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

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ginsenosides present in the roots of Panax ginseng C.A. Meyer have been shown to induce a number of hepatocyte gene expression. We have recently demonstrated that ginsenoside-Rg1 (G-Rg1) stimulated the enzyme activity of tyrosine aminotransferase (TAT), a hepatocyte specific enzyme, of which enzyme activity was dose-dependently inhibited by RU486, a specific glucocorticoid antagonist. This study was therefore designed to determine whether G-Rg1 induces the transcriptional activity of TAT gene and to investigate whether G-Rg1 induces the gene transcription by glucocorticoid receptor- or cAMP-mediated induction mechanism. The slot blot hybridization analysis revealed that the TAT-mRNA level was increased by 9.3-fold in hepatocyte cultures in response to G-Rg1 stimulation. In contrast, the inductive effect of G-Rg1 was almost equally inhibited, that is, by 49% or 50% respectively in the presence of RU486 or Rp-cAMPs, a specific competitive inhibitor of protein kinase A. These results in hepatocyte cultures suggest that G-Rg1 modulates the TAT gene transcription through its influence on a functional or cooperative interaction between glucocorticoid receptor- and cAMP-mediated induction mechanism.
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PMID:Ginsenoside-Rg1 regulates the induction of tyrosine aminotransferase gene transcription in rat hepatocyte cultures. 781 Dec 53

The phosphoenolpyruvate carboxykinase (PEPCK) gene is regulated at the transcriptional level by a variety of effectors in a tissue-specific fashion. In order to study the parameters involved in the tissue-specific hormonal regulation of the PEPCK gene, we have used a transient expression test in well-differentiated rat hepatoma cells as well as in dedifferentiated variants. In this test, the PEPCK promoter is induced by glucocorticoids in well-differentiated FGC4 cells, but not in H5 dedifferentiated variants, in spite of the presence in H5 cells of the glucocorticoid receptor. Study of the PEPCK promoter using electrophoretic mobility shift assays reveals binding sites for the liver-enriched transcription factors HNF1, vHNF1, HNF3, HNF4, and CAAT/enhancer binding protein members. Overexpression of the liver-enriched transcription factors absent in the dedifferentiated variants, such as HNF1 and HNF4, is not sufficient to restore glucocorticoid response of the PEPCK promoter in the variants. Moreover, systematic analysis of the PEPCK promoter reveals that the presence of a region covering a cAMP-responsive element (CRE1 at -80) and a CAAT box is necessary for full response of the PEPCK promoter to glucocorticoids in well-differentiated rat hepatoma cells. In a cotransfection test, overexpression of the regulatory subunit of protein kinase A (PKA), causing sequestering of PKA, abolishes the glucocorticoid response of the promoter in well-differentiated cells. On the other hand, in dedifferentiated variants, overexpression of the catalytic subunit of PKA restores the response to glucocorticoids. The action of PKA on the glucocorticoid response requires the presence of the CRE1 element and is promoter specific because it does not concern nonhepatic promoters such as the long terminal repeats of the mouse mammary tumor virus. These results suggest that the full response of the PEPCK promoter to glucocorticoids requires activation of another signal transduction pathway, the cAMP-mediated pathway.
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PMID:Response of the phosphoenolpyruvate carboxykinase gene to glucocorticoids depends on the integrity of the cAMP pathway. 781 33

The biological effects of pituitary adenylate cyclase-activating peptide (PACAP) 27 and 38 on peptide secretion and gene regulation were studied in the mouse corticotrope-derived cell line AtT20. Treatment of these cells with PACAP 27/38 led to a dose-dependent increase in cAMP content and ACTH accumulation in the medium with an apparent ED50 value close to 10(-9) M. The genomic effects of PACAP were first investigated by using a reporter gene containing a cAMP responsive element (CRE: TGACGTCA) PACAP 27/38 stimulate transcription from this construction and the effect is further increased when cells are cotreated with the phosphodiesterase inhibitor rolipram. Furthermore, we show by measuring nuclear heterologous proopiomelanocortin (POMC) RNA levels or by using a reporter gene containing the POMC promoter region, that PACAP stimulates POMC transcription. This transcriptional stimulation is mediated by the cAMP-dependent protein kinase (PKA) since genetic inactivation of PKA by a dominant inhibitory mutant of this enzyme completely abolished the effect of PACAP on POMC transcription. Finally, we show that the transcriptional stimulation of POMC by PACAP is repressed by the glucocorticoid receptor agonist dexamethasone. Taken together, these data suggest that PACAP is a hypophysiotropic hormone that exert similar if not identical functions as corticotropin-releasing hormone (CRH) on corticotrope cells.
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PMID:Pituitary adenyl cyclase-activating peptide: a hypophysiotropic factor that stimulates proopiomelanocortin gene transcription, and proopiomelanocortin-derived peptide secretion in corticotropic cells. 784 39

Ginsenoside-Rg1 (G-Rg1) present in the roots of Panax ginseng (C. A. Meyer) has been shown to induce the enzyme activity of tyrosine aminotransferase (TAT) EC(2.6.1.5) in rat hepatocyte cultures. Thus, we investigated whether the inductive effect of G-Rg1 may act through glucocorticoid receptor- or cAMP-mediated action mechanism in the hepatocyte cultures. G-Rg1 induced the TAT activity by 2-fold with a similar time course to that of dexamethasone in the cell cultures. This effect of G-Rg1 was abolished to the basal level when RU486, a specific glucocorticoid antagonist was added to 10(-5)M. Furthermore, the additive effect of G-Rg1 and dexamethasone was inhibited as well by RU486. G-Rg1 and dibutyryl-cAMP (Bt2-cAMP) also revealed an additive effect but this additive effect was inhibited only to the G-Rg1-induced level by Rp-cAMPS, a specific inhibitor of protein kinase A. From these results, we suggest that the action mechanism of G-Rg1 leading to the induction of TAT activity may be mediated through glucocorticoid receptor binding and may not directly act through cAMP-mediated induction mechanism.
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PMID:Inductive effect of ginsenoside-Rg1 on tyrosine aminotransferase gene expression in rat primary hepatocyte cultures. 786 12

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.
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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

The somatostatin (SS) gene is transcriptionally regulated via the cyclic AMP (cAMP) response element (CRE), located in the proximal promoter (-41 to -48 bp). We have previously reported that glucocorticoids induce dose-dependent cell-specific alterations in the steady-state SS mRNA level. Here we have investigated direct transcriptional control of the SS gene by glucocorticoids. We have examined transcriptional interaction between glucocorticoids and the cAMP signalling pathway and mapped the 5' upstream regulatory region of the SS gene involved in glucocorticoid transactivation. Transcriptional regulation was determined by analysis of chloramphenicol acetyltransferase (CAT) activity in PC12 rat pheochromocytoma cells and A126-1B2 (protein kinase A-deficient mutant PC12) cells, by acute transfection of 5' flanking SS DNA (- 750, -250 and -71 bp) ligated to the reporter (CAT) gene. Dexamethasone (DEX) induced a dose-dependent 2.2-fold stimulation of SS gene transcription in PC12 cells, but not in A126-1B2 cells. Other steroid and thyroid hormones tested, and retinoic acid, were ineffective, while cAMP and forskolin stimulated gene transcription 4-5-fold in PC12 cells but not in A126-1B2 cells. DEX exerted an additive effect on cAMP-induced gene transcription. Deletion of the promoter from -750 to -71 bp (but not from -750 to -250 bp) abolished all stimulatory effects of DEX without affecting cAMP responsiveness. Mutation of the CRE abrogated both DEX- and cAMP-dependent gene enhancement. Gel electrophoretic mobility shift assays confirmed that the -250 to -71 bp region of the SS promoter (but not the -71 to +55 bp domain) binds specifically to a glucocorticoid response element-sensitive nuclear protein(s) from PC12 cells, suggesting a putative glucocorticoid receptor interaction with SS promoter DNA. We conclude that glucocorticoids regulate SS gene transcription positively. Glucocorticoid-induced transactivation shows dependence on protein kinase. A activity, and may be mediated via protein-protein interaction between the glucocorticoid receptor and the CRE binding protein. DNA sequences upstream from the CRE between -250 and -71 bp in the SS promoter appear to be the target of glucocorticoid action.
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PMID:Glucocorticoids activate somatostatin gene transcription through co-operative interaction with the cyclic AMP signalling pathway. 791 2

We have examined phosphorylation of the rat liver glucocorticoid receptor (GR) and GR-associated protein kinase (PK) activity in the immunopurified receptor preparations. Affinity labeling of hepatic cytosol with [3H]dexamethasone 21-mesylate showed a covalent association of the steroid with a 94 kDa protein. GR was immunopurified with antireceptor monoclonal antibody BuGR2 (Gametchu & Harrison, Endocrinology 114: 274-279, 1984) to near homogeneity. A 23 degrees C incubation of the immunoprecipitated protein A-Sepharose adsorbed GR with [gamma-32P]ATP,Mg2+ and the catalytic subunit of cAMP-dependent PK (cAMP-PK) from bovine heart, led to an incorporation of radioactivity in the 94 kDa protein. Phosphorylation of GR was not evident in the absence of the added kinase. Of the radioinert nucleotides (ATP, GTP, UTP or CTP) tested, only ATP successfully competed with [gamma-32P]ATP demonstrating a nucleotide specific requirement for the phosphorylation of GR. Other divalent cations, such as Mn2+ or Ca2+, could not be substituted for Mg2+ during the phosphorylation reaction. Phosphorylation of GR was sensitive to the presence of the protein kinase inhibitor, H-8, an isoquinoline sulfonamide derivative. In addition, the incorporation of radioactivity into GR was both time- and temperature-dependent. The phosphorylation of GR by cAMP-PK was independent of the presence of hsp-90 and transformation state of the receptor. The results of this study demonstrate that GR is an effective substrate for action of cAMP-PK and that the immunopurified protein A-Sepharose adsorbed GR lacks intrinsic kinase activity but can be conveniently used for the characterization of the phosphorylation reaction in the presence of an exogenous kinase.
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PMID:Phosphorylation of immunopurified rat liver glucocorticoid receptor by the catalytic subunit of cAMP-dependent protein kinase. 796 99

Glucocorticoids induce a programmed cell death in immature murine T cells through a process that has been named apoptosis. Cyclic AMP-dependent protein kinase (PKA) activity contributes to this response but acts through an undefined mechanism. Steroid-induced cytolysis can be completely blocked by the glucocorticoid antagonist RU 486, which inhibits the transformation of the glucocorticoid receptor (GR) into a fully activated transcription factor. However, the ability of cAMP to act synergistically with steroids to cause apoptosis has revealed that a limited portion of RU 486-bound GR can translocate to the nucleus and contribute to a loss of cell viability. The combination of cAMP and RU 486 was also found to act cooperatively to regulate mRNA levels of specific genes. A 5-kilobase VL30 retroviral element transcript, which had previously been shown to be regulated synergistically by cAMP and dexamethasone, was strongly induced by the combination of RU 486 and cAMP. There was no agonist effect of RU 486 on the induction of the VL30 5-kilobase transcript in a variant cell line with defective PKA. Thus, the ability of RU 486 to act as an agonist, in this instance, was cAMP dependent. A similar response was also seen with the chondroitin sulfate proteoglycan core protein gene. On the other hand, mouse mammary tumor virus mRNA levels, which were not affected by cAMP alone, did not respond to a combination of RU 486 and cAMP. Studies of GR function, evaluating nuclear translocation and DNA binding at a GR-specific DNA regulatory element site found no evidence for a general effect of PKA activation on these receptor functions. We propose that cAMP may contribute to the induction of apoptosis at a step beyond receptor transformation by promoting an interaction between GR and other gene-specific regulatory proteins. Moreover, this interaction is sufficient to overcome the inhibition imposed by RU 486 on the functional capacity of nuclear glucocorticoid receptors.
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PMID:Synergistic induction of apoptosis with glucocorticoids and 3',5'-cyclic adenosine monophosphate reveals agonist activity by RU 486. 838 86

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.
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PMID:Latent agonist activity of the steroid antagonist, RU486, is unmasked in cells treated with activators of protein kinase A. 839 51

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.
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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


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