Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.1.1.32 (phosphoenolpyruvate carboxykinase)
4,204 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the presence of the messenger RNA (mRNA) for the cytosolic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), in rat lung by Northern blot hybridization to a complementary DNA (cDNA) probe. Lung from normal rats contained substantial amounts of this mRNA, although its relative concentration was approximately six times lower than in liver. Fasting produced an eightfold increase in the content of the enzyme mRNA in lung, which could be reverted to normal values by glucose refeeding. Induced diabetes also resulted in a sevenfold increase of the levels of PEPCK mRNA in lung. Dexamethasone, thyroid hormone, dibutyryl cyclic adenosine monophosphate (cAMP), histamine, and serotonin also induced important accumulations of the enzyme mRNA without affecting the concentration of beta-tubulin mRNA measured as reference. Thus, the PEPCK gene appears to be regulated in a similar manner in lung and liver. The results suggest that PEPCK may be involved in lung metabolism in starvation, diabetes, and other specific hormonal situations.
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PMID:Detection and hormonal regulation of the mRNA for cytosolic phosphoenolpyruvate carboxykinase in rat lung. 162

Insulin stimulates transcription and cytoplasmic accumulation of a specific mRNA (termed p33), while inhibiting transcription and accumulation of phosphoenolpyruvate carboxykinase (PEPCK) mRNA in rat H4IIE (H4) hepatoma cells. The present work examines the role of protein synthesis in regulation of these genes by insulin and dexamethasone. Like insulin, cycloheximide and anisomycin, two protein synthesis inhibitors, induced p33 transcription and reduced PEPCK transcription. The combination of either protein synthesis inhibitor and insulin did not induce p33 transcription or inhibit PEPCK transcription beyond that observed with either protein synthesis inhibitor alone. Dexamethasone induced both p33 and PEPCK transcription. The combination of insulin and dexamethasone, or protein synthesis inhibitors and dexamethasone, abolished dexamethasone-induced PEPCK transcription. Thus, protein synthesis inhibitors regulate transcription of the p33 and the PEPCK genes in an insulin-like manner.
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PMID:Protein synthesis and insulin regulation of p33 and PEPCK gene expression. 163 18

A gluconeogenic strain of renal epithelial cells (LLC-PK1-F+) was used to characterize the effect of pH and bicarbonate concentration on the levels of phosphoenolpyruvate carboxykinase (PCK) and glutaminase (GA) mRNAs. The levels of both mRNAs are markedly dependent upon medium glucose concentration. The level of PCK mRNA is increased with increasing glucose concentration from 0 to 40 mM, whereas the level of GA mRNA is maximal between 3 and 5 mM glucose. When LLC-PK1-F+ cells are grown with 5 mM glucose and then subjected to an acute decrease in pH (from 7.4 to 6.9) and bicarbonate concentration (from 25 to 10 mM), the level of PCK mRNA exhibits a biphasic response. The PCK mRNA is initially increased 4-fold within 3 h, then decreases slightly and subsequently increases between 10 and 20 h to a level that is 17-fold greater than normal. Only the initial increase parallels the changes observed in vivo. In contrast, after onset of acidosis, the level of GA mRNA initially remains unchanged, is then increased 8-fold between 10 and 16 h, and then decreases slightly. This response closely mimics the results obtained in vivo. A decrease in media pH at constant bicarbonate causes a marked increase in both mRNAs. However, the levels of the two mRNAs are also elevated by decreasing bicarbonate at a constant pH. Thus, both parameters independently affect the level of the two mRNAs. The use of actinomycin D to measure the half-lives of PCK and GA mRNAs at pH 7.4 and 6.9 indicates that stabilization may fully account for the induction of GA mRNA and contributes to the inductive effects of decreased pH and/or bicarbonate on PCK mRNA. Following recovery from acidic conditions, the two mRNAs exhibit a rapid and coordinate decrease (t1/2 approximately 20 min). Dexamethasone had no effect on the level of either mRNA, whereas cAMP increased only PCK mRNA. The latter effect was additive with the increase caused by decreased pH and/or bicarbonate and was reversed by incubating in alkalotic media. Thus, the induction of PCK and GA mRNAs during acidosis is initiated in direct response to a decrease in extracellular pH and/or bicarbonate.
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PMID:Effect of pH and bicarbonate on phosphoenolpyruvate carboxykinase and glutaminase mRNA levels in cultured renal epithelial cells. 185 45

Dexamethasone rapidly stimulated transcription of the tyrosine aminotransferase and metallothionein-I genes--but not of the phosphoenolpyruvate carboxykinase gene--in rat hepatocytes cultured in serum-free medium. This differential response was not observed for cyclic AMP. The results suggest that the phosphoenolpyruvate carboxykinase gene--but not the tyrosine aminotransferase and metallothionein-I genes--requires a factor which is permissive for stimulation of transcription by the glucocorticoid receptor.
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PMID:Differential induction of transcription for glucocorticoid-responsive genes in cultured rat hepatocytes. 196 35

Dexamethasone is necessary and sufficient to induce mRNA for phosphoenolpyruvate carboxykinase (GTP) (PEPCK) by 19-fold in rat hepatocytes cultured in serum-free medium. However, the time required for maximum induction is 16 h. The slow induction suggested that glucocorticoids regulate the expression of an intermediate gene product(s) which is required for glucocorticoid stimulation of PEPCK-gene expression. Consistent with this notion was the finding that cycloheximide completely blocked the response to dexamethasone. In contrast, cycloheximide did not block the response to a cyclic AMP analogue.
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PMID:Induction of mRNA for phosphoenolpyruvate carboxykinase (GTP) by dexamethasone in cultured rat hepatocytes requires on-going protein synthesis. 282 94

The effect of hormones on the transcription rate of cytosolic phosphoenolpyruvate carboxykinase and level of mRNA for this enzyme in the rat kidney has been investigated. In renal nuclei isolated from rats given dibutyryladenosine cyclic 3',5'-phosphate (Bt2cAMP) or 8-bromoadenosine cyclic 3',5'-phosphate (8-Br-cAMP), [32P]UMP incorporation into hybridizable phosphoenolpyruvate carboxykinase mRNA increased severalfold within 1 h. Changes in the concentration of cytosolic phosphoenolpyruvate carboxykinase mRNA, measured by hybridization of [32P]cDNA to poly(A)+ mRNA, paralleled alterations in the transcription rate. Dexamethasone treatment of adrenalectomized rats increased the transcription rate and the level of phosphoenolpyruvate carboxykinase mRNA 3-4-fold after 4 h. Both parameters then declined to control values by 8 h. When dexamethasone (5 mg/kg) and Bt2cAMP (25 mg/kg) were given together, the rate of phosphoenolpyruvate carboxykinase RNA synthesis and the level of cytosolic mRNA were not increased more than those with either drug alone. Transcription of the gene for renal phosphoenolpyruvate carboxykinase was not affected by diabetes or glucose refeeding but was increased 2-fold after 24 h of starvation and reduced by bicarbonate feeding after 2 h. We conclude that glucocorticoids and cAMP change the rate of transcription of the phosphoenolpyruvate carboxykinase gene in rat kidney, leading to changes of similar magnitude in mRNA level and, hence, enzyme activity. The results presented here and in previous work [Lamers, W., Hanson, R. W., & Meisner, H. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 5137] indicate that the transcription rate of the gene for phosphoenolpyruvate carboxykinase in liver and kidney responds to hormones in a tissue-specific manner.
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PMID:Effect of hormones on transcription of the gene for cytosolic phosphoenolpyruvate carboxykinase (GTP) in rat kidney. 298 57

Renal and hepatic levels of the rate-limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) were determined in control and intrauterine growth-retarded rate neonates and dams. Dexamethasone and surgically induced intrauterine growth retardation (IUGR) resulted in an elevation of neonatal renal PEPCK activity, but did not affect hepatic PEPCK levels. In the dam, glucocorticoid administration resulted in an increase in renal PEPCK, but did not affect the hepatic enzyme. We have demonstrated that, unlike the hepatic enzyme, renal PEPCK could potentially contribute to gluconeogenesis in utero, since dexamethasone administration significantly increased renal PEPCK at birth. This study confirms the hypothesis that hepatic and renal PEPCK activities are regulated independently in both the adult and neonatal animal.
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PMID:The effect of dexamethasone and surgically induced intrauterine growth retardation on renal and hepatic levels of phosphoenolpyruvate carboxykinase in the rat. 394 91

By using very low concentrations of cells to minimize alterations in substrate concentrations, we demonstrated that the lactate/pyruvate ratio of the incubation medium, which determines the cytosolic NADH/NAD+ ratio, affects gluconeogenic flux in suspensions of isolated hepatocytes from fasted rats. At a fixed extracellular pyruvate concentration of 1 mM and with the lactate/pyruvate ratio varied from 0.6 to 10 and to 50, glucose production rates increased from 2.5 to 5.5 and then decreased to 1.8 nmol/mg of cell protein/min. This finding paralleled the observation of Sugano et al. (Sugano, T., Shiota, M., Tanaka, T., Miyamae, Y., Shimada, M., and Oshino, N. (1980) J. Biochem. (Tokyo) 87, 153-166) who noted a similar biphasic response in the perfused liver system when lactate was held constant and pyruvate varied. The biphasic relationship can be explained by the influence of the NADH/NAD+ ratio on the near-equilibrium reactions catalyzed by glyceraldehyde-3-phosphate dehydrogenase and malate dehydrogenase in the hepatocyte cytosol. By shifting the equilibrium of the glyceraldehyde-3-phosphate dehydrogenase reaction, a rise in the NADH/NAD+ ratio decreases the concentration of 3-phosphoglycerate which, because of the linkage of 3-phosphoglycerate to phosphoenolpyruvate through two near-equilibrium reactions, reduces the concentration of phosphoenolpyruvate and therefore causes a decline in flux through pyruvate kinase. This decrease in pyruvate kinase flux results in an enhanced gluconeogenic flux. At higher NADH/NAD+ ratios, however, the oxalacetate concentration drops to such an extent that the consequent decreased flux through phosphoenolpyruvate carboxykinase exceeds the decline in flux through pyruvate kinase, producing a decrease in gluconeogenic flux. The lactate/pyruvate ratio was found to influence the actions of three hormones thought to stimulate gluconeogenesis by different mechanisms. Except for an inhibition by glucagon seen at the lowest lactate/pyruvate ratio tested, the stimulations by this hormone were relatively insensitive to lactate/pyruvate ratios, while angiotensin II produced greater stimulations of gluconeogenesis as the lactate/pyruvate ratio was increased. Dexamethasone, added in vitro, stimulated gluconeogenesis significantly only at very low and very high lactate/pyruvate ratios.
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PMID:The interaction between the cytosolic pyridine nucleotide redox potential and gluconeogenesis from lactate/pyruvate in isolated rat hepatocytes. Implications for investigations of hormone action. 404 7

We used a nuclear RNA transcript elongation assay to show that cAMP analogs and dexamethasone cause a selective increase of transcription of the P-enolpyruvate carboxykinase gene in H4IIE hepatoma cells. 8-(4-chlorophenylthio)-cAMP increased transcription within 5 min and the maximal rate, generally 10-15-fold above the basal rate, was attained by 30 min. This increase was of sufficient magnitude to account for the effect on mRNAPEPCK (for example, where PEPCK is phosphoenolpyruvate carboxykinase) accumulation. After the initial increase, and with continued presence of cAMP, transcription of this gene declined to a new steady-state level which was 2-3 times the basal value. The effect of cAMP analogs on P-enolpyruvate carboxykinase gene transcription was obtained in the absence of protein synthesis. This, and the rapidity of the response, indicates that the effect of cAMP is exerted directly on the P-enolpyruvate carboxykinase gene. Dexamethasone results in a specific, 6-fold increase of transcription, sufficient to account for the increase of mRNAPEPCK which follows treatment of H4IIE cells with this glucocorticoid. When 1 nM insulin was added to either untreated H4IIE cells, or cells first treated with a cAMP analog or dexamethasone, there was a marked reduction of cytoplasmic mRNAPEPCK. The inhibitory effect of insulin was readily reversible, as cells regained the basal level of mRNAPEPCK and full responsiveness to cAMP within 1 h after removing insulin. The transcript elongation assay was used to show that insulin inhibits transcription of the gene coding for mRNAPEPCK. The concentration of insulin required for 50% inhibition was 2-5 pM, whereas approximately 200 pM of proinsulin was required to achieve the same inhibition of transcription. This effect was specific, since insulin did not affect the synthesis of total RNA; it was rapid, as 5 nM insulin decreased the rate of P-enolpyruvate carboxykinase gene transcription by 50% within 15 min; and it also does not require ongoing protein synthesis. The magnitude and kinetics of the response suggest that the primary action of insulin in the regulation of P-enolpyruvate carboxykinase synthesis is exerted at the level of mRNAPEPCK transcription. The insulin-mediated inhibition of mRNAPEPCK transcription was noted in untreated cells and in cells first treated with 8-(4-chlorophenylthio)-cAMP, dexamethasone, or both of these agents. Hence, among these compounds, insulin is the dominant regulatory molecule.
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PMID:Multihormonal regulation of phosphoenolpyruvate carboxykinase gene transcription. The dominant role of insulin. 609 65

In hepatocytes precultured for 24 h with dexamethasone glucagon increased phosphoenolpyruvate carboxykinase activity 3-4-fold with a half maximal activity increase at 30 pM. The half maximal effective glucagon concentration was enhanced 10-fold to 300 pM when insulin was added simultaneously. The glucagon-insulin antagonism was maximally expressed when glucagon was present at low physiological concentrations. At equimolar doses it was only in the concentration range around 0.1 nM that glucagon and insulin became powerful antagonists; at higher levels glucagon was the dominant hormone. In hepatocytes not pretreated with dexamethasone glucagon still enhanced phosphoenolpyruvate carboxykinase activity, but the half maximal effective dose raised more than 30-fold to 1 nM. The degree of stimulation, however, remained essentially unchanged. Thus dexamethasone shifted the glucagon sensitivity of the cells into the physiological concentration range; it exerted a half maximal effect at 10 nM. Dexamethasone was not required for the enzyme induction proper if the cells had been pretreated with the glucocorticoid. The amount of the glucagon-stimulated enzyme induction was dependent on the time period of cell pretreatment with dexamethasone. Glucagon enhanced enzyme activity to the same constant suboptimal level irrespective of whether cells had been pretreated with glucocorticoid for 1 or for 14 h. If cells were pretreated for more than 15 h, glucagon linearly increased enzyme activity further until the maximal value was reached after 24 h pretreatment. The glucagon-insulin antagonism and the glucagon-glucocorticoid synergism were observed at physiological hormone concentrations indicating that the interaction should be effective also in vivo. Dexamethasone does not seem to be generally permissive for the inducing action of glucagon, but rather sensitizes the cell towards lower physiological hormone concentrations.
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PMID:The glucagon-insulin antagonism and glucagon-dexamethasone synergism in the induction of phosphoenolpyruvate carboxykinase in cultured rat hepatocytes. 636 20


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