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)

The type 2 isoform of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD2), which catalyzes the conversion of cortisol to hormonally inactive cortisone in man, is principally expressed in the placenta and mineralocorticoid target tissues, kidney and colon. To date, few studies have addressed the regulation of this novel 11 beta-HSD2 isoform. We have characterized the nature and regulation of the 11 beta-HSD activity expressed in a human cytotrophoblastic cell line, the JEG-3 choriocarcinoma cell. The 11 beta-HSD activity in JEG-3 cell homogenates required NAD+ as cofactor with NADP+ ineffective and demonstrated a high affinity for cortisol (apparent Km 31 nM). Incubation of JEG-3 cells with forskolin and dibutyryl cyclic AMP increased 11 beta-HSD2 activity several-fold in a time-dependent manner, while treatment with phorbol ester had little, if any, effect on 11 beta-HSD2 activity. Northern blot analysis of RNA isolated from JEG-3 cells after these treatments demonstrated a marked increase in a 1.9 kb 11 beta-HSD2 mRNA species in cells treated with forskolin for 24 h. We conclude that 11 beta-HSD2 is regulated by activation of the protein kinase A pathway, but not the protein kinase C pathway in human choriocarcinoma cells, and that this regulation occurs at a pretranslational level. JEG-3 cells provide an excellent model for further studies on the regulation of 11 beta-HSD2 gene expression in human trophoblast tissue.
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PMID:Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity and mRNA in human choriocarcinoma cells. 878 85

The regulation of 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) gene expression was studied in primary cultures of rat adrenocortical cells. The protein kinase A (PKA) pathway agonists forskolin, dibutyryl cAMP and ACTH caused a 5-10 fold increase in 11beta-HSD2 mRNA as determined by semiquantitative PCR. The effect of forskolin could be partially inhibited by the addition of the phorbol ester TPA, an activator of the protein kinase C (PKC) pathway. The increase in mRNA encoding 11beta-HSD2 was accompanied by increased synthesis of 11beta-HSD2 as measured by immunoprecipitation of labeled protein. It is concluded that both the PKA and PKC pathways are involved in the regulation of rat adrenal 11beta-HSD2 gene expression.
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PMID:Regulation of 11beta-hydroxysteroid dehydrogenase type II in rat adrenocortical cells. 988 53

Granulosa cells from preovulatory follicles show increased expression of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) at the time of ovulation. As ovulation may be an inflammatory process, this may be a mechanism of local enhancement of the activity of anti-inflammatory glucocorticoids. In this study, we examined direct effects of LH, the proinflammatory cytokine, interleukin-1beta (IL-1beta), and pharmacological activators of protein kinase A (PKA) (forskolin and dibutyryl (db) cAMP) and PKC (LH-releasing hormone and phorbol 12-myristate 13-acetate (PMA)) signalling on the expression of 11betaHSD1 mRNA in vitro. Granulosa cells from immature female rat ovaries were cultured (pretreatment) in serum-free medium 199 containing recombinant human (rh) FSH (1 ng/ml) for 48 h to induce responsiveness to LH. Cell monolayers were then washed and cultured (test treatment) for a further 12 h in the presence of rhLH (0-100 ng/ml), IL-1beta (0-50 ng/ml), or both. Total RNA was extracted from granulosa cell monolayers and taken for quantitative ribonuclease protection analysis of 11betaHSD1 mRNA. The low level of 11betaHSD1 mRNA detectable in unstimulated (control) cultures was increased approximately twofold by the 48-h pretreatment with rhFSH. Subsequent exposure to rhLH (1-100 ng/ml) for a further 12 h dose-dependently increased 11betaHSD1 mRNA expression by an additional two- to threefold. Forskolin (10 microM), db-cAMP (2 mM), LH-releasing hormone (LHRH; 1 microM) and PMA (200 nM) were also stimulatory. IL-1beta (0.05-50 ng/ml) stimulated 11betaHSD1 mRNA expression in a dose-related manner, both in the absence and in the presence of rhLH (3 ng/ml). The interaction between IL-1beta (5 ng/ml) and rhLH (3 ng/ml) was additive. Co-treatment with a 50-fold excess of IL-1 receptor antagonist fully reversed the action of IL-1beta. We conclude that 11betaHSD1 mRNA expression in functionally mature granulosa cells is directly stimulated by gonadotrophins and IL-1beta in vitro, potentially involving post-receptor signalling via PKA- and PKC-mediated pathways. Thus both LH and IL-1beta may serve physiological roles in the upregulation of 11betaHSD1 gene expression by granulosa cells in ovulatory follicles.
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PMID:Regulation of 11beta-hydroxysteroid dehydrogenase type 1 gene expression by LH and interleukin-1beta in cultured rat granulosa cells. 1058 15

1. This study investigated the effect of magnolol, a compound purified from Magnolia officinalis, on glucocorticoid production by primary adrenal cell culture. 2. Magnolol increased corticosterone secretion in a dose-dependent manner, this effect being maximal at 40 microM. A similar effect was seen in a minced adrenal gland system. 3. In magnolol-treated cells, the number and total area of cytoplasmic lipid droplets were reduced, suggesting a high utilization rate of cholesterol esters stored in lipid droplets. In control cells, the capsule of the lipid droplet was clearly delineated by immunostaining with antibody A2, whereas capsular staining was discontinuous or undetectable following magnolol treatment. The percentage of decapsulated cells increased significantly from 20% in the control group to 80% in the magnolol-treated group. 4. Magnolol-induced steroidogenesis was not mediated either via the traditional ACTH-cyclic AMP-protein kinase A pathway or by protein kinase C, since the intracellular cyclic AMP level did not change and inhibition of protein kinase A or C did not block the action of magnolol. Furthermore, calcium/calmodulin-dependent protein kinase II was not involved in magnolol-induced steroidogenesis. 5. The stimulatory effect of magnolol on steroidogenesis apparently requires new protein synthesis, since cycloheximide inhibited magnolol-induced corticosterone production by 50%. 6. Although other studies have shown that high concentrations of magnolol inhibit acyl-CoA: cholesterol acyltransferase and 11 beta-hydroxysteroid dehydrogenase in a cell-free system, our data show that, in adrenal cell cultures, low concentrations of magnolol have a stimulatory effect on steroidogenesis, and the glucocorticoid produced may explain the effective control of asthma by Magnolia officinalis.
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PMID:Magnolol stimulates steroidogenesis in rat adrenal cells. 1108 25

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.
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PMID:Protein kinase C increases 11beta-hydroxysteroid dehydrogenase oxidation and inhibits reduction in rat Leydig cells. 1178 Sep 17

The discovery of antidiabetic agents that inhibit hepatic glucose production is a popular and potentially fruitful research area for the pharmaceutical research community. Metformin, a marketed agent with this mechanism of action, is widely used for the treatment of type 2 diabetes, however, more efficacious agents are sought. A number of promising proteins are being targeted for modulation by new compounds, including the glucagon receptor, glycogen phosphorylase, glucocorticoid receptor, 11 beta-hydroxysteroid dehydrogenase-1, fructose-1,6-bisphosphatase, carnitine palmitoyltransferase-1, glycogen synthase kinase-3, glucose-6-phosphate T1 translocase and the A2B receptor. Compounds designed to work against these targets are at the early clinical or preclinical phase of study. Glucagon receptor antagonists, glycogen phosphorylase inhibitors, 11 beta-hydroxysteroid dehydrogenase-1 inhibitors, carnitine palmitoyltransferase-1 inhibitors and fructose-1,6-bisphosphatase inhibitors are, or have been, clinically evaluated. Preclinical studies against the other targets have yielded compounds that demonstrate efficacy in diabetic animal models and clinical activity will continue.
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PMID:Pharmacological regulation of hepatic glucose production. 1280 81

The regulation of 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2) expression at the level of specific mRNA and 11betaHSD2 protein was investigated in primary culture of renal epithelial cells of the rat. It has been shown that treatment of the SE cells with adenylyl cyclase activator, forskolin, known to stimulate the protein kinase A (PKA) pathway, resulted in an increase in 11betaHSD2 mRNA content in these cells. Semi-quantitative RT-PCR revealed that the effect of forskolin was attenuated by the addition of phorbol ester, tetradecanoyl phorbol acetate (TPA), an activator of the protein kinase C (PKC) pathway, whereas TPA on its own slightly reduced the basal level of 11betaHSD2 expression judging from the content of specific mRNA. Measurements of [35S]-methionine incorporation into immunoprecipitable 11betaHSD2 revealed an increased synthesis of this protein in renal epithelial cells treated with forskolin. Phorbol ester TPA markedly reduced the effect of forskolin on the synthesis of 11betaHSD2 and attenuated the basal level of synthesis of this protein. It is concluded that in renal epithelial cells in primary culture, stimulation of PKA pathway results in the induction of 11betaHSD2 both at a specific mRNA and at a protein level and that this effect is markedly reduced by activation of PKC pathway.
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PMID:Regulation of 11beta-hydroxysteroid dehydrogenase type II expression in the renal epithelial cells. 1285 8

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

Contribution of the protein kinase A (PKA) and protein kinase C (PKC) signalling pathways to the regulation of 11beta-hydroxysteroid dehydrogenase type II (HSD11B2) gene expression was investigated in human breast cancer cell line MCF-7. Treatment of the cells with an adenylyl cyclase activator, forskolin, known to stimulate the PKA pathway, resulted in an increase in HSD11B2 mRNA content. Semi-quantitative RT-PCR revealed attenuation of the effect of forskolin by phorbol ester, tetradecanoyl phorbol acetate (TPA), an activator of the PKC pathway. It was also demonstrated that specific inhibitors significantly reduced the effect of activators of the two pathways. Stimulation of the PKA pathway did not affect, whereas stimulation of the PKC pathway significantly reduced MCF-7 cell proliferation in a time-dependent manner. A cell growth inhibitor, dexamethasone, at high concentrations, caused a 40% decrease in proliferation of MCF-7 cells and this effect was abolished under conditions of increased HSD11B2 expression. It was concluded that in MCF-7 cells, stimulation of the PKA signal transduction pathway results in the induction of HSD11B2 expression and that this effect is markedly reduced by activation of the PKC pathway. Activation of the PKC pathway also resulted in inhibition of cell proliferation, while activation of the PKA pathway abolished the antiproliferative effect of dexamethasone. These effects might be due to oxidation of dexamethasone by the PKA-inducible HSD11B2.
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PMID:Contribution of protein kinase A and protein kinase C signalling pathways to the regulation of HSD11B2 expression and proliferation of MCF-7 cells. 1562 63

Methionine restriction (MR) limits age-related adiposity in Fischer 344 (F344) rats. To assess the mechanism of adiposity resistance, the effect of MR on adipose tissue (AT) 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) was examined. MR induced 11beta-HSD1 activity in all ATs, correlating with increased tissue corticosterone. However, an inverse relationship between 11beta-HSD1 activity and adipocyte size was observed. Because dietary restriction controls lipogenic and lipolytic rates, MR's effects on lipogenic and lipolytic enzymes were evaluated. MR increased adipose triglyceride lipase and acetyl-coenzyme A carboxylase (ACC) protein levels but induced ACC phosphorylation at serine residues that render the enzyme inactive, suggesting alterations of basal lipolysis and lipogenesis. In contrast, no changes in basal or phosphorylated hormone-sensitive lipase levels were observed. ACC-phosphorylated sites were specific for AMP-activated protein kinase (AMPK); therefore, AMPK activation was evaluated. Significant differences in AMPKalpha protein, phosphorylation, and activity levels were observed only in retroperitoneal fat from MR rats. No differences in protein kinase A phosphorylation and intracellular cAMP levels were detected. In vitro studies revealed increased lipid degradation and a trend toward increased lipid synthesis, suggesting the presence of a futile cycle. In conclusion, MR disrupts the lipogenic/lipolytic balance, contributing importantly to adiposity resistance in F344 rats.
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PMID:Methionine restriction effects on 11 -HSD1 activity and lipogenic/lipolytic balance in F344 rat adipose tissue. 1790 24


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