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

Nuclear factor I (NFI) binds to a region of the phosphoenolpyruvate carboxykinase (GTP) (PEPCK) gene promoter adjacent to the cAMP regulatory element (CRE) and inhibits the induction of transcription from the gene promoter caused by the catalytic subunit of protein kinase A. In vivo footprinting studies demonstrated that both the CRE and the NFI-binding site are occupied by transcription factors, regardless of the presence of factors that stimulate (dibutyryl cAMP or dexamethasone) or inhibit (insulin) transcription from the PEPCK gene promoter. The NFI effects on transcription from the PEPCK gene promoter were observed even in the absence of the NFI binding site, suggesting the possibility of other weaker binding sites on the promoter or an interaction of NFI with a transcriptional co-activator. A mammalian two-hybrid system was used to demonstrate direct interaction between the transactivation domain of NFI-C and the CREB binding domain of the CREB-binding protein (CBP). Overexpression of a gene fragment encoding the CREB binding domain of CBP stimulates transcription from the PEPCK gene promoter. The inhibitory effect of NFI on transcription of the PEPCK gene induced by the catalytic subunit of protein kinase A appears to be the result of an interaction between NFI and the CREB-binding protein in which NFI competes with CREB for binding to the CREB-binding site on CBP. In contrast, glucocorticoids and thyroid hormone use the steroid hormone receptor binding domain of CBP to stimulate transcription from the PEPCK gene promoter. NFI-A combines with dexamethasone or thyroid hormone in an additive manner to stimulate PEPCK gene transcription. We conclude that CBP coordinates the action of the multiple factors known to control transcription of the PEPCK gene.
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PMID:CREB binding protein coordinates the function of multiple transcription factors including nuclear factor I to regulate phosphoenolpyruvate carboxykinase (GTP) gene transcription. 1008 23

Cyclic AMP-response element modulator alpha (CREMalpha) is a transcription factor that is highly related to cAMP-response element-binding protein (CREB) but represses cAMP-induced gene expression from simple artificial promoters containing a cAMP-response element (CRE). CREMalpha lacks two glutamine-rich Q regions that, in CREB, are thought to be necessary for transcriptional activation. Nevertheless, protein kinase A stimulation induces CREMalpha to activate the complex native promoter in the phosphoenolpyruvate carboxykinase (PEPCK) gene. To study this phenomenon in the absence of protein kinase A stimulation, we introduced a mutation into CREMalpha to allow constitutive binding to the coactivator CREB-binding protein. This mutant, CREMalpha(DIEDML), constitutively activated the PEPCK promoter. By engineering the leucine zipper regions of CREMalpha(DIEDML) and CREB(DIEDML) to direct their patterns of dimerization, we found that only CREMalpha(DIEDML) homodimers fully activated the PEPCK promoter. By using a series of deletion and block mutants of the PEPCK promoter, we found that activation by CREMalpha(DIEDML) depended on the CRE and two CCAAT/enhancer-binding protein (C/EBP) sites. A dominant negative inhibitor of C/EBP, A-C/EBP, suppressed activation by CREMalpha(DIEDML). Furthermore, a GAL4-C/EBPalpha fusion protein and CREMalpha(DIEDML) cooperatively activated a promoter containing three GAL4 sites and the PEPCK CRE. Thus, we propose that the C/EBP sites in the PEPCK promoter allow CREMalpha to activate transcription despite its lack of Q regions.
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PMID:Cooperative mechanism of transcriptional activation by a cyclic AMP-response element modulator alpha mutant containing a motif for constitutive binding to CREB-binding protein. 1109 86

Thyroid hormone and cAMP stimulate transcription of the gene for phosphoenolpyruvate carboxykinase (PEPCK). CCAAT enhancer-binding proteins (C/EBP(alpha) and beta) are involved in multiple aspects of the nutritional, developmental and hormonal regulation of PEPCK gene expression. Previously, we have identified a thyroid hormone response element in the PEPCK promoter and demonstrated that C/EBP proteins bound to the P3(I) site are participants in the induction of PEPCK gene expression by thyroid hormone and cAMP. Here, we identify several peptide regions within the transactivation domain of C/EBP(alpha) that enhance the ability of T(3) to stimulate gene transcription. We also demonstrate that several conserved amino acids in the transactivation domain of C/EBP(alpha) and C/EBPbeta are required for the stimulation of basal gene expression and identify amino acids within C/EBPbeta that participate in the cAMP induction of the PEPCK gene. Finally, we show that the CREB-binding protein (CBP) enhanced the induction of PEPCK gene transcription by thyroid hormone and that CBP is associated with the PEPCK gene in vivo. Our results indicate that both C/EBP proteins and CBP participate in the regulation of PEPCK gene transcription by thyroid hormone.
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PMID:Conserved amino acids within CCAAT enhancer-binding proteins (C/EBP(alpha) and beta) regulate phosphoenolpyruvate carboxykinase (PEPCK) gene expression. 1199 89

Hormones regulate glucose homeostasis, in part, by controlling the expression of gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK). Insulin and glucocorticoids reciprocally regulate PEPCK expression primarily at the level of gene transcription. We demonstrate here that glucocorticoids promote, whereas insulin disrupts, the association of CREB-binding protein (CBP) and RNA polymerase II with the hepatic PEPCK gene promoter in vivo. We also show that accessory factors, such as CCAAT/enhancer-binding protein beta (C/EBP beta), can recruit CBP to drive transcription. Insulin increases protein levels of liver-enriched transcriptional inhibitory protein (LIP), an inhibitory form of C/EBP beta, in a phosphatidylinositol 3-kinase-dependent manner. LIP concomitantly replaces liver-enriched transcriptional activator protein on the PEPCK gene promoter, which can abrogate the recruitment of CBP and polymerase II, culminating in the repression of PEPCK expression and the attenuation of hepatocellular glucose production.
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PMID:Insulin inhibits hepatocellular glucose production by utilizing liver-enriched transcriptional inhibitory protein to disrupt the association of CREB-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter. 1207 Jan 72

Expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene is repressed during fetal liver development and activated at birth. It has been shown that the PEPCK gene is a retinoid-responsive gene, but whether it is regulated by vitamin A in the fetus has not been established. In this study, we found that PEPCK mRNA can be detected in the murine fetal liver as early as gestational d 17. In addition, expression and cAMP induction of the PEPCK gene during late gestation and at birth require vitamin A sufficiency in the fetus and neonate. The PEPCK promoter contains several regulatory elements that bind a diverse array of transcription factors and nuclear coregulators, although it is largely unknown which of these factors are expressed early in liver development. Expression of some of these nuclear factors in livers of fetal mice was investigated by immunohistochemistry (IHC). Fetuses were from dams that were fed from the beginning of gestation diets that were adequate or devoid of vitamin A. Hepatocyte nuclear factor 4alpha (HNF4alpha) was expressed at the earliest stage of liver development on d 11, whereas retinoid X receptor alpha (RXRalpha) and nuclear coactivator CREB-binding protein (CBP) were expressed from d 16 onward. Although expressions of RXRalpha and CBP in livers of vitamin A-sufficient and vitamin A-depleted fetal mice did not differ, the level of HNF4alpha was consistently lower in the latter. Our findings strongly suggest that vitamin A is required during liver development for staged expression of the PEPCK gene and that HNF4alpha may be involved in mediating vitamin A regulation of the PEPCK gene at these critical periods.
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PMID:Vitamin A depletion is associated with low phosphoenolpyruvate carboxykinase mRNA levels during late fetal development and at birth in mice. 1284 Jan 67

Activation of phosphoenolpyruvate carboxykinase (PEPCK) gene transcription in response to all-trans-retinoic acid (RA) or a glucocorticoid such as dexamethasone (Dex) requires a distinct arrangement of DNA-response elements and their cognate transcription activators on the gene promoter. Two of the accessory factor-binding elements involved in the Dex response (gAF1 and gAF3) coincide with the DNA-response elements involved in the RA response. We demonstrate here that the combination of Dex/RA has a synergistic effect on endogenous PEPCK gene expression in rat hepatocytes and H4IIE hepatoma cells. Reporter gene studies show that the gAF3 element and one of the two glucocorticoid receptor-binding elements (GR1) are most important for this effect. Chromatin immunoprecipitation assays revealed that when H4IIE cells were treated with Dex/RA, ligand-activated retinoic acid receptors (retinoic acid receptor/retinoid X receptor) and glucocorticoid receptors are recruited to this gene promoter, as are the transcription coregulators p300, CREB-binding protein, p/CIP, and SRC-1. Notably, the recruitment of p300 and RNA polymerase II to the PEPCK promoter is increased by the combined Dex/RA treatment compared with Dex or RA treatment alone. The functional importance of p300 in the Dex/RA response is illustrated by the observation that selective reduction of this coactivator, but not that of CREB-binding protein, abolishes the synergistic effect in H4IIE cells.
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PMID:The synergistic effect of dexamethasone and all-trans-retinoic acid on hepatic phosphoenolpyruvate carboxykinase gene expression involves the coactivator p300. 1516 31

The pathophysiology of type 2 diabetes mellitus (T2DM) is characterized by not only insulin resistance, but also the abnormal regulation of glucagon secretion, suggesting that antagonizing the glucagon-induced signaling pathway has therapeutic potential in the treatment of T2DM. Although various Kampo medicines (traditional herbal medicines) are often utilized to ameliorate the symptoms of T2DM, their effects on glucagon signaling have not yet been clarified. In the present study, we examined the effects of nine types of representative Kampo formulations prescribed for T2DM on glucagon-induced CREB activation in HEK293T cells stably expressing glucagon receptor (Gcgr) and a hepatic cell line HepG2. Among these Kampo medicines, Rokumigan, Hachimijiogan, and Goshajinkigan significantly suppressed the glucagon-induced transactivation of the cAMP-responsive element (CRE)-binding protein (CREB) by inhibiting its interaction with CREB-binding protein (CBP), which led to a reduction in the expression of phosphoenolpyruvate carboxykinase (PEPCK) mRNA. Furthermore, among the crude drugs commonly contained in these three Kampo medicines, Rehmannia Root (Jio), Moutan Bark (Botampi), and Cornus Fruit (Shanzhuyu) exerted inhibitory effects on glucagon-induced CREB activation. Collectively, the present results provide a novel mechanism, the inhibition of glucagon signaling, by which Rokumigan, Hachimijiogan, and Goshajinkigan improve the symptoms of T2DM.
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PMID:Kampo medicines, Rokumigan, Hachimijiogan, and Goshajinkigan, significantly inhibit glucagon-induced CREB activation. 3221 30