Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Mood stabilizers block some central effects induced by stress and glucocorticosteroids; however, little is known about interaction of these drugs with glucocorticoid receptor function. In the present study, we evaluated effects of lithium, valproate and carbamazepine on glucocorticoid receptor-mediated gene expression in mouse fibroblast cells (L929), stably transfected with mouse mammary tumor virus (MMTV)-chloramphenicol acetyltransferase reporter plasmid (LMCAT cells). Treatment of LMCAT cells with lithium (1-4 mM), valproate (0.1-3 mM) and carbamazepine (30 and 100 microM) inhibited corticosterone-induced activity of reporter gene in a time- and concentration-dependent manner. Furthermore, it was found that valproate, but not two other antimanic drugs, decreased the glucocorticoid receptor level in cytosolic and nuclear fraction, and its inhibitory effect on glucocorticoid receptor-mediated transcriptional activity was attenuated by c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) inhibitor. Protein kinase B (PKB), glycogen synthase kinase (GSK), p38-MAPK and depletion of inositol were not shown to be involved in the mechanism of mood-stabilizer action on glucocorticoid receptor function under present experimental condition. In contrast to mood stabilizers, amphetamine (1-100 microM) had no effect on glucocorticoid receptor-mediated transcriptional activity. These findings corroborate the hypothesis that direct effects of antidepressants and mood stabilizers on glucocorticoid receptor function is an important mechanism, by which these drugs may inhibit some deleterious effects of stress and glucocorticoids on the central nervous system.
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PMID:Mood stabilizers inhibit glucocorticoid receptor function in LMCAT cells. 1524 58

Nuclear receptors and their coactivators are key regulators of numerous physiological functions. GRIP1 (glucocorticoid receptor-interacting protein) is a member of the steroid receptor coactivator family. Here, we show that GRIP1 is regulated by cAMP-dependent protein kinase (PKA) that induces its degradation through the ubiquitin-proteasome pathway. GRIP1 was down-regulated in transiently transfected COS-1 cells after treatment with 8-para-chlorophenylthio-cAMP or forskolin and 3-isobutyl-1-methylxanthine and in adrenocortical Y1 cells after incubation with adrenocorticotropic hormone. Pulse-chase experiments with transiently transfected COS-1 cells demonstrated that the half-life of GRIP1 was markedly reduced in cells overexpressing the PKA catalytic subunit, suggesting that activation of PKA increases the turnover of GRIP1 protein. The proteasome inhibitors MG132 and lactacystin abolished the PKA-mediated degradation of GRIP1. Using ts20 cells, a temperature-sensitive cell line that contains a thermolabile ubiquitin-activating E1 enzyme, it was confirmed that PKA-mediated degradation of GRIP1 is dependent upon the ubiquitin-proteasome pathway. Coimmunoprecipitation studies of COS-1 cells transfected with expression vectors encoding GRIP1 and ubiquitin using anti-GRIP1 and anti-ubiquitin antibodies showed that the ubiquitination of GRIP1 was increased by overexpression of PKA. Finally, we show that PKA regulates the intracellular distribution pattern of green fluorescent protein-GRIP1 and stimulates recruitment of GRIP1 to subnuclear foci that are colocalized with the proteasome. Taken together, these data demonstrate that GRIP1 is ubiquitinated and degraded through activation of the PKA pathway. This may represent a novel regulatory mechanism whereby hormones down-regulate a nuclear receptor coactivator.
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PMID:cAMP-dependent protein kinase regulates ubiquitin-proteasome-mediated degradation and subcellular localization of the nuclear receptor coactivator GRIP1. 1534 61

Excessive hepatic glucose production is thought to be a major contributor to the type 2 diabetic state. Drug discovery efforts have yielded small synthetic inhibitors for gluconeogenic and glycogenic regulators of this pathway. The most advanced targets are outlined in this mini-review and include: the glucocorticoid receptor, 11 beta-hydroxysteroid dehydrogenase type 1, fructose 1,6-bisphosphatase, the glucagon receptor, glycogen phosphorylase, glycogen synthase kinase-3, and glucose-6-phosphatase.
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PMID:Intervention of hepatic glucose production. Small molecule regulators of potential targets for Type 2 diabetes therapy. 1554 51

Antidepressants up-regulate the cAMP response element binding protein (CREB) and the brain-derived neurotrophic factor (BDNF) in hippocampus and these effects contribute to the protection of hippocampal neurons from stressful stimuli such as high glucocorticoid levels. CREB can be activated by both protein kinase A and by Ca2+-calmodulin-dependent protein kinases (CaMKs), which are in turn phosphorylated by their upstream activators CaMKKalpha and CaMMKKbeta. Using in situ hybridization, we examined the effects of chronic treatment with fluoxetine (FLU) or desipramine (DMI) on BDNF, CaMKKalpha and CaMKKbeta mRNAs in the hippocampus of wild-type (Wt) and transgenic (TG) mice characterized by glucocorticoid receptor (GR) dysfunction. Basal levels of CaMKKbeta were down regulated in the CA3 region of TG mice. DMI decreased the expression of both CaMKKalpha and CaMMKKbeta in the CA3 region of Wt mice. FLU up-regulated BDNF mRNA levels in the CA3 of TG animals while both FLU and DMI increased BDNF gene expression in the dentate gyrus (DG) of TG animals. Our results demonstrate a different regulation of BDNF expression by antidepressant drugs in the hippocampus of Wt and TG animals. Moreover, for the first time, a role for CaMKKs in the mechanism of action of antidepressant agents, at least in the hippocampus, is reported. These data are discussed in view of interactions existing between CaMK pathway and GR-mediated gene transcription.
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PMID:Chronic treatment with desipramine and fluoxetine modulate BDNF, CaMKKalpha and CaMKKbeta mRNA levels in the hippocampus of transgenic mice expressing antisense RNA against the glucocorticoid receptor. 1555 40

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

cAMP-mediated signaling potentiates glucocorticoid-mediated apoptosis in lymphoid cells, but an effective means by which to take advantage of this observation in the treatment of lymphoid malignancies has not been identified. The primary objective of the current study was to determine whether PDE4 inhibitors, a class of compounds in late clinical development that raise intracellular cAMP levels by inhibiting type 4 cyclic nucleotide phosphodiesterases (PDE4), increase the efficacy of glucocorticoid-mediated apoptosis in leukemic cells from patients with B cell chronic lymphocytic leukemia (B-CLL). Rolipram, a prototypic PDE4 inhibitor, synergized with glucocorticoids in inducing B-CLL but not T cell apoptosis. Rolipram also augmented glucocorticoid receptor element (GRE) transactivation in B-CLL cells. In contrast, inhibition of protein kinase A (PKA) with the cAMP antagonist Rp-8Br-cAMPS reversed both glucocorticoid-induced apoptosis and GRE transactivation. CCRF-CEM cells, a well-studied model of glucocorticoid and cAMP-induced apoptosis, differed from B-CLL cells in that stimulation of adenylyl cyclase with the diterpene forskolin was required to increase both glucocorticoid-mediated apoptosis and GRE activation, while PDE4 inhibition had no effect. Consistent with these results, inhibition of PDE4 induced cAMP elevation in B-CLL but not CCRF-CEM cells, while forskolin augmented cAMP levels in CCRF-CEM but not B-CLL cells. While rolipram treatment up-regulated PDE4B in B-CLL, forskolin treatment up-regulated PDE4D in CCRF-CEM cells. These studies suggest that PKA is required for and enhances glucocorticoid-induced apoptosis in B-CLL by modulating glucocorticoid receptor signal transduction. Clinical trials that examine whether PDE4 inhibitors enhance the efficacy of glucocorticoid-containing chemotherapy regimens in B-CLL are indicated.
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PMID:Type 4 cAMP phosphodiesterase (PDE4) inhibitors augment glucocorticoid-mediated apoptosis in B cell chronic lymphocytic leukemia (B-CLL) in the absence of exogenous adenylyl cyclase stimulation. 1565 38

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

The ALCR/alcA (alc) two-component, ethanol-inducible gene expression system provides stringent control of transgene expression in genetically modified plants. ALCR is an ethanol-activated transcription factor that can drive expression from the ALCR-responsive promoter (alcA). However, the alc system has been shown to have constitutive expression when used in plant callus or cell suspension cultures, possibly resulting from endogenous inducer produced in response to lowered oxygen availability. To widen the use of the alc system in plant cell culture conditions, the receptor domain of the rat glucocorticoid receptor (GR) was translationally fused to the C terminus of ALCR to produce ALCR-GR, which forms the basis of a glucocorticoid-inducible system (alc-GR). The alc-GR switch system was tested in tobacco (Nicotiana tabacum) Bright Yellow-2 suspension cells using a constitutively expressed ALCR-GR with four alternative alcA promoter-driven reporter genes: beta-glucuronidase, endoplasmic reticulum-targeted green fluorescent protein, haemagglutinin, and green fluorescent protein-tagged Arabidopsis (Arabidopsis thaliana) Arath;CDKA;1 cyclin-dependent kinase. Gene expression was shown to be stringently dependent on the synthetic glucocorticoid dexamethasone and, in cell suspensions, no longer required ethanol for induction. Thus, the alc-GR system allows tight control of alcA-driven genes in cell culture and complements the conventional ethanol switch used in whole plants.
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PMID:The alc-GR system: a modified alc gene switch designed for use in plant tissue culture. 1601

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


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