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:4.1.1.49 (phosphoenolpyruvate carboxykinase)
4,654 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several hormones, including insulin, glucagon, and glucocorticoids, regulate the expression of the rate-limiting gluconeogenic enzyme, phosphoenolpyruvate carboxykinase [GTP: oxaloacetate carboxy-lyase (transphosphorylating); EC 4.1.1.32; PEPCK] in liver. In this report we demonstrate that retinoic acid (RA) also regulates PEPCK expression by inducing a 3-fold increase in the rate of transcription of the PEPCK gene. A RA response element located between -468 and -431 in the PEPCK promoter mediates a 7-fold increase in expression of a chimeric construct containing the basal PEPCK promoter ligated to the chloramphenicol acetyltransferase reporter gene. This element confers RA responsiveness through the heterologous thymidine kinase promoter and functions relatively independent of position and orientation. An 18-base-pair core sequence (-451 to -434) (i) mediates an effect of RA on PEPCK gene expression and contains motifs found in two other RA response elements; (ii) corresponds to AF1, an accessory factor element that is an integral component of the complex glucocorticoid response unit in the PEPCK gene promoter; (iii) is in a region involved in the developmental expression of the PEPCK gene; and (iv) shows homology to elements involved in the tissue-specific regulation of genes, including the hepatic apolipoprotein genes and the alpha 1-antitrypsin gene.
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PMID:A retinoic acid response element is part of a pleiotropic domain in the phosphoenolpyruvate carboxykinase gene. 184 96

A sequential pattern of interactions of trans-acting factors in rat liver with the phosphoenolpyruvate carboxykinase promoter during late development was observed. A liver-enriched factor, possibly AF1, interacted with the promoter in fetal liver, whereas a factor with the characteristics of C/EBP bound the promoter after birth with the onset of the gene expression.
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PMID:Developmentally regulated interactions of liver nuclear factors with the rat phosphoenolpyruvate carboxykinase promoter. 232 58

Glucocorticoids stimulate hepatic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) gene expression, thereby increasing the rate of gluconeogenesis. The effect of glucocorticoids on PEPCK gene expression is mediated by a set of promoter elements collectively referred to as the glucocorticoid response unit. The response unit spans a 100-bp segment and includes two glucocorticoid receptor binding sites (GR1 and GR2) and two accessory factor binding sites (AF1 and AF2), all of which are required for a maximal glucocorticoid response. The AF1 element also serves as a retinoic acid response element and may be involved in developmental and tissue-specific expression of the gene. In this study we report that COUP-TF and HNF-4, two orphan members of the nuclear receptor superfamily, bind to the AF1 element and function as accessory factors for the glucocorticoid response of the PEPCK gene.
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PMID:The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. 783 1

Transcription of the phosphoenolpyruvate carboxykinase gene is stimulated by glucocorticoids, retinoic acid, and cAMP and is dominantly inhibited by insulin and phorbol esters. The glucocorticoid response is mediated by a complex regulatory unit that consists of two glucocorticoid receptor (GR) binding sites (GR1 and GR2) and two adjacent accessory factor elements (AF1 and AF2). Deletion of either the AF1 or the AF2 element results in a 50-75% reduction of the glucocorticoid response. In addition to their accessory role in glucocorticoid action, the AF1 and AF2 elements mediate retinoic acid and insulin/phorbol ester effects, respectively. Site-directed mutagenesis was performed on AF1 and AF2 to precisely locate the sequences responsible for accessory activity in each element. The glucocorticoid accessory activity of the AF1 element maps to the same 12-base pair sequence (TGACCTTTGGCC) involved in the response of the PEPCK gene to retinoic acid. The glucocorticoid accessory activity of the AF2 region maps to the same 10-base pair sequence (TGGTGTTTTG) responsible for mediating the insulin and phorbol ester responses through this element. The AF1 and AF2 elements bind different sets of nuclear proteins, and this binding is not qualitatively or quantitatively affected by treatment of the rat H4IIE hepatoma cells with retinoic acid (AF1) or insulin (AF2). AF2 functions in a heterologous context (a consensus glucocorticoid response element and the thymidine kinase promoter), whereas AF1 functions in this context only if the retinoic acid receptor is overexpressed in the cells. These results show that the AF1 and AF2 elements affect the glucocorticoid response through different protein DNA interactions, and that a small sequence in each serves multiple functions. Together with GR1 and GR2, they form a complex hormone response unit which provides an integrated response of the phosphoenolpyruvate carboxykinase gene to a variety of positive and negative signals.
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PMID:Integration of multiple signals through a complex hormone response unit in the phosphoenolpyruvate carboxykinase gene promoter. 805 68

The phosphoenolpyruvate carboxykinase (PEPCK) gene encodes the rate-limiting enzyme in gluconeogenesis. Glucocorticoids enhance PEPCK gene expression through a multicomponent regulatory complex. We show that a full response to glucocorticoids requires two DNA segments: 1) a glucocorticoid response unit (GRU), centered at about position -400, which contains two accessory factor elements (AF1 and AF2) and two glucocorticoid receptor binding sites (GR1 and GR2), and 2) a basal promoter/cyclic AMP response element (E/CRE) at about position -90, which binds the transcription factor CREB. A protein-protein interaction was observed in vitro between GR and CREB that might account for the role of the E/CRE in the glucocorticoid response of the PEPCK gene.
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PMID:Glucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phosphoenolpyruvate carboxykinase gene to glucocorticoids. 844 98

Transcription of the hepatic phosphoenolpyruvate carboxykinase gene is stimulated by glucocorticoids and inhibited by insulin. The glucocorticoid response is mediated by a complex glucocorticoid response unit that consists of two glucocorticoid receptor (GR)-binding sites (GR1 and GR2) and two accessory factor-binding sites (AF1 and AF2). The complete unit is required for the full glucocorticoid response. The dominant insulin effect is mediated in part through an insulin response sequence that is coincident with the AF2 element. Members of the hepatic nuclear factor 3 (HNF3) and CCAAT enhancer binding protein (C/EBP) families bind to the AF2 element; however, there is no correlation between binding of these factors and the ability of the AF2 element to mediate an insulin response. We show here that binding of HNF3 does correlate with the stimulation of the glucocorticoid response by the AF2 element and that C/EBP is apparently not involved in this effect. This requirement for HNF3 is quite specific since the substitution of elements known to enhance the action of the GR in other promoters fails to recapitulate AF2 accessory factor activity. By contrast, an HNF3-binding site from the transthyretin gene is able to substitute for the wild type AF2 sequence and elicit a maximal glucocorticoid response. Based on current and previous observations, the glucocorticoid response unit consists of four DNA elements that bind four different proteins. These are: AF1 (hepatic nuclear factor 4/chicken ovalbumin upstream promoter transcription factor), AF2 (HNF3), GR1 (GR), and GR2 (GR).
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PMID:Hepatic nuclear factor 3 is an accessory factor required for the stimulation of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. 881 20

The phosphoenolpyruvate carboxykinase (PEPCK) gene promoter contains a glucocorticoid response unit (GRU) that includes, as a linear array, two accessory factor binding sites (AF1 and AF2) and two glucocorticoid receptor binding sites. All of these elements are required for a complete glucocorticoid response. AF1 and AF2 also partially account for the response of the PEPCK gene to retinoic acid and insulin, respectively. A second retinoic acid response element was recently located just downstream of the GRU. In this study we show that mutation of the 3' half-site of this element results in a 60% reduction of the glucocorticoid response of PEPCK promoter-chloramphenicol acetyltransferase (CAT) fusion constructs in transient transfection assays, thus the half-site is now termed AF3. A variety of assays were used to show that chicken ovalbumin upstream promoter transcription factor (COUP-TF) binds specifically to AF3 and that upstream stimulatory factor (USF) binds to an E-box motif located 2 base pairs downstream of AF3. Mutations of AF3 that diminish binding of COUP-TF reduce the glucocorticoid response, but mutation of the USF binding site has no effect. The functional roles of AF1, AF2, and AF3 in the glucocorticoid response were explored using constructs that contained combinations of mutations in all three elements. All three elements are required for a maximal glucocorticoid response, and mutation of any two abolish the response.
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PMID:The orphan receptor COUP-TF binds to a third glucocorticoid accessory factor element within the phosphoenolpyruvate carboxykinase gene promoter. 894 35

Glucocorticoids inhibit basal and hormone-induced phosphoenolpyruvate carboxykinase (PEPCK) gene transcription in adipocytes whereas beta-adrenergic agonists and fibrates are stimulatory. Here we show that dexamethasone inhibits the induction of PEPCK mRNA by isoprenaline or clofibrate in 3T3-F442A adipocytes. RU 38486 antagonizes dexamethasone effect, suggesting the involvement of the glucocorticoid receptor. In H4IIE hepatoma cells, glucocorticoids enhance PEPCK gene transcription through a complex region which encompasses an element, AF1, with a direct repeat 1-type sequence. Mutations in the AF1 sequence abolish binding of nuclear factors from liver and from 3T3-F442A adipocytes. We transiently transfected 3T3-F442A cells with a wild type or an AF1-mutated PEPCK-CAT construct comprising -2100 to +69 base pairs of the promoter fused to the chloramphenicol acetyltransferase (CAT) gene. With both constructs, CAT activity is decreased by dexamethasone and is increased by isoprenaline or by clofibrate. However, dexamethasone is unable to inhibit clofibrate induction of CAT activity in cells transfected with the AF1-mutated construct whereas it prevents isoprenaline action on both constructs. Hence, although a single hormone can repress stimulations originating from different intracellular routes, sites in the promoter which mediate inhibition of a specific stimulation are distinct.
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PMID:Glucocorticoids use a positive liver element to repress fibrate-induced adipose transcription of the phosphoenolpyruvate carboxykinase gene. 909 12

The phosphoenolpyruvate carboxykinase (PEPCK) gene promoter contains a glucocorticoid response unit (GRU) that includes three accessory factor-binding sites (AF1, AF2, and AF3), two glucocorticoid receptor-binding sites (GR1 and GR2), and a cAMP response element. All of these elements, and the proteins that bind to them, are required for a complete glucocorticoid response. The PEPCK promoter also contains a retinoic acid response unit (RARU) that consists of two retinoic acid response elements (RARE1 and RARE2) that bind retinoic acid receptor/9-cis-retinoic acid receptor heterodimers. The sequences of RARE1 and RARE2 coincide with those for AF1 and AF3, respectively. Thus, the PEPCK promoter can mediate different hormone responses through hormone response units that utilize common elements, but that bind different sets of proteins. We reasoned that each response might require a unique structural assembly and therefore tested how various arrangements of the PEPCK promoter affect the actions of either glucocorticoids or retinoic acid. The activation of the PEPCK gene in response to glucocorticoids requires a specific set of cis-acting elements that must be precisely positioned within the GRU. The distance between AF2 and GR1 is critical for the glucocorticoid response, and since the AF2 factor, HNF3, interacts with GR in vitro, this protein-protein interaction may be important for the glucocorticoid response. By contrast, the distance and orientation requirements of AF1 and AF3 with respect to GR1 are more flexible. In the case of the RARU, although the relative positions of RARE1 and RARE2 are important for the retinoic acid response, more tolerance for distance and stereospecific alignment between RARE1 and RARE2 is allowed. In addition, we show that the GRU and the RARU can act as a module, within a restricted region, in the context of the PEPCK promoter and in limited contexts of a heterologous promoter. These observations suggest that the structural requirements of the GRU and the RARU are different, and this may have important implications for how multiple hormonal signals are integrated through this promoter.
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PMID:Structural requirements of the glucocorticoid and retinoic acid response units in the phosphoenolpyruvate carboxykinase gene promoter. 977 73

Complete induction of hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene transcription by glucocorticoids requires a complex glucocorticoid response unit (GRU). The GRU is comprised of two glucocorticoid receptor (GR)-binding sites (GR1 and GR2) and four accessory factor-binding sites [AF1, AF2, AF3, and cAMP response element (CRE)] that bind distinct transcription factors. Hepatic nuclear factor 4 (HNF4) and chicken ovalbumin upstream promoter transcription factor (COUP-TF) bind to the AF1 element and account for AF1 activity. Members of the hepatic nuclear factor 3 (HNF3) family bind to the AF2 element and provide AF2 activity. In this report, we show that the functions of AF1 and AF2 are dependent on their positions in the promoter, since they cannot substitute for each other nor can they be exchanged without a reduction in the response to glucocorticoids. We also identified the domains of HNF4 and HNF3 beta that are required for the AF1 and AF2 activities, respectively. The carboxy-terminal transactivation domain of HNF4 (amino acids 128-374) confers most of the AF1 activity, while the carboxyterminal transactivation domain of HNF3 beta (amino acids 361-458) mediates AF2 activity. These domains of HNF4 and HNF3 beta appear to have distinct roles in the response to glucocorticoids, as there are unique structural requirements for each, as judged by the failure of most other classes of transactivation domains to serve as accessory factors. These results suggest that the regulation of the PEPCK gene by glucocorticoids requires specific interactions between GR, accessory factors, and coactivators, and that the transactivation domains of AF1 and AF2 are of fundamental importance in the assembly of this multiprotein complex.
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PMID:The phosphoenolpyruvate carboxykinase gene glucocorticoid response unit: identification of the functional domains of accessory factors HNF3 beta (hepatic nuclear factor-3 beta) and HNF4 and the necessity of proper alignment of their cognate binding sites. 1019 66


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