Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modulator is an endogenous low-molecular-weight regulator of both glucocorticoid and mineralocorticoid receptors as well as protein kinase C. Structural analysis of modulator purified to apparent homogeneity suggests that it is a novel ether aminophosphoglyceride. In this report, we show that modulator inhibits cytosolic human glucocorticoid receptor (GR) complex activation as measured by DNA-cellulose binding. In addition, modulator blocks glucocorticoid-induced nuclear translocation of the GR in intact human leukemic (CEM C-7) cells, as illustrated by immunocytochemical localization. Furthermore, we demonstrate that modulator, by blocking the activation and subsequent translocation of GR, inhibits glucocorticoid-mediated apoptosis, characterized by chromatin condensation, internucleosomal DNA fragmentation, and cell death in glucocorticoid-sensitive CEM C-7 cells. Modulator inhibits glucocorticoid-induced c-myc gene repression and glucocorticoid receptor gene up-regulation. These data suggest that modulator functions to regulate the GR in intact cells as well as in cytosolic preparations. In addition, the inhibition of glucocorticoid-induced programmed cell death by modulator sheds light on the cellular function of modulator as well as on the mechanism by which apoptosis occurs in CEM C-7 cells.
...
PMID:Modulator inhibits nuclear translocation of the glucocorticoid receptor and inhibits glucocorticoid-induced apoptosis in the human leukemic cell line CEM C-7. 783 24

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to induce aryl hydrocarbon hydroxylase in several tissues in the rat. This effect of TCDD is mediated by the Ah receptor. However, TCDD does not significantly enhance aryl hydrocarbon hydroxylase activity in the rat thymus. Analysis of 3H-TCDD bound Ah receptor on sucrose gradients revealed the presence of radioactivity sedimenting at 8-9S and 5-6S in the cytosol and nuclei of thymus respectively. Incubation of rat thymic cytosol with TCDD increased protein kinase C dependent phosphorylation, which reached saturation levels at high concentrations of TCDD, but the TCDD bound receptor did not appreciably retard 32P-labeled XRE-3 as determined by electrophoretic mobility shift assay. Incubation of rat hepatic cytosol with TCDD also increased protein kinase C dependent phosphorylation in a concentration dependent manner as well as retarded the mobility of 32P-labeled XRE far more than that observed with thymic cytosol. The ability of the Ah receptor to bind to XRE was temperature dependent. Incubation of thymic cytosol either with okadaic acid or with sodium fluoride did not increase the binding of the Ah receptor to XRE. On mixing hepatic cytosol with thymic cytosol prior to the electrophoretic mobility shift assay, the binding of the hepatic Ah receptor to XRE was reduced in a concentration-dependent manner. A similar effect was observed when renal cytosol was used instead of hepatic cytosol. Thymic cytosol also reduced the binding of the hepatic glucocorticoid receptor to its cognate responsive element. Thymic cytosol did not alter the topology/integrity of XRE. These data suggest that the thymus contains a factor(s) which interferes with the binding of AhR to its cognate responsive element.
...
PMID:An inhibitory factor in rat thymus which interferes with binding of cytosol Ah receptor to xenobiotic responsive element. 784 25

Transcription of the rat tyrosine aminotransferase gene (TAT) is stimulated in liver by glucocorticoid hormones or by cAMP-increased protein kinase A activity via enhancers located 2.5 kilobases (kb) and 3.6 kb upstream of the start site of transcription. The proteins mediating induction have been characterized, and protein binding in the two enhancer regions has been analyzed in vivo and in vitro. The TAT gene is therefore a useful model system with which to study cross-talk between different signal transduction pathways. We find that activation of the second messenger pathway leading from protein kinase C to the transcription factor AP-1 by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) impairs induction of the TAT gene both by glucocorticoid hormones and cAMP. The effects of TPA treatment on chromatin structure of the TAT gene and protein-DNA interactions in vivo were assayed. Under conditions in which TPA impairs glucocorticoid induction of TAT mRNA, the glucocorticoid receptor and other proteins binding within the glucocorticoid-inducible enhancer occupy their binding sites, indicating that inhibition occurs at a later step necessary for transcriptional stimulation. On the other hand, inhibition of cAMP induction correlates with reduced occupancy of the cAMP response element in vivo.
...
PMID:Cross-talk modulation of signal transduction pathways: two mechanisms are involved in the control of tyrosine aminotransferase gene expression by phorbol esters. 791 48

Modulator is an endogenous low-molecular weight regulator of both glucocorticoid and mineralocorticoid receptors, as well as protein kinase C. Analogs of the putative modulator structure have been synthesized. These compounds include 1-O-(3'-carboxypropyl) or (5'-carboxypentyl)-L-glycero-3-phospho-L-serine or L-threonine, and the D-glycerol stereoisomers. These compounds were tested for in vitro modulator activity using the glucocorticoid-receptor complex activation inhibition and steroid-binding stabilization assays. One of the ether phosphoglycerides, 1-O-(5'-carboxypentyl)-L-glycero-3-phospho-L-threonine (H-GPT-1), partially inhibited steroid-receptor complex activation in a dose-dependent manner. However, none of the other compounds exhibited any modulator activity towards the glucocorticoid-receptor complex. Like modulator, H-GPT-1 did not inhibit activated glucocorticoid-receptor complex binding to DNA-cellulose. Surprisingly, in contrast to modulator, H-GPT-1 partially inhibited unoccupied receptor steroid-binding in a dose-dependent manner. These results suggest that although modulator is not exactly mimicked by this compound, H-GPT-1 is the first synthetic organic molecule to exhibit some modulator activity towards the glucocorticoid receptor.
...
PMID:A new synthetic ether aminophosphoglyceride exhibits partial modulator activity towards the glucocorticoid receptor. 807 85

Glucocorticoids have a wide variety of effects which result in the dampening of inflammatory and immune responses and other challenges to homeostasis. An important site of steroid action may be on the control of transcription factor binding to DNA. The interaction of the transcription factors, activator protein 1 (AP-1) and nuclear factor kappa from B cells (NF kappa B) with DNA and glucocorticoid receptors was analysed by gel mobility shift assays following stimulation by tumour necrosis factor alpha (TNF alpha) and a phorbol ester (PMA) that activates protein kinase C. PMA and TNF alpha both caused significant (180-340%) increases in AP-1 and NF kappa B DNA binding which peaked at 15 minutes and decreased to a constant elevated level at between 1-3 hrs and was sustained for 24hrs. Dexamethasone (1 microM) caused a rapid and long lasting 40-50% decrease in both AP-1 and NF kappa B DNA binding lasting over 24hrs. Combined treatment with dexamethasone and PMA or TNF alpha prevented the increase in both AP-1 and NF kappa B binding due to PMA and TNF alpha returning levels to those seen in control untreated samples. This suggests that in human lung, the glucocorticoid receptor functionally interacts within the nucleus with other transcription factors that are induced by inflammatory mediators such as cytokines. This may be an important molecular site of steroid action in chronic inflammatory lung diseases such as asthma.
...
PMID:The effects of glucocorticoids on phorbol ester and cytokine stimulated transcription factor activation in human lung. 809 56

Apoptosis is induced in immature thymocytes by physiological peak levels of glucocorticoid hormones, especially in murine and rat cells. Endogenous glucocorticoids may have some role in thymic selection. Glucocorticoid-induced thymocyte apoptosis appears to be dependent on protein kinase C (PKC), since it is inhibited by PKC inhibitors. PKC is a family of closely related enzymes, consisting of Ca(2+)-dependent (PKC-alpha, -beta I, -beta II, and -gamma) and Ca(2+)-independent (PKC-delta, -epsilon, -eta (L), -theta, -zeta, and -lambda) isozymes. In the present study, we analyzed the role of PKC in glucocorticoid-induced apoptosis in murine thymocytes and found that glucocorticoid selectively induces an increase in Ca(2+)-independent PKC activity in the particulate fraction of immature thymocytes but not in that of mature T cells. The increase as well as the apoptosis was inhibited by actinomycin D, cycloheximide, or the glucocorticoid receptor antagonist, RU 38486. Immunoblotting studies revealed the selective translocation of PKC-epsilon from the cytosolic fraction to the particulate fraction upon glucocorticoid treatment. These results suggest that glucocorticoid-induced apoptosis in immature thymocytes involves glucocorticoid receptor-mediated and selective activation of PKC-epsilon through de novo synthesis of macromolecules.
...
PMID:Involvement of protein kinase C-epsilon in glucocorticoid-induced apoptosis in thymocytes. 818 94

Interaction between protein kinase C (PKC)- and glucocorticoid receptor (GR)-mediated signaling is suggested by the ability of the PKC activating phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to inhibit GR-dependent transcription of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR). Here we report that this interference is cell specific, as TPA augmented dexamethasone-induced transcriptional activation of the MMTV LTR in several T cell lines but was inhibitory in NIH-3T3 fibroblasts. TPA-GR synergism was determined to have occurred at the GR-responsive element (GRE) level by functional analysis of deletion mutants or synthetic GRE oligonucleotides driving chloramphenicol acetyl-transferase expression. Synergism required an intact GR DNA-binding domain, whereas amino- or carboxyl-terminal domains were dispensable. The effect was abrogated by the PKC inhibitor staurosporine, suggesting a role for PKC. Increased c-jun, jun-B, and jun-D expression above basal levels and increased transcriptional activity of AP-1/TPA responsive elements fused to chloramphenicol acetyl-transferase vectors were observed in T cells treated with TPA alone or in combination with dexamethasone. The ability of Jun proteins to cooperate with GR in T cells has been investigated after transfection of c-jun, jun-B, or jun-D expression vectors, which augmented GR-dependent transcription from either MMTV LTR or GRE. Conversely, c-jun and jun-B transfection blunted GR-dependent transcription in HeLa cells. The presence of c-fos had a negative influence on GR function and correlated with the cell-specific synergistic or antagonistic activity of Jun with respect to GR; high basal expression of c-fos as well as AP-1 DNA binding and transcriptional activity were observed in HeLa cells, but not in T cells. Furthermore overexpression of exogenous c-fos has an inhibitory effect on GR-dependent transcription from GRE in T cells. We propose that Jun plays a bifunctional role on GR-dependent transcriptional activation of GRE, selecting either synergistic or antagonistic activity depending on the cell-specific microenvironment. In this regard, intracellular levels of c-fos appear to be influential.
...
PMID:Cell-specific bifunctional role of Jun oncogene family members on glucocorticoid receptor-dependent transcription. 838 98

RU486 is a glucocorticoid and progesterone antagonist. In glucocorticoid-responsive fibroblasts, it mediates little or no induction of a truncated, hormone-responsive mouse mammary tumor virus promoter; moreover, it abrogates the induction mediated by the glucocorticoid agonist, dexamethasone. However, when the fibroblasts are treated with activators of protein kinase A, 8-Br-cAMP or forskolin, along with RU486, the steroid now acts as a partial agonist, capable of mediating an induction of hormone-responsive reporter genes. In addition, the ability of RU486 to block the action of the glucocorticoid agonist, dexamethasone, is compromised by concomitant treatment with 8-Br-cAMP. Activators of protein kinase C fail to elicit these phenomena. Induction of gene expression in the presence of 8-Br-cAMP is dependent on the dose of RU486 over a range consistent with a glucocorticoid receptor-mediated mechanism. An antagonist, ZK98 299, which unlike RU486 is not thought to permit receptor binding to DNA, is not activated by 8-Br-cAMP. The elicitation of RU486 agonist activity cannot be attributed solely to idiosyncrasies of the cell line or the promoter. Similar phenomena are observed in another glucocorticoid-responsive fibroblast line. Furthermore, RU486 can induce a minimal promoter bearing two copies of a synthetic receptor target site. However, we have identified at least one promoter toward which RU486 still behaves as an antagonist despite 8-Br-cAMP treatment. These observations suggest that the unmasking of latent agonist activity in a type II antagonist is not an isolated phenomenon and may, therefore, be seen with other receptors and antagonists. The finding that modulation of cellular signal transduction pathways can unmask agonist activity in an otherwise effective steroid antagonist has significant implications for the use of steroid antagonists in the clinical setting and could represent a heretofore unrecognized mechanism for the development of steroid resistance.
...
PMID:Latent agonist activity of the steroid antagonist, RU486, is unmasked in cells treated with activators of protein kinase A. 839 51

We examined the effect of chronic human immunodeficiency virus 1 (HIV-1) infection on the growth of human leukemic CEM T cells exposed to compounds which act through several major hormone or hormone-like signal transduction systems. Three were not altered by HIV-1 infection. Micromolar 8-bromo-cAMP inhibited cell growth equally in uninfected and infected cells. At the concentrations tested, neither (Bu)2cAMP nor the stimulator of protein kinase C, phorbol 12-myristate 13-acetate, altered the growth of infected or uninfected cells. The synthetic prostaglandin analog enisoprost also inhibited both equally. However, responses to two basic signal transduction systems, calcium uptake and the glucocorticoid pathway, were influenced by HIV infection. In chronically HIV-infected cells increased sensitivity to lysis by the calcium ionophore A23187 was observed. Additionally, the infected cells contained reduced amounts of glucocorticoid receptor sites and showed a statistically significant shift toward resistance to glucocorticoid-induced apoptosis.
...
PMID:Interactions between human immunodeficiency virus infection and hormonal pathways: enhancement of calcium-induced but reduction of glucocorticoid-induced cell death. 839 9

A novel member of the serine/threonine protein kinase gene family, designated sgk, for serum and glucocorticoid-regulated kinase, was identified in a differential screen for glucocorticoid-inducible transcripts expressed in the Con8.hd6 rat mammary tumor cell line. sgk encodes a protein of 49 kDa which has significant sequence homology (45 to 55% identity) throughout its catalytic domain with rac protein kinase, the protein kinase C family, ribosomal protein S6 kinase, and cyclic AMP-dependent protein kinase. sgk mRNA is expressed in most adult rat tissues, with the highest levels in the thymus, ovary, and lung, as well as in several rodent and human cell lines. sgk mRNA was stimulated by glucocorticoids and by serum within 30 min, and both inductions were independent of de novo protein synthesis. The transcriptional regulation by glucocorticoids is a primary response, since the promoter of sgk contains a glucocorticoid response element consensus sequence 1.0 kb upstream of the start of transcription which is able to stimulate chloramphenicol acetyltransferase reporter gene activity in a dexamethasone-dependent manner. Antibodies that specifically recognize sgk-encoded protein on an immunoblot were generated. This protein was shown to increase in abundance with glucocorticoid treatment in a manner which paralleled the mRNA accumulation. This is the first report of a presumed serine/threonine protein kinase that is highly regulated at the transcriptional level by glucocorticoid hormones and suggests a novel interplay between glucocorticoid receptor signalling and a protein kinase of the second messenger family.
...
PMID:Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. 845 96


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

---