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)

Polymorphonuclear leukocytes (PMNL) release superoxide anions formed by a membrane-bound NADPH oxidase induced by stimulations. Properties of the inducers and their antagonists indicate that Ca2+, GTP-binding protein (G-protein), phospholipase C and Ca2+, phospholipid-dependent protein kinase (C-kinase) are mainly associated with the stimulation of receptors. Low concentrations of ATP induce the oxidase accompanied by the increase in the intracellular Ca2+ due to the flux from the medium and the storage site. ATP-gamma-S, UTP and ITP are effective but mononucleotides, dinucleotides, GTP and CTP are not. Leukotriene B4 (LTB4) which acts as a chemotactic agent and the inducer of the NADPH oxidase is catabolized. It is hydroxylated by a specific cytochrome P450 and then oxidized to a carboxy derivative by a cytosolic alcohol dehydrogenase and a microsomal aldehyde dehydrogenase in PMNL. Active NADPH oxidase was obtained by incubating membrane and cytosolic components of resting PMNL in the presence of sodium dodecyl sulfate (SDS). Two cytosolic components were obtained by an affinity chromatography on 2',5'-ADP Sepharose. One component is active in the presence of GTP or GTP-gamma-S and the other component in the presence of another cytosolic fraction.
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PMID:Metabolism of stimulated polymorphonuclear leukocytes. 254 77

A sequential mechanism for endothelium-dependent vasorelaxation is proposed. The following events appear to be involved: Endothelial cell: activation of a receptor----activation of membrane phospholipases----increase in intracellular free Ca2+----formation of endothelium-derived relaxing factor(s) (EDRF) via a cytochrome P450-dependent epoxygenase or non-enzymatic lipid peroxidation pathway----release of EDRF----diffusion of EDRF to the smooth muscle cell; Smooth muscle cell: activation of guanyl cyclase----activation of protein kinase----protein phosphorylation----dephosphorylation of myosin light chain----relaxation. Relationships between endothelium-dependent and endothelium-independent vasorelaxation are indicated. EDRF-candidates include aldehydes and epoxides.
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PMID:Mechanism of endothelium-dependent vasorelaxation. 286 27

Thio-substituted ATP is a sensitive probe for detecting protein kinase C activity as demonstrated in bovine adrenocortical cell membrane preparations. A single endogenous protein substrate with a molecular weight of approximately 47 Kd was rapidly phosphorylated with [3 5S] gamma-thio-ATP as phosphate donor. Phosphorylation was significantly increased in 30 seconds and reached a plateau by 3 minutes. The activity of the endogenous membrane kinase was unaffected by ACTH, cAMP, calmodulin or trifluoperazine but was responsive to combinations of calcium (Ca), diolein and phosphatidyl serine (PS). In addition, the kinase was activated by the tumor promoting phorbol ester, 12-0-tetradecanoylphorbol-13-acetate, indicating that the membrane contains a protein kinase C and a single 47 Kd phosphorylatable protein substrate. The same substrate is phosphorylated by Ca/diolein/PS activated kinase in membrane preparations from a broad range of rat tissues. Attempts to identify the substrate indicate that it is neither the type I regulatory subunit of cAMP dependent protein kinase nor mitochondrial cytochrome P450.
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PMID:Evidence for protein kinase C in bovine adrenocortical membrane preparations using [35S] gamma-thio-ATP as a phosphate donor. 369 26

Adrenal cortical mitochondria contain a mixed function oxidase capable of converting cholesterol to pregnenolone; this enzyme requires NADPH, oxygen and cholesterol. This cholesterol side chain cleavage enzyme system contains a Flavoprotein, an iron sulphur protein and a specific cytochrome P450 termed cytochrome P450scc. ACTH stimulates the adrenal cortex by activating adenyl cyclase producing an elevated intracellular concentration of cAMP. This in turn increases the activity of a cytosolic cAMP dependent protein kinase. Adrenal cortical cytosol contains a cholesterol ester hydrolase which is activated by ATP and a protein kinase. This enzyme may be deactivated by a phosphoprotein phosphatase. The adrenal cortex contains lipid droplets that are rich in esterified cholesterol. Cholesterol ester hydrolase can release free cholesterol from the lipid droplets. The free cholesterol released may be used to supplement the mitochondrial cholesterol as a pregnenolone precursor. Steroid hormone production by the adrenal cortex exhibits a diurnal rhythm and correlates with the activity of the cytosolic cholesterol ester hydrolase. The acute steroidogenic response to ACTH may be in part attributed to the availability of free cholesterol to the mitochondrial cholesterol side chain cleavage enzyme complex. The intracellular movement of free cholesterol from lipid droplets to mitochondrial inner membranes may be impeded by protein synthesis inhibitors such as cycloheximide. The precise mechanism of this block in steroidogenesis remains to be elucidated. Various drugs and oestrogenic hormones suppress the plasma and adrenal cholesterol concentrations. If adrenal cells are deficient in cholesterol, these cells exhibit a diminished response to ACTH. The response to this hormone can be corrected by supplying cholesterol via exogenous plasma lipoproteins. The route that free cholesterol follows within the adrenal cortical cell and the physiological factors influencing free cholesterol movement in such cells are important issues to be explored in future.
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PMID:Cholesterol metabolism in the adrenal cortex. 631 Feb 52

Although changes in the expression of key steroidogenic enzymes such as cytochrome P450 cholesterol side-chain cleavage, 17 alpha-hydroxylase (P450c17), aldosterone synthase, and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) in the human adrenal cortex are known to be controlled by factors activating the protein kinase A or protein kinase C signaling pathways, little is known concerning the effects of increased intracellular Ca2+. In this study we describe the effects of K+, an agent known to increase intracellular Ca2+ through the opening of voltage-sensitive Ca2+ channels, on steroidogenesis in H295R human adrenocortical cells and corresponding changes in expression of these vital steroidogenic enzymes. Treatment of cells for 48 h with K+ (14 mM) resulted in an increase in aldosterone (3.5-fold) as well as the 17 alpha-hydroxylated steroids cortisol (2.9-fold) and dehydroepiandrosterone (DHEA; 3.7-fold). This action of K+ was accompanied by a dose-dependent (P < 0.05 at 6 mM K+ or above) and time-dependent (P < 0.05 at 24 h and beyond) increase in expression of P450c17 and, to a lesser extent, cytochrome P450 cholesterol side-chain cleavage messenger RNA (mRNA). Treatment with K+ also caused a time-dependent increase in aldosterone synthase mRNA levels, which were detectable by 12 h. Treatment with K+, however, was without effect on 3 beta HSD expression. These effects contrast with those of (Bu)2cAMP, which stimulated a greater increase in cortisol and DHEA secretion as well as P450c17 expression. The effects of K+ treatment also differ from those of AII, which promoted a greater aldosterone secretory response (5.7-fold), but a lesser effect on DHEA secretion (2.2-fold) and P450c17 expression. Although AII and TPA (known activators of protein kinase C) as well as forskolin and (Bu)2cAMP (known activators of protein kinase A) increased the expression of 3 beta HSD mRNA, K+ treatment was without effect, suggesting that elevation of [Ca2+]i in response to K+ did not activate the protein kinase C or protein kinase A signaling pathways. Furthermore, the effects of K+ on steroid secretion and 17 alpha-hydroxylase activity were reproduced by the voltage-sensitive Ca2+ channel activator BAYK 8644, and increases in P450c17 mRNA in response to K+ were reversed by the Ca2+ channel antagonist, nifedipine. We conclude that K+ can modulate the expression of key steroidogenic enzymes in H295R cells through the Ca2+ signaling pathway without involvement of the protein kinase A or protein kinase C pathways.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ca(2+)-regulated expression of steroid hydroxylases in H295R human adrenocortical cells. 758 23

The chimeric gene E2A-PBX1 is formed by the t(1;19) chromosomal translocation exclusively associated with pediatric pre-B cell acute lymphoblastic leukemia (pre-B ALL). The resultant fusion protein from this chimeric gene contains the DNA-binding homeodomain of Pbx1. The first and only functional Pbx1 binding site has been localized in bovine CYP17 to a sequence (CRS1) that participates in cAMP-dependent transcription of this gene encoding the steroid hydroxylase, 17 alpha-hydroxylase cytochrome P450. Because Pbx1 is not expressed in pre-B cells, it may be possible that the E2a-Pbx1 fusion protein expressed in pre-B cells having this translocation will activate, in response to cAMP, transcription of genes not normally expressed in these cells leading to arrest of differentiation at the pre-B cell stage. We have now shown that reporter genes comprising CRS1 are activated transcriptionally by protein kinase A (PKA) in the pre-B cell line 697, which endogenously expresses the fusion protein, and that overexpression of E2A-Pbx1 in additional cell lines enhances transcription of reporter genes in a PKA-dependent fashion. Thus, it seems plausible that arrest in the pre-B stage leading to pre-B ALL includes cAMP-dependent activation of E2A-Pbx1.
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PMID:Protein kinase A-dependent transactivation by the E2A-Pbx1 fusion protein. 759 95

Two sequence elements located at -111 to -100 base pairs and -70 to -50 base pairs in the 5'-flanking region of the bovine CYP11A gene and in closely related positions in CYP11A of other species contain G-rich regions that are similar to the consensus Sp1-binding site. These sequences bind the purified transcription factor Sp1 as well as nuclear proteins from mouse Y1 adrenal cells that interact with an antibody specific for Sp1. Both of these CYP11A sequences support basal and cAMP-dependent transcription of reporter gene plasmids transfected into Y1 cells, and mutations within the G-rich -111/-100-base pair sequence that reduce or eliminate the binding of Sp1-related Y1 nuclear proteins also markedly reduce cAMP-induced transcription. cAMP-dependent transcription supported by both CYP11A sequence elements is mediated by protein kinase A at levels comparable to that promoted by different cAMP-response sequences and transcription factors in other genes involved in steroidogenesis. These results indicate that ACTH-dependent regulation of cholesterol side chain cleavage cytochrome P450 levels in the adrenal cortex which is mediated through cAMP involves the ubiquitous transcription factor Sp1.
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PMID:Two Sp1-binding sites mediate cAMP-induced transcription of the bovine CYP11A gene through the protein kinase A signaling pathway. 759 7

The effects of elevated intracellular cyclic adenosine monophosphate (cAMP) in regulating phenobarbital (PB)-inducible gene expression in primary rat hepatocyte cultures were investigated. Cells were exposed to various concentrations (0.1-100 microM) of cAMP analogs and/or activators of intracellular cAMP-dependent pathways. Effects of these treatments were assessed either using a 1-h pulse prior to PB (100 microM) exposure or in conjunction with PB during a 24-h exposure period. PB-inducible responses were measured in hepatocytes by hybridization to cytochrome P450 (CYP) CYP2B1, CYP2B2, and CYP3A1 mRNAs. The cAMP analogs, 8-bromo-cAMP, 8-(4-chlorophenylthio)-cAMP, dibutyryl cAMP, and (Sp)-5,6-DCl-cBiMPS ((Sp)-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3', 5'-monophosphorothioate), and the activators of adenylate cyclase, forskolin and glucagon, dramatically inhibited PB-mediated induction of CYP2B1 and CYP2B2 in a concentration-dependent manner. A similar inhibition of PB-induced CYP3A1 mRNA levels was effected by the cAMP analogs and glucagon. The phosphodiesterase inhibitors isobutylmethylxanthine and RO 201724 potentiated the cAMP responses. Increasing the concentration of PB (0.05-1.00 mM) did not alleviate the cAMP-mediated repression. A requirement for protein kinase A (PKA) was demonstrated by the use of (Sp)-cAMPS, a highly specific activator of PKA, whereas the inactive diastereoisomer, (Rp)-cAMPS, was ineffective in modulating PB induction. The response to cAMP was specific since elevated intracellular cAMP levels did not perturb beta-naphtholflavone-mediated induction of CYP1A1, CYP1A2, microsomal epoxide hydrolase, or dexamethasone-mediated induction of CYP3A1 gene expression. Nor did elevated intracellular cAMP modulate the liver-selective albumin gene expression levels. The results of the present study demonstrated striking inhibition of PB-mediated CYP gene induction by cAMP and PKA activators, indicating a negative regulatory role for the cAMP signal transduction pathway on PB gene induction.
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PMID:cAMP-associated inhibition of phenobarbital-inducible cytochrome P450 gene expression in primary rat hepatocyte cultures. 775 30

Dehydroepiandrosterone sulfate is the major steroid secretory product of the human fetal adrenal gland. Several factors have been shown to modulate the secretion of this steroid by cultured fetal adrenal cells. In addition to the cytochrome P450 enzymes that are important in steroid biosynthesis, dehydroepiandrosterone sulfotransferase (DST) is likely to be a key regulated enzyme in the formation of sulfated steroids, which are characteristic of the human adrenal cortex, particularly that of the fetus and the adult zona reticularis. In the present investigation, we sought to evaluate the cellular localization of DST in cultures derived from the fetal zone, neocortex, and adrenal capsule and to determine the effects of ACTH and other agonists of the protein kinase-A pathway on the abundance of DST in such cells. Cells derived from the fetal zone, neocortex, and adrenal capsule were either precultured for 3-13 days in plastic flasks followed by culture on coverslips or were cultured directly on coverslips in control medium (McCoy's 5A medium that contained 5% fetal bovine serum) or control medium plus ACTH, forskolin, or dibutyryl cAMP for 1-4 days. Cells were fixed in buffered formalin and then immunostained for DST by use of a rabbit polyclonal antiserum prepared against human liver DST. DST immunoreactivity was abundant in freshly isolated cortical cells derived from fetal zone and neocortex. DST immunoreactivity was still observable in fetal zone and neocortex cells as well as in cells prepared from enzymatic digests of adrenal capsule after scraping off adherent neocortex cells following culture for 9-14 days in control medium. Adrenal fibroblasts were negative for DST. DST abundance in cortical cells was increased in cultures supplemented with ACTH, forskolin, or dibutyryl cAMP compared to that in cultures grown in control medium alone. The results of Western blot analyses of DST in these cells were consistent with the immunocytochemical data. These results suggest that DST is present in both fetal zone and neocortex cells of the human fetal adrenal at midgestation and that the production of DST is stimulated by ACTH and agonists of the protein kinase-A signal transduction pathway in the human fetal adrenal gland.
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PMID:Immunocytochemical analyses of dehydroepiandrosterone sulfotransferase in cultured human fetal adrenal cells. 788 17

ACTH-dependent transcriptional activation of the bovine CYP17 gene (the gene encoding cytochrome P450 steroid 17 alpha-hydroxylase) involves two cAMP-responsive sequences (CRS1 and CRS2) located in the promoter region. Here we demonstrate that two nuclear orphan receptors, chicken ovalbumin upstream promoter transcription factor (COUP-TF) and steroidogenic factor-1 (SF-1), bind to the part of the CRS2 element that contains the repeated sequences AAGTCA and AGGTCA spaced by six nucleotides (repCRS2). Overexpression of COUP-TF and SF-1 in both steroidogenic and nonsteroidogenic cells demonstrated that SF-1 is an activator of repCRS2-dependent transcription of reporter genes. Furthermore, the SF-1-dependent transcription could be further stimulated by activation of the cAMP-dependent protein kinase. In contrast, COUP-TF alone had no effect on repCRS2-dependent reporter gene activity. Mutations that interfere with the binding of SF-1 to repCRS2 in vitro abolished the cAMP-induced activities mediated by the element in transfected Y1 cells. The mutational analysis of repCRS2 further indicated that the binding sites for the two receptors overlap, and electrophoretic mobility shift assays demonstrated that the receptors bound in a mutually exclusive manner. Overexpression of both SF-1 and COUP-TFI simultaneously demonstrated that COUP-TFI inhibited SF-1-dependent activation of reporter genes. Transient transfection experiments with a construct containing a -100/+19 base pair fragment from the bovine CYP17 gene demonstrated that SF-1 and COUP-TF had similar effects on the intact promoter as on the repCRS2/reporter gene constructs. Our data suggest that the two orphan receptors bind in a mutually exclusive manner to repCRS2 and that SF-1 is involved in the activation and COUP-TF in the repression of repCRS2-dependent transcription.
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PMID:Mutually exclusive interactions of two nuclear orphan receptors determine activity of a cyclic adenosine 3',5'-monophosphate-responsive sequence in the bovine CYP17 gene. 777 79


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