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)

Cyclic AMP has been implicated to a greater or lesser extent in the regulation of four key enzymes which interact to regulate intracellular cholesterol metabolism; HMG CoA reductase; ACAT; cholesteryl ester hydrolase; and cholesterol 7 alpha hydroxylase. The relationship between these enzymes and the sites where current evidence suggests that cyclic AMP may be involved are summarized in Fig. 3. Cholesterol 7 alpha hydroxylase controls the catabolism of cholesterol to bile acids in the liver, and thus its removal from the body via the bile, but does not have a major role in cholesterol metabolism in extrahepatic tissues. It is clear that cyclic AMP is able to influence the activity of this enzyme in liver sub-cellular fractions and isolated hepatocytes in vitro, and studies in our laboratory have shown that changes in Ca2+ fluxes within the cell may be important in its mechanism of action. Whether or not the cyclic nucleotide has a role regulating cholesterol 7 alpha hydroxylase activity in vivo, however, is not known. HMG CoA reductase is inactivated by phosphorylation both in vitro and in vivo, but although cyclic AMP and glucagon have been shown to inhibit the enzyme, cyclic AMP-dependent protein kinase is not directly involved. The exact mechanism by which the cyclic nucleotide influences the system remains unclear, but it may be related to activation of microsomal phosphatases. The activity of ACAT has been shown to be modulated by phosphorylation in a number of tissues in vitro, but the involvement of cyclic AMP has not been unequivocally demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic AMP and the regulation of cholesterol metabolism. 132 21

1. Octimibate, 8-[(1,4,5-triphenyl-1H-imidazol-2-yl)oxy]octanoic acid, is reported to have antithrombotic properties. This is in addition to its antihyperlipidaemic effects which are due to inhibition of acylCoA:cholesterol acyltransferase (ACAT). The aim of this study was to investigate the mechanism of the antithrombotic effect of octimibate, and to determine whether the effects of octimibate are mediated through prostacyclin receptors. 2. In suspensions of washed (plasma-free) human platelets, octimibate is a potent inhibitor of aggregation; its IC50 is approx. 10 nM for inhibition of aggregation stimulated by several different agonists, including U46619 and ADP. The inhibitory effects of octimibate on aggregation are not competitive with the stimulatory agonist; the maximal response is suppressed but there is no obvious shift in potency of the agonist. In platelet-rich plasma, octimibate inhibits agonist-stimulated aggregation with an IC50 of approx. 200 nM. 3. Octimibate also inhibits agonist-stimulated rises in the cytosolic free calcium concentration, [Ca2+]i, in platelets. Both Ca2+ influx and release from intracellular stores are inhibited. The effects of octimibate on aggregation and [Ca2+]i are typical of agents that act via elevation of adenosine 3':5'-cyclic monophosphate (cyclic AMP). Similar effects are seen with forskolin, prostacyclin (PGl2) and iloprost (a stable PGl2 mimetic). 4. Octimibate increases cyclic AMP concentrations in platelets and increases the cyclic AMP-dependent protein kinase activity ratio. Octimibate stimulates adenylyl cyclase activity in human platelet membranes, with an EC50 of 200 nM. The maximal achievable activation of adenylyl cyclase by octimibate is 60% of that obtainable with iloprost. Octimibate has no effect on the cyclic GMP-inhibited phosphodiesterase (phosphodiesterase-ITI), which is the major cyclic AMP-degrading enzyme in human platelets.5. Octimibate inhibits, apparently competitively, the binding of [3H]-iloprost (a stable PGl2 mimetic) to platelet membranes; the estimated Ki is 150 nm. 6. The platelets of different species show considerable differences in the apparent potency of their inhibition of aggregation by octimibate; platelets from cynomolgus monkeys are 3 fold more sensitive than those from humans, while rat, cat and cow platelets are 50, 100, and 250 fold less sensitive than human platelets. The sensitivity of these different species to iloprost, however, varies over a range of only 10 fold with no obvious difference between primates and non-primates. 7. Octimibate appears to be a potent agonist (aggregation), or partial agonist (adenylyl cyclase), at prostacyclin receptors and is the first non-prostanoid agent of this type to be identified. The species differences in relative potency of octimibate and iloprost may reflect the existence of receptor subtypes.
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PMID:Octimibate, a potent non-prostanoid inhibitor of platelet aggregation, acts via the prostacyclin receptor. 171 May 26

The regulation by cAMP of cholesteryl ester hydrolysis and net depletion of cellular cholesteryl ester (cholesteryl ester clearance) in J774 murine macrophages was explored. Using Sandoz 58035 to selectively inhibit acyl CoA:cholesterol acyltransferase, we showed that the absolute rate of cholesteryl ester hydrolysis was stimulated 2-fold in J774 cells by the cAMP analogues 8-(4-chlorophenylthio)adenosine 3':5'-cyclic monophosphate and dibutyryl-cAMP. The rate of hydrolysis was also stimulated by prostaglandin E1, by cholera toxin, and by a mixture of forskolin and isobutylmethylxanthine, but was not affected by epinephrine or dibutyryl-cGMP. These data demonstrate that cholesteryl ester hydrolysis in J774 cells can be stimulated by cAMP-dependent protein kinase. Cholesteryl ester clearance from J774 cells was achieved upon incubation with high density lipoproteins (HDL) plus CPT-cAMP but not with HDL alone. HDL-mediated cholesteryl ester clearance was dependent on the concentration of both HDL and CPT-cAMP. The data suggest that the defect responsible for the lack of HDL-mediated cholesteryl ester clearance in J774 cells involves a failure to modulate cAMP levels.
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PMID:cAMP stimulates cholesteryl ester clearance to high density lipoproteins in J7774 macrophages. 184 91

The effects of the slow Ca++ channel blocker, nifedipine, and ACAT inhibitor, octimibate, on the cholesterol metabolism of cholesterol-loaded macrophages were compared. We demonstrated that apolipoprotein A-I containing high density lipoproteins (HDL) bind to specific receptor sites on macrophages, are internalized, take up cholesterol, and are then released from the cells as native lipoproteins. The ACAT inhibitor enhances HDL receptor activity and promotes HDL-mediated cholesterol efflux from cultured mouse peritoneal macrophages. In contrast, the Ca++ antagonist increases acetyl LDL-mediated cholesterol influx, abolishes the increase in HDL binding induced by cholesterol accumulation, enhances apo E synthesis, and promotes cholesterol efflux by a mechanism independent of the presence of HDL in the surrounding medium. Concomitantly, a decrease in nucleoside transporter activity, an increase in intracellular ATP hydrolysis, adenosine and cyclic AMP concentration, and a stimulation of the activities of acid and neutral cholesteryl ester hydrolase and ACAT indicated that protein kinase A-catalyzed phosphorylation reactions might be involved in the increase in cholesterol efflux. The Ca++ antagonist-induced efflux occurred only with lysosomal-associated cholesterol, while the ACAT inhibitor acted on the formation of cytoplasmic lipid droplets. The secreted lipoprotein particles contained 68% unesterified cholesterol and 21% phospholipids, 8% esterified cholesterol, and 3% triglycerides. The phospholipid components were: 72% phosphatidylcholine, 22% sphingomyelin, and 6% phosphatidylserine, phosphatidylinositol, and phosphatidylethanolamine. We conclude that macrophages release cholesterol in two ways: 1) an HDL-mediated release of unesterified cholesterol increasing upon ACAT inhibition, and 2) an HDL-independent secretion of cholesterol which can be amplified by Ca++ antagonists.
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PMID:Ca++ antagonists and ACAT inhibitors promote cholesterol efflux from macrophages by different mechanisms. I. Characterization of cellular lipid metabolism. 282 3

Acyl-coenzyme A:cholesterol O-acyltransferase (ACATase; EC 2.3.1.26) is a membrane-bound microsomal enzyme that catalyzes the formation of long-chain fatty-acyl cholesterol esters in rat liver and other tissues. This enzyme is important in regulating the concentration of unesterified cholesterol in the cell. Having recently demonstrated that rat liver 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase; EC 1.1.1.34), the major regulatory enzyme in cholesterol biosynthesis, undergoes in vivo phosphorylation and inactivation after a single cholesterol meal, we decided to test the hypothesis that the enzyme ACATase, important in cholesterol utilization and storage, is also subject to regulation by phosphorylation/dephosphorylation. The results show that rat liver ACATase can be reversibly inactivated/activated, in vitro, by incubation conditions that favor dephosphorylation/phosphorylation. Activation was also achieved by using a partially purified protein kinase extracted from microsomes. It is significant that HMG-CoA reductase is inactivated by phosphorylation whereas ACATase is activated by phosphorylation. ACATase is, therefore, regulated by phosphorylation in a manner exactly opposite to that of HMG-CoA reductase. We propose that the coordinate regulation of ACATase and HMG-CoA reductase by phosphorylation/dephosphorylation provides a mechanism for short-term intracellular cholesterol homeostasis.
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PMID:Evidence for phosphorylation/dephosphorylation of rat liver acyl-CoA:cholesterol acyltransferase. 630 Aug 97

Basic fibroblast growth factor (bFGF) has been implicated in the regulation of cell proliferation and cholesterol metabolism. In studies reported herein, we show bFGF increases low density lipoprotein (LDL) binding, uptake, and degradation in arterial smooth muscle cells in a dose-dependent manner. This increase was paralleled by an increase in LDL receptor mRNA steady state levels. To determine if bFGF activated transcription of the LDL receptor gene, we transiently transfected smooth muscle cells with a gene construct consisting of the 5'-upstream promoter region of the DNA from the human LDL receptor gene ligated to a plasmid containing the luciferase gene. We found that bFGF and a protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate, significantly induced luciferase activity driven by the LDL receptor promoter, whereas 25-hydroxycholesterol reduced the luciferase activity in bFGF-stimulated cells. These findings show that bFGF and PKC are inducing LDL receptor gene transcription. We also evaluated potential signal transduction pathways induced by bFGF to establish the mechanism(s) leading to the activation of the LDL receptor gene. Activation of the activity of FGF receptor tyrosine kinase in smooth muscle cells by ligand binding resulted in tyrosine phosphorylation of one of the FGF receptors and a 90-kDa-protein as well as increased tyrosine phosphorylation of phospholipase C-gamma. Parallel observations were made in that increased PKC and protein kinase A activities occurred with bFGF as compared with control cells. Inhibitors of receptor tyrosine kinase and other protein kinases significantly reduced transcription and surface expression of LDL receptor. Finally, several key enzymes that are central to the regulation of LDL-cholesteryl ester metabolism were also studied in bFGF-stimulated cells. An increase in acyl-CoA:cholesterol acyltransferase activity and cholesterol esterification was observed with bFGF stimulation, but there was no effect on the lysosomal or cytoplasmic cholesteryl ester hydrolase activities. Our findings suggest potential signal transduction pathways activated by bFGF which play a role in regulating transcription and surface expression of the LDL receptor.
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PMID:Basic fibroblast growth factor-induced low density lipoprotein receptor transcription and surface expression. Signal transduction pathways mediated by the bFGF receptor tyrosine kinase. 751 Jul 5

The effects of exogenous oxidative stress due to passive smoking on cholesteryl ester (CE)-metabolizing enzymes and their regulatory kinases were examined by exposing rats to cigarette smoke (CS) for a 1-h period twice a day for 8, 12, or 20 wk. An oxidatively modified low density lipoprotein (Ox-LDL) with a high lipid peroxide was identified in three CS groups after all three exposure periods. The rat aortic acid and neutral CE hydrolases (ACEH and NCEH) were activated to similar extents by both cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) in the presence of their respective cofactors. The aortic PKC activity in the three CS groups exhibited significant reductions of 72, 84, and 75% as compared with the respective controls, which coincided with the reductions in the ACEH activities (86, 71, and 80%, respectively), whereas the PKA activities increased to 121, 197, and 252% in the three CS groups, respectively. Reflecting the increase of the PKA activity, the NCEH activity exhibited increases of 112% at 8 wk and 140% until 12 wk of exposure and decreased by 50% of the control value at 20 wk of exposure, suggesting inactivation of NCEH itself. The activation of acyl-CoA:cholesterol O-acyltransferase activity was associated with an increase of free cholesterol in aorta. The vitamin E diet prevented the formation of Ox-LDL and the oxidative inactivation of most enzymes, especially PKC, until 12 wk, but was less effective by 20 wk. The oxidative inactivation of PKC, particularly its activated form that translocated to the membrane fraction, was confirmed in the in vitro exposure to active oxygen generators at an optimal concentration; this inactivation was prevented by catalase and superoxide dismutase. These results suggested that the formation of Ox-LDL and alterations in CE-metabolizing enzymes caused by passive smoking could contribute to a twofold increase in the aortic CE content, thereby contributing to one of the mechanisms for atherosclerosis associated with smoking.
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PMID:Effects of passive smoking on the regulation of rat aortic cholesteryl ester hydrolases by signal transduction. 1090 85

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

Angiotensin II (Ang II) is known to accelerate the progression of macrophage-driven atherosclerotic lesions. Acyl-CoA:cholesterol acyltransferase-1 (ACAT1) converts intracellular free cholesterol into cholesterol ester (CE) for storage in lipid droplets, and promotes foam cell formation in atherosclerotic lesions. The present study explored the effect of Ang II on ACAT1 expression as a molecular mechanism of foam cell formation in primary cultured human monocyte-macrophages. Ang II significantly increased ACAT1 protein expression in a time- or concentration-dependent manner. Application of an Ang II type 1 (AT(1)) receptor agonist (L162313), but not an Ang II type 2 (AT(2)) receptor agonist (CGP42112A), mimicked the effects of Ang II treatment in inducing ACAT1 protein expression. ACAT activity and ACAT1 mRNA levels were also significantly increased by Ang II. Two-fold increases in ACAT1 protein expression and ACAT activity with Ang II treatment were completely inhibited by AT(1) receptor antagonists (candesartan, [Sar(1),Ile(8)]-Ang II), but not by an AT(2) receptor antagonist (PD123319). Treatment with a G-protein inactivator (GDP-beta-S), a c-Src tyrosine kinase inhibitor (PP2), a protein kinase C (PKC) inhibitor (rottlerin), or a mitogen activated protein kinase (MAPK) kinase inhibitor (PD98059) significantly reduced Ang II-induced ACAT1 protein expression. Macrophage foam cell formation assessed using acetylated low-density lipoprotein (LDL)-induced CE accumulation was significantly enhanced by Ang II, which was completely inhibited by treatment with candesartan. These results suggested that Ang II enhances foam cell formation by upregulating ACAT1 expression predominantly through the actions of AT(1) receptor via the G protein/c-Src/PKC/MAPK pathway in human monocyte-macrophages.
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PMID:Angiotensin II upregulates acyl-CoA:cholesterol acyltransferase-1 via the angiotensin II Type 1 receptor in human monocyte-macrophages. 1897 44

Several studies indicate that cholesterol esterification is deregulated in cancers. The present study aimed to characterize the role of cholesterol esterification in proliferation and invasion of two tumor cells expressing an activated cholecystokinin 2 receptor (CCK2R). A significant increase in cholesterol esterification and activity of Acyl-CoA:cholesterol acyltransferase (ACAT) was measured in tumor cells expressing a constitutively activated oncogenic mutant of the CCK2R (CCK2R-E151A cells) compared with nontumor cells expressing the wild-type CCK2R (CCK2R-WT cells). Inhibition of cholesteryl ester formation and ACAT activity by Sah58-035, an inhibitor of ACAT, decreased by 34% and 73% CCK2R-E151A cell growth and invasion. Sustained activation of CCK2R-WT cells by gastrin increased cholesteryl ester production while addition of cholesteryl oleate to the culture medium of CCK2R-WT cells increased cell proliferation and invasion to a level close to that of CCK2R-E151A cells. In U87 glioma cells, a model of autocrine growth stimulation of the CCK2R, inhibition of cholesterol esterification and ACAT activity by Sah58-035 and two selective antagonists of the CCK2R significantly reduced cell proliferation and invasion. In both models, cholesteryl ester formation was found dependent on protein kinase zeta/ extracellular signal-related kinase 1/2 (PKCzeta/ERK1/2) activation. These results show that signaling through ACAT/cholesterol esterification is a novel pathway for the CCK2R that contributes to tumor cell proliferation and invasion.
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PMID:Signaling through cholesterol esterification: a new pathway for the cholecystokinin 2 receptor involved in cell growth and invasion. 1950 90


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