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 NPLC-KC human hepatoma cell line expresses corticotropin-releasing factor (CRF) and it has been demonstrated that CRF secretion and synthesis in this cell line increases in response to activators of the protein kinase A (PKA) and C (PKC) pathways as well as interleukin-1 (IL1). CRF expression with all three agents can be inhibited with the synthetic steroid-dexamethasone (DEX). In this report, we have examined the effect of IL1 (beta form) in the presence and absence of DEX on CRF mRNA (mRNA) expression as well as the expression of human glucocorticoid receptor (GR) mRNA and the mRNA of the proto-oncogenes (c-jun and c-fos) that have been implicated in CRF regulation. NPLC-KC cells were incubated with picomolar concentrations of IL1. Following this total RNA was extracted from the cells and Northern Blots were probed with 32P-labelled human DNA probes for the CRF, GR, c-jun and c-fos genes. Levels of mRNA expression were measured using a PhosphoImager and were normalized to mRNA levels of control probe glyceraldehyde-3-phosphate dehydrogenase (GAPD). CRF mRNA was significantly increased with IL1 treatment in a time and concentration dependent manner. CRF mRNA expression increased with increasing concentrations of IL1 over the range of 1-100 pM; expression of CRF mRNA also peaked after 24 h of 100 pM IL1 treatment and reached a level of expression approximately seven times higher than control. This pattern of expression was significantly inhibited in the presence of 100 nM DEX. Levels of the GR, c-fos and c-jun mRNAs were also significantly increased in the presence of IL1 and inhibited when DEX was co-incubated with IL1. The results reveal that IL1 stimulation of CRF mRNA expression by IL1 in the NPLC-KC cell line is accompanied by activation of GR mRNA as well as the mRNA of the immediate early genes--c-fos and c-jun. The results also demonstrate that this cell line may serve as a model system for the molecular mechanisms by which IL1 regulates CRF in central nervous system (CNS) neurons.
 ...
PMID:Interleukin-1 regulation of corticotropin-releasing factor (CRF), glucocorticoid receptor, c-fos and c-jun messenger RNA in the NPLC-KC cell line. 960 26

We have examined the human androgen receptor (hAR) for its ability to activate AR-dependent transcription of a transgene in a ligand-independent manner. The transcriptional activity was determined by analysis of chloramphenicol acetyltransferase (CAT) activity in T47D cells cotransfected with a plasmid expressing the hAR and a natural AR-regulated promoter (the MVDP androgen-dependent enhancer) ligated to the reporter CAT gene. In this study, the effects of the protein kinase C (PKC) activator 12-O-tetradecanoyphorbol-13 acetate (TPA) on AR activity were tested. We demonstrated that in the absence of androgen, TPA enhanced AR-mediated transactivation by 10-12-fold. This effect was specific of the PKC pathway since stimulation to the PKA pathway did not activate the unliganded AR. This ligand-independent pathway can function through another androgen-regulated promoter as shown by the use of the mouse mammary tumor virus MMTV-CAT reporter. The human glucocorticoid receptor (hGR) and the rabbit progesterone receptor (rPR) could not be activated by TPA, indicating that the effects are not universal for steroid receptors. A reporter plasmid containing the MVDP androgen response element (ARE) in front of the thymidine kinase promoter ligated to the CAT gene was activated by DHT but not by TPA, indicating that the context of the natural promoter is critical for ligand-independent activation of the AR. Exogenous c-jun enhanced transcriptional activation by the AR in a ligand-dependent manner, but had no effect in the absence of DHT. Base pair substitutions in both AR-binding (5'-TGTTCT-3' to 5'-TTTTTT-3') and NF1-binding (5'-GTGGCTG-3' to 5'-GTTTTTG-3') sites resulted in a loss of TPA responsiveness. Our results suggest that ligand-independent activation of the AR by TPA results from interaction of unliganded AR with other proteins in the transcription machinery.
 ...
PMID:Phorbol ester causes ligand-independent activation of the androgen receptor. 978 Feb 30

Dietary energy restriction (DER) inhibits carcinogenesis in numerous animal models. DER is a potent and reproducible inhibitor of two-stage mouse skin carcinogenesis when administered during the promotion phase. Previous research demonstrated that adrenalectomy abolished cancer prevention by food restriction. Several lines of evidence suggest that glucocorticoid elevation in the DER mouse mediates the prevention of skin cancer. Our research tested the hypothesis that elevated glucocorticoid hormone activates the glucocorticoid receptor (GR) and that this activated receptor interferes with the activator protein-1 (AP-1) transcription factor. Induction of AP-1 by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is essential to tumor promotion. We have been unable to demonstrate elevated activated GR in the epidermis of the DER mouse, perhaps because only indirect strategies have been possible with the use of epidermis from DER mice. However, DER blocked the induction of AP-1 and c-jun, a constituent protein of AP-1, in the epidermis of mice. Current studies are focused on the inhibition of signaling down the MAP-1/Raf-1 kinase pathway that leads to induction of constituent proteins of AP-1, including c-Jun. Although several pathways lead to the induction of AP-1 transcriptional activity, the MAP-1/Raf-1 pathway can be activated by protein kinase C (PKC); previous studies from our laboratory demonstrated an inhibition of PKC activity and a reduction in selected isoforms of PKC in the epidermis of the DER mouse. Our current working hypothesis is that elevated glucocorticoid hormone in the DER mouse reduces the amount and activity of PKC isoforms important in the activation of MAP-1/Raf-1 kinase pathway. We propose that this results in attenuation in the induction of the AP-1 transcription factor by TPA. Because AP-1 induction by TPA is obligatory for mouse skin promotion, we propose this as an essential component of the mechanism of DER prevention of mouse skin carcinogenesis.
 ...
PMID:Glucocorticoid mediation of dietary energy restriction inhibition of mouse skin carcinogenesis. 1006 35

The signaling pathways involved in the regulation of glucocorticoid on Pi uptake were examined in primary cultured rabbit renal proximal tubule cells (PTCs). Dexamethasone (DEX, 10(-9) M) inhibited Pi uptake, although aldosterone, a mineralocorticoid, did not affect Pi uptake. Its effect was due to a 23% decrease in the V(max) value. DEX-induced inhibition of Pi uptake was prevented by actinomycin D, cycloheximide, and the glucocorticoid receptor antagonists, progesterone and cortexolone. SQ 22536 (adenylate cyclase inhibitor) and the myristoylated protein kinase A inhibitor amide 14-22 (PKI) did not block the DEX-induced inhibition of Pi uptake. Indeed, DEX did not affect cAMP production. However, neomycin and U 73122 (PLC inhibitors), staurosporine and bisindolylmaleimide I (PKC inhibitors) blocked the DEX-induced inhibition of Pi uptake. In addition, DEX increased the membrane-bound PKC activity from 2. 82+/-0.21 to 4.16+/-0.34 pmol/mg protein/min. These findings demonstrate that glucocorticoid inhibits Pi uptake and its effect is genomic and receptor-mediated and the activation of the PLC/PKC pathway is involved in its effect on the PTCs.
 ...
PMID:Regulatory mechanisms of Na/Pi cotransporter by glucocorticoid in renal proximal tubule cells: involvement of cAMP and PKC. 1056 47

1. Antidepressant drugs are known to inhibit some changes evoked by glucocorticoids, as well as a hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, often observed in depression. 2. The aim of present study was to investigate effects of various antidepressant drugs on the glucocorticoid-mediated gene transcription in fibroblast cells, stably transfected with an MMTV promoter (LMCAT cells). 3. The present study have shown that antidepressants (imipramine, amitriptyline, desipramine, fluoxetine, tianeptine, mianserin and moclobemide), but not cocaine, inhibit the corticosterone-induced gene transcription in a concentration- and a time-dependent manner. 4. Drugs which are known to augment clinical effects of medication in depressed patients (lithium chloride, amantadine, memantine), do not affect the inhibitory effects of imipramine on the glucocorticoid receptor (GR)-mediated gene transcription. 5. Inhibitors of phospholipase C (PLC), protein kinase C (PKC), Ca(2+)/calmodulin-dependent protein kinase (CaMK) and antagonists of the L-type Ca(2+) channel also inhibit the corticosterone-induced gene transcription. 6. Inhibitors of protein kinase A (PKA) and protein kinase G (PKG) are without effect on the GR-induced gene transcription. 7. Phorbol ester (an activator of PKC) attenuates the inhibitory effect of imipramine on the GR-induced gene transcription. 8. Imipramine decreases binding of corticosterone-receptor complex to DNA. 9. It is concluded that antidepressant drugs inhibit the corticosterone-induced gene transcription, and that the inhibitory effect of imipramine depends partly on the PLC/PKC pathway.
 ...
PMID:Antidepressant drugs inhibit glucocorticoid receptor-mediated gene transcription - a possible mechanism. 1090 80

We have investigated the nongenomic as well as the genomic effects of glucocorticoids on phosphate (Pi) uptake in primary rabbit renal proximal tubule cells (PTCs) and have defined the involved signaling pathways. In the present study, cortisol-BSA (cortisol-BSA) (>10(-9) M, 30 min) was found to inhibit Pi uptake in a time- and concentration-dependent manner. However, progesterone-BSA (P(4)-BSA), 17ss-estradiol-BSA (E(2)-BSA), testosterone-BSA (T(4)-BSA), aldosterone, P(4), E(2), and T(4) (10(-9) M, 1 h) had no effect on Pi uptake. In addition, cortisol-BSA (10(-9) M) did not affect either Na(+) uptake or alpha-methylglucopyranoside (alpha-MG) uptake. The cortisol-BSA-induced inhibition of Pi uptake was associated with a decrease in the V(max) for Pi uptake, rather than the K(m). The inhibitory effect of cortisol-BSA was not blocked either by actinomycin D (an inhibitor of transcription), cycloheximide (an inhibitor of translation), or classical glucocorticoid receptor antagonists (RU 486 or P(4)). The cortisol-BSA-induced inhibition of Pi uptake was blocked by two phospholipase C (PLC) inhibitors (neomycin or U73122), and two protein kinase C (PKC) inhibitors (staurosporine or bisindolylmaleimide I) but not by two adenylate cyclase/protein kinase A inhibitors [SQ 22536 (an adenylate cyclase inhibitor) or myristoylated protein kinase A inhibitor amide 14-22]. Furthermore, cortisol-BSA promoted the translocation of PKC from the cytosolic fraction to the membrane fraction, while having no effect on the activity of adenylate cyclase. Our observations may thus be interpreted as indicating that cortisol does indeed inhibit renal Pi uptake via a nongenomic mechanism, which involves the PLC/PKC pathway.
 ...
PMID:Regulation of phosphate uptake in primary cultured rabbit renal proximal tubule cells by glucocorticoids: evidence for nongenomic as well as genomic mechanisms. 1115 43

The Y1 receptor for neuropeptide Y (NPY-Y1) is constitutively expressed in PC12 cells. In this study, we examined the role of nerve growth factor (NGF), pituitary adenylyl cyclase activating polypeptide (PACAP) and dexamethasone on the expression of the gene encoding the rat NPY-Y1 receptor in PC12 cells. A fusion gene (pY1-Luc) was constructed where the reporter enzyme firefly luciferase was placed under the control of 700 bp of the promoter region of the rat NPY-Y1 receptor gene. This promoter region contains recognition consensus sequences for various transcription factors, including one activation protein-1 (AP-1) site, two cyclic AMP responsive element sites, one estrogen receptor element site and four glucocorticoid receptor element sites. NGF increased luciferase activity in a concentration dependent manner. This increase was inhibited by K-252a, a trk A receptor inhibitor, and calphostin C, a PKC inhibitor. PACAP-38 increased luciferase activity in a concentration dependent manner. This activation was inhibited by H-89. Dexamethasone increased transcription of NPY-Y1 gene in PC12 cells. These results indicate that differentiation of PC12 cells into endocrine-like phenotype by dexamethasone and into a neuronal-like phenotype by either NGF or PACAP-38 increases the transcriptional activity of the NPY-Y1 receptor gene in PC12 cells.
 ...
PMID:Regulation of the Y1 neuropeptide Y receptor gene expression in PC12 cells. 1140 93

Gene activation mediated by nuclear receptors is regulated in a tissue-specific manner and requires interactions between nuclear receptors and their cofactors. Here, we identified and characterized a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors. GT198 was originally described as a genomic transcript that mapped to the human breast cancer susceptibility locus 17q12-q21 with unknown function. We show that GT198 exhibits a tissue-specific expression pattern in which its mRNA is elevated in testis, spleen, thymus, pituitary cells, and several cancer cell lines. GT198 is a 217-amino-acid nuclear protein that contains a leucine zipper required for its dimerization. In vitro binding and yeast two-hybrid assays indicated that GT198 interacted with nuclear receptors through their DNA-binding domains. GT198 potently stimulated transcription mediated by estrogen receptor alpha and beta, thyroid hormone receptor beta1, androgen receptor, glucocorticoid receptor, and progesterone receptor. However, the action of GT198 was distinguishable from that of the ligand-binding domain-interacting nuclear receptor coactivators, such as TRBP, CBP, and SRC-1, with respect to basal activation and hormone sensitivity. Furthermore, protein kinase A, protein kinase C, and mitogen-activated protein kinase can phosphorylate GT198 in vitro, and cotransfection of these kinases regulated the transcriptional activity of GT198. These data suggest that GT198 is a tissue-specific, kinase-regulated nuclear receptor coactivator that interacts with the DNA-binding domains of nuclear receptors.
 ...
PMID:Identification and characterization of a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors. 1173 47

Glucocorticoid hormone controls Leydig cell steroidogenic function through a receptor-mediated mechanism. The enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD) plays an important role in Leydig cells by metabolizing glucocorticoids, and catalyzing the interconversion of corticosterone (the active form in rodents) and 11-dehydrocorticosterone (the biologically inert form). The net direction of this interconversion determines the amount of biologically active ligand, corticosterone, available for glucocorticoid receptor binding. We hypothesize that 11betaHSD oxidative and reductive activities are controlled separately in Leydig cells, and that shifts in the favored direction of 11betaHSD catalysis provide a mechanism for the control of intracellular corticosterone levels. Therefore, in the present study, we tested the dependency of 11betaHSD oxidative and reductive activities on protein kinase C (PKC) and calcium-dependent signaling pathways. 11betaHSD oxidative and reductive activities were measured in freshly isolated intact rat Leydig cells using 25 nM radiolabeled substrates after treatment with protein kinase modulators. We found that PKC and calcium-dependent signaling had opposing effects on 11betaHSD oxidative and reductive activities. Stimulation of PKC using the PKC activator, 6-[N-decylamino]-4-hydroxymethylinole (DHI), increased 11betaHSD oxidative activity from a conversion rate of 5.08% to 48.23% with an EC50 of 1.70 +/- 0.44 microM (mean +/- SEM), and inhibited reductive activity from 26.90% to 3.66% conversion with an IC50 of 0.22 +/- 0.05 microM. This indicated that PKC activation in Leydig cells favors 11betaHSD oxidation and lower levels of corticosterone. The action of DHI was abolished by the PKC inhibitor bisindolylmaleimide I. In contrast, addition of calcium to Leydig cells increased 11betaHSD reductive activity while decreasing oxidative activity, thereby favoring reduction and conversion of inert 11-dehydrocorticosterone into active corticosterone. The opposite effect was seen after elimination of calcium-dependent signaling, including removal of calcium by EGTA or addition of the calmodulin (calcium binding protein) inhibitor SKF7171A, or the calcium/calmodulin-dependent protein kinase I (CaMK II) inhibitor, KN62. We conclude that 11betaHSD oxidative and reductive activities are separately regulated and that, in contrast to calcium-dependent signaling, PKC stimulates 11betaHSD oxidation while inhibiting 11betaHSD reduction. Maintenance of a predominantly oxidative 11betaHSD could serve to eliminate adverse glucocorticoid-induced action in Leydig cells.
 ...
PMID:Protein kinase C increases 11beta-hydroxysteroid dehydrogenase oxidation and inhibits reduction in rat Leydig cells. 1178 Sep 17

Since prednisolone and dexamethasone are known as potent anti-inflammatory agents, the effects of prednisolone and dexamethasone on production of intracellular reactive oxygen species (ROS) were investigated in human platelets. Platelet ROS were measured using the intracellular fluorescent dye dichlorofluorescein diacetate after activation of protein kinase C by phorbol-12-myristate-13-acetate (PMA) or 1-oleoyl-2-acetyl-sn-glycerol (OAG). NAD(P)H oxidase activity was measured photometrically. PMA and OAG significantly increased ROS in platelets (P<0.001). Prednisolone or dexamethasone concentration-dependently reduced the PMA-induced ROS production. The PMA-induced ROS increase was significantly reduced in the presence of 10 micromol/l prednisolone to 9+/-1% (n=31; P<0.001) or in the presence of 10 micromol/l dexamethasone to 9+/-1% (n=24; P<0.001). The inhibitory effect of prednisolone or dexamethasone could also be observed in the presence of the glucocorticoid receptor inhibitor, mifepristone (RU486). Administration of testosterone or aldosterone did not significantly reduce PMA-induced ROS increase. Prednisolone had no effect on platelet NAD(P)H oxidase activity. The inhibition of oxidative phosphorylation by sodium azide reduced platelets ROS to 8+/-1% (n=35). It is concluded that glucocorticoids, prednisolone and dexamethasone, directly inhibit production of intracellular ROS. This effect may contribute to the anti-inflammatory actions of these agents.
 ...
PMID:Effects of glucocorticoids on generation of reactive oxygen species in platelets. 1211 19


<< Previous 1 2 3 4 5 6 7 8 9 Next >>