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)

Differentiation of 3T3-L1 fibroblasts to adipocyte-like cells was accompanied by a 19-fold increase in neutral triglyceride lipase activity, a 12-fold increase in diglyceride lipase activity, a 10-fold increase in monoglyceride lipase activity, and a 280-fold increase in cholesterol esterase activity. In contrast, acid acylhydrolase activities did not increase during differentiation. The rate of glycerol release from unstimulated intact cells increased by more than 1 order of magnitude upon differentiation. Isoproterenol (1 microM) and 1-methyl-3-isobutylxanthine (0.1 mM) further stimulated this rate of glycerol release 3-fold. The neutral triglyceride lipase activity in cell-free preparations of differentiated cells was activated 105% by cyclic AMP-dependent protein kinase. Neutral cholesterol esterase, diglyceride lipase, and monoglyceride lipase were also activated (117%, 10%, and 37+, respectively) by cyclic AMP-dependent protein kinase. In contrast, protein kinase had no effect on any of the four lysosomal acid acylhydrolase activities. Thus, hormone-sensitive lipase, the most characteristic and functionally important enzyme of adipose tissue, has been characterized in differentiated 3T3-L1 cells. The 3T3-L1 cell should be a valuable model system in which to study regulation of hormone-sensitive lipase, particularly its long-term regulation.
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PMID:Hormone-sensitive lipase in differentiated 3T3-L1 cells and its activation by cyclic AMP-dependent protein kinase. 626 67

Adrenocortical mitochondrial cholesterol side chain cleavage reactions are regulated by the influence of pituitary ACTH. The mechanism of the stimulation involves adenyl cyclase, cAMP-dependent protein kinase, cholesterol esterase, and ribosomal labile protein synthesis. Through these reactions the stimulus reaches the mitochondrial side chain cleavage enzyme system. In this review article, the current implications on the stimulus transfer from the plasma membrane to the mitochondrial inner membrane are summarized. In particular the availability of cholesterol to P-450scc was discussed in terms of the distribution of cholesterol molecules in the membranes.
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PMID:ACTH stimulation on cholesterol side chain cleavage activity of adrenocortical mitochondria. Transfer of the stimulus from plasma membrane to mitochondria. 626 82

Cholesterol esterase with optimal activity at pH 6.8 was found in the 40,000 X g supernatant fraction prepared from rabbit alveolar macrophages, thioglycolate-elicited mouse peritoneal macrophages, and the J774 macrophage cell line. The neutral cholesterol esterase activity in these three types of macrophages was of the same order of magnitude as that in the 40,000 X g supernatant fraction of adrenal, heart, and liver but considerably lower than that in adipose tissue. The enzyme prepared from J774 cells was activated about 60% by preincubation with cAMP and Mg-ATP; half-maximal activation was obtained at 2.5 X 10(-7) M cAmP. The activation was completely blocked by a specific protein inhibitor of cAMP-dependent protein kinase. These findings suggest that cytoplasmic cholesterol esters stored in macrophages can be mobilized for release by action of the neutral enzyme described and, further, that this process may be regulated by factors that affect intracellular cAMP levels.
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PMID:Neutral cholesterol esterase activity in macrophages and its enhancement by cAMP-dependent protein kinase. 627 1

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

We describe here an activable neutral cholesteryl esterase (EC 3.1.1.13) in arteries similar to the hormone-sensitive lipase of adipose tissue and adrenal cortex. Maximum enzyme activity in rabbit aorta was given by cholesteryl ester substrates dispersed as a mixed micelle with phosphatidylcholine and Na taurocholate (molar ratio 1:4:2). A quantitative assay of enzymic activity was obtained with the following component concentrations: 6.0 microM cholesteryl [1-14C]oleate, 23.7 microM phosphatidylcholine, 12.5 microM Na taurocholate, 0.04% serum albumin, and 85 mM K phosphate buffer, pH 7.0. The enzymic activity in aortic homogenates was stimulated 2-fold by addition of 5 microM glucagon or 100 microM dibutyryl cAMP. This activation was Mg-ATP dependent. Addition of 50 micrograms/ml of exogenous protein kinase could reverse the action of protein kinase inhibitor on dibutyryl cAMP activation of the neutral cholesteryl esterase. In addition to activation by cAMP-dependent protein kinase, the enzyme could be distinguished from the more active arterial lysosomal cholesteryl esterase by its pH 7.0 optimum, relative stability to preincubation at elevated temperatures, and exclusive localization in the cell cytosol. Subcellular fractionation of lipid-laden arterial foam cells revealed a significant portion of the neutral cholesteryl esterase bound to cytoplasmic cholesteryl ester-rich lipid droplets. Our results suggest that the breakdown of cytoplasmic cholesteryl ester droplets in arterial cells may be under hormonal regulation.
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PMID:Arterial neutral cholesteryl esterase. A hormone-sensitive enzyme distinct from lysosomal cholesteryl esterase. 684 93

The cytosolic cholesterol ester hydrolase from bovine corpus luteum has been purified 760-fold, using isoelectric precipitation and gel filtration chromatography, followed by ion-exchange and adsorption chromatographies in the presence of non-ionic detergent. Further purification was achieved by affinity chromatography on triacylglycerol-containing polyacrylamide-agarose. The partially purified enzyme was inhibited by NaF, HgCl2 and DFP. Incubation with [3H]DFP resulted in specific labelling of a polypeptide of Mr = 84000, the same subunit molecular weight as that of the enzyme from adrenal cortex. This Mr 84000 polypeptide from corpus luteum was phosphorylated by the catalytic subunit of cyclic AMP-dependent protein kinase, phosphorylation causing greater than 2-fold activation of the enzyme. Several properties of the cholesterol ester hydrolase from corpus luteum show striking similarities to those of hormone-sensitive lipase from adipose tissue. This provides further evidence that hormone-sensitive lipase, in addition to its role in adipose tissue lipolysis, has a key role in steroidogenic tissues, namely catalysing the supply of free cholesterol from the cholesterol ester stores.
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PMID:Cytosolic cholesterol ester hydrolase from bovine corpus luteum. Its purification, identification, and relationship to hormone-sensitive lipase. 684 67

Several properties of the cytosolic cholesterol ester hydrolase from bovine adrenal cortex were investigated and those properties were compared directly with those of the well-characterised hormone-sensitive lipase, the rate-limiting enzyme in adipose tissue lipolysis. Properties examined included: (a) activity against different substrates; (b) susceptibility to inhibition by NaF, Hg2+ ions and diisopropyl fluorophosphonate; (c) subunit molecular weight as determined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate; (d) ability to serve as a substrate for cyclic AMP-dependent protein kinase; (e) effect of phosphorylation on enzyme activity; and (f) degradation pattern of polypeptides following limited proteolysis. In all respects the two enzymes exhibited essentially identical characteristics. It is therefore concluded that the same protein, or two very similar proteins, catalyses the hydrolysis of cholesterol esters in adrenal cortex and lipolysis in adipose tissue. The implication of this finding is discussed in relation to the hormonal control of steroidogenesis in adrenal cortex and of lipolysis in adipose tissue.
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PMID:Direct evidence that cholesterol ester hydrolase from adrenal cortex is the same enzyme as hormone-sensitive lipase from adipose tissue. 710 23

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

Okadaic acid, a potent and specific inhibitor of protein phosphatases 1 (IC50 10-20 nM) and 2A (IC50 0.05-2 nM) caused early and sustained inhibitions of microsomal cholesterol ester hydrolase activity in hepatocyte suspensions. The changes in the kinetic properties of the esterase and its response to exogenous alkaline phosphatase and cyclic AMP-dependent protein kinase after cell exposure to 1 microM or 1 nM okadaic acid differed markedly among themselves, which suggests the involvement of both protein phosphatases 1 and 2A in the regulation of the microsomal hydrolysis of cholesterol esters. Furthermore, the inhibitory effect of okadaic acid is likely to be independent of the dibutyryl-cyclic AMP promoted cell events leading to stimulation of esterase activity.
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PMID:Inhibition of microsomal cholesterol ester hydrolase by okadaic acid in isolated rat hepatocytes. 754 88

Steroidogenic cells store cholesteryl esters, precursors for steroid hormone synthesis, in intracellular lipid droplets. Cholesteryl ester hydrolysis is activated by protein kinase A and catalyzed by cholesteryl esterase. The esterase is similar, if not identical, to hormone-sensitive lipase in adipocytes where an analogous lipolytic mechanism occurs. Perilipins, proteins located exclusively at lipid droplet surfaces in adipocytes, are polyphosphorylated by protein kinase A in response to lipolytic stimuli, suggesting a role for these proteins in mediating lipid metabolism. The present study reveals that perilipins are associated with cholesteryl ester droplets in two steroidogenic cell lines: Y-1 adrenal cortical cells and MA-10 Leydig cells. The relative abundance of perilipin mRNAs and protein is much less in steroidogenic cells than in adipocytes. Like adipocytes, steroidogenic cells express perilipin A; additionally, the latter cells contain relatively abundant amounts of perilipin C, a protein that is not detectable in adipocytes by Western analysis. The data suggest a strong link between perilipins and lipid hydrolysis that is mediated by the hormone-sensitive lipase/cholesteryl esterase class of enzymes.
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PMID:Perilipins are associated with cholesteryl ester droplets in steroidogenic adrenal cortical and Leydig cells. 762 16


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