maximal induction was observed at 10nM. Induction of 15-PGDH expression was also achieved by other synthetic glucocorticoids. Induction was inhibited by the addition of pro-inflammatory cytokines and phorbol ester. These pro-inflammatory agents were also shown to induce COX-2 expression. PMA was found to be the most effective stimulator of COX-2 expression and the most potent inhibitor of dexamethasone-induced 15-PGDH expression. Attenuation of dexamethasone-induced 15-PGDH expression by PMA was, in part, due to a protein kinase C-mediated mechanism. The induction of 15-PGDH expression by dexamethasone was blocked by a glucocorticoid receptor antagonist RU 486 and by a nuclear translocation inhibitor geldanamycin, indicating that the induction is a genetic mechanism. The induction of 15-PGDH expression by dexamethasone and other glucocorticoids at the therapeutic level provides an additional biochemical mechanism for the anti-inflammatory action of these glucocorticoids.
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PMID:15-Hydroxyprostaglandin dehydrogenase can be induced by dexamethasone and other glucocorticoids at the therapeutic level in A549 human lung adenocarcinoma cells. 1568 Sep 6

Rapid activation of JNK and p38 and their translocation to the cell nucleus by glucocorticoids, corticosterone (Cort), and bovine serum-conjugated corticosterone (Cort-BSA) were studied in primary cultured hippocampal cells by using immunoblotting and immunofluorescence confocal microscopy. The rapid activation occurred 5 min after stimulation and was maintained at plateau for as long as 2-4 hr; i.e., the response persisted for 2 hr after washing out the 15-min application of Cort-BSA. The activation occurred at a minimal concentration of 10(-9) M for Cort and 10(-8) M for Cort-BSA. GDPbetaS blocked the activation, but RU38486, a nuclear glucocorticoid receptor antagonist, could not block the activation, indicating the involvement of the membrane-delineated receptor in this reaction. The protein kinase C (PKC) inhibitor Go6976 blocked the response, whereas the protein kinase A inhibitor H89 could not, implying the involvement of PKC in the intracellular signal transduction pathway. The nongenomic nature of the responses and the transduction pathway and the significance of persistent action and biological significance are discussed.
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PMID:Rapid activation of JNK and p38 by glucocorticoids in primary cultured hippocampal cells. 1584 79

Spinal NMDA receptor (NMDAR), protein kinase C (PKC), and glucocorticoid receptor (GR) have all been implicated in the mechanisms of morphine tolerance; however, how these cellular elements interact after chronic morphine exposure remains unclear. Here we show that the expression of spinal NMDAR and PKCgamma after chronic morphine is regulated by spinal GR through a cAMP response element-binding protein (CREB)-dependent pathway. Chronic morphine (10 microg, i.t.; twice daily for 6 d) induced a time-dependent upregulation of GR, the NR1 subunit of NMDAR, and PKCgamma within the rat's spinal cord dorsal horn. This NR1 and PKCgamma upregulation was significantly diminished by intrathecal coadministration of morphine with the GR antagonist RU38486 or a GR antisense oligodeoxynucleotide. Intrathecal coadministration of morphine with an adenylyl cyclase inhibitor (2',5'-dideoxyadenosine) or a protein kinase A inhibitor (H89) also significantly attenuated morphine-induced NR1 and PKCgamma expression, whereas intrathecal treatment with an adenylyl cyclase activator (forskolin) alone mimicked morphine-induced expression of GR, NR1, and PKCgamma. Moreover, the expression of phosphorylated CREB was upregulated within the spinal cord dorsal horn after chronic morphine, and a CREB antisense oligodeoxynucleotide coadministered intrathecally with morphine prevented the upregulation of GR, NR1, and PKCgamma. These results indicate that spinal GR through the cAMP-CREB pathway played a significant role in NMDAR and PKCgamma expression after chronic morphine exposure. The data suggest that genomic interaction among spinal GR, NMDAR, and PKCgamma may be an important mechanism that contributes to the development of morphine tolerance.
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PMID:Expression of spinal NMDA receptor and PKCgamma after chronic morphine is regulated by spinal glucocorticoid receptor. 1631 14

Dexamethasone inhibits insulin secretion from isolated islets. In the present experiments, possible underlying biochemical mechanisms responsible for defective secretion were explored. Dexamethasone (1 micromol/L) had no immediate deleterious effect on 15 mmol/L glucose-induced insulin release from perifused rat islets. However, a 3-hour preincubation period with 1 micromol/L dexamethasone resulted in parallel reductions in both the first (64%) and second phases (74%) of 15 mmol/L glucose-induced insulin secretion monitored during a dynamic perifusion. When measured after the perifusion, there were no differences in insulin content or in the capacity of control or dexamethasone-treated islets to use glucose. Dexamethasone (1 micromol/L) preexposure also reduced phorbol ester- and potassium-induced secretion. In additional experiments, islets were labeled for 3 hours with 3H-inositol in the presence or absence of 1 micromol/L dexamethasone. The steroid did not affect total 3H-inositol incorporation during the labeling period. However, the capacity of 15 mmol/L glucose, 30 mmol/L KCl, and 100 micromol/L carbachol to activate phospholipase C (PLC), monitored by the accumulation of labeled inositol phosphates, was significantly reduced in dexamethasone-pretreated islets. Inclusion of the nuclear glucocorticoid receptor antagonist RU486 (mifepristone, 10 micromol/L) abolished the adverse effects of dexamethasone on both glucose-induced inositol phosphate accumulation and insulin secretion. Quantitative Western blot analyses revealed that the islet contents of PLCdelta1, PLCbeta1, beta2, beta3, and protein kinase C alpha were unaffected by dexamethasone pretreatment. These findings demonstrate that dexamethasone pretreatment impairs insulin secretion via a genomic action and that impaired activation of the PLC/protein kinase C signaling system is involved in the evolution of its inhibitory effect on secretion.
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PMID:Dexamethasone suppresses phospholipase C activation and insulin secretion from isolated rat islets. 1632 17

Sphingosine 1-phosphate (S1P) the product of sphingosine kinase (SK) action plays an important role in various pathological conditions like inflammation and cancer. In this study, we show that in the human breast cancer cell line MCF7, epidermal growth factor (EGF) stimulates SK-1 activity in a biphasic manner with a first peak after 15 min and a second delayed activation occurring after 1 h up to 18 h and thereafter declining again. This delayed activation is accompanied by increased mRNA and protein expression of SK-1, but not SK-2. Mechanistically, the transcriptional upregulation is dependent on the classical mitogen-activated protein kinase, protein kinase C (PKC) and the phosphoinositide 3-kinase, since specific inhibitors of these enzymes all abolish the EGF-induced mRNA upregulation and activity of SK-1. Moreover, dexamethasone also suppressed EGF-induced SK-1 mRNA expression and activity which is reversed by the glucocorticoid receptor antagonist RU486. To see whether EGF-induced upregulation of SK-1 is of relevance for tumor progression, we investigated two hallmarks of carcinogenesis, i.e., cell proliferation and migration. Stimulation of cells with EGF leads to enhanced [(3)H]thymidine incorporation into DNA and also to stimulated migration in a modified Boyden chamber assay. When cells are depleted of SK-1, but not SK-2, by siRNA transfection or by dexamethasone treatment, EGF-induced proliferation and migration are drastically reduced. In summary, these data show that EGF causes an acute stimulation of SK-1 activity and, moreover, triggers a delayed SK activation which is due to increased gene transcription and de novo synthesis of SK-1, which in turn directs cells towards growth and increased motility. Thus, the sphingosine kinase-1 may represent a novel attractive target for cancer therapy.
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PMID:The epidermal growth factor stimulates sphingosine kinase-1 expression and activity in the human mammary carcinoma cell line MCF7. 1641 7


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