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)

Insulin-like growth factor-II (IGF-II) is an important regulator of embryonic growth and differentiation, but its function in postnatal life is unclear. To address this point, we generated transgenic mice harboring fusion genes in which a human IGF-II complementary DNA is placed under the transcriptional control of the rat phosphoenolpyruvate carboxykinase promoter. Transgene-specific messenger RNA was detected in liver, kidney, and several parts of the gut. Serum IGF-II levels in transgenic mice were 2-3 times higher than those in controls and increased after starvation. Circulating IGF-I correlated negatively and IGF-binding protein-2 (IGFBP-2) positively with IGF-II levels, suggesting that IGF-I is displaced from IGFBPs by IGF-II and that IGF-II is a major regulator of IGFBP-2. Serum levels of IGFBP-3 and IGFBP-4 tended to be higher in phosphoenolpyruvate carboxykinase-IGF-II transgenic mice than in controls, as evaluated by ligand blot analysis. Starvation reduced serum IGF-I, but increased IGFBP-2 in transgenic mice more markedly than in controls. Fasting insulin levels were significantly reduced in transgenic mice, whereas glucose levels were not influenced by elevated IGF-II. The body growth of 4- and 12-week-old mice was not significantly influenced by elevated IGF-II, but transgenic mice displayed increased kidney and testis weight at the age of 4 weeks, and increased adrenal weight at the age of 12 weeks. Our results demonstrate that elevated IGF-II in postnatal life has multiple endocrine consequences and subtle time-specific effects on organ growth.
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PMID:Consequences of postnatally elevated insulin-like growth factor-II in transgenic mice: endocrine changes and effects on body and organ growth. 752 57

To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in C and I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0.05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two- to threefold in B and IB mice (P < 0.001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0.001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory.
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PMID:Interactions of insulin-like growth factor (IGF)-II and growth hormone in vivo: circulating levels of IGF-I and IGF-binding proteins in transgenic mice. 943 40

Insulin regulates the expression of multiple hepatic genes through a conserved insulin response sequence (IRS) (CAAAAC/TAA) by an as yet undetermined mechanism. Protein kinase B/Akt (PKB/Akt), a member of the PKA/PKC serine/threonine kinase family, functions downstream from phosphatidylinositol 3'-kinase (PI3K) in mediating effects of insulin on glucose transport and glycogen synthesis. We asked whether PKB/Akt mediates sequence-specific effects of insulin on hepatic gene expression using the model of the insulin-like growth factor binding protein-1 (IGFBP-1) promoter. Insulin lowers IGFBP-1 mRNA levels, inhibits IGFBP-1 promoter activity, and activates PKB/Akt in HepG2 hepatoma cells through a PI3K-dependent, rapamycin-insensitive mechanism. Constitutively active PI3K and PKB/Akt are each sufficient to mediate effects of insulin on the IGFBP-1 promoter in a nonadditive fashion. Dominant negative K179 PKB/Akt disrupts the ability of insulin and PI3K to activate PKB/Akt and to inhibit promoter activity. The IGFBP-1 promoter contains two IRSs each of which is sufficient to mediate sequence-specific effects of insulin, PI3K, and PKB/Akt on promoter activity. Highly related IRSs from the phosphoenolpyruvate carboxykinase and apolipoprotein CIII genes also are effective in this setting. These results indicate that PKB/Akt functions downstream from PI3K in mediating sequence-specific effects of insulin on the expression of IGFBP-1 and perhaps multiple hepatic genes through a conserved IRS.
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PMID:Protein kinase B/Akt mediates effects of insulin on hepatic insulin-like growth factor-binding protein-1 gene expression through a conserved insulin response sequence. 949 82

Highly related insulin response sequences (IRSs) mediate effects of insulin on the expression of multiple genes in the liver, including insulin-like growth factor binding protein-1 (IGFBP-1) and phosphoenolpyruvate carboxykinase (PEPCK). Gel shift studies reveal that oligonucleotide probes containing an IRS from the IGFBP-1 or PEPCK gene form a similar complex with hepatic nuclear proteins. Unlabeled competitors containing the IGFBP-1 or PEPCK IRS or a binding site for C/EBP proteins inhibit the formation of this complex. Antibody against C/EBPbeta (but not other C/EBP proteins) supershifts this complex, and Western blotting of affinity purified proteins confirms that C/EBPbeta is present in this complex. Studies with affinity purified and recombinant protein indicate that C/EBPbeta does not interact directly with the IRS, but that other factors are required. Gel shift assays and reporter gene studies with constructs containing point mutations within the IRS reveal that the ability to interact with factors required for the formation of this complex correlates well with the ability of insulin to regulate promoter activity via this IRS (r = 0.849, p < 0.01). Replacing the IRS in reporter gene constructs with a C/EBP-binding site (but not an HNF-3/forkhead site or cAMP response element) maintains the effect of insulin on promoter activity. Together, these findings indicate that a nucleoprotein complex containing C/EBPbeta interacts with IRSs from the IGFBP-1 and PEPCK genes in a sequence-specific fashion and may contribute to the ability of insulin to regulate gene expression.
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PMID:A nucleoprotein complex containing CCAAT/enhancer-binding protein beta interacts with an insulin response sequence in the insulin-like growth factor-binding protein-1 gene and contributes to insulin-regulated gene expression. 1111 47

The insulin response sequence (IRS) of the phosphoenolpyruvate carboxykinase (PEPCK) promoter, located within the glucocorticoid response unit, was first characterized by its ability to mediate insulin inhibition when inserted into a thymidine kinase promoter. The IRSs of the PEPCK and insulin-like growth factor binding protein-1 (IGFBP-1) promoters have been proposed to contribute to regulation by glucocorticoids and insulin. Forkhead (FKHR) recognizes IRS sequences, is phosphorylated in response to insulin, and mediates insulin inhibition of basal IGFBP-1 transcription in an IRS-dependent manner. Here, we investigate the contributions of FKHR and IRSs to insulin inhibition of basal and glucocorticoid-induced transcription of PEPCK and IGFBP-1. Expression of T/S/S, in which three putative protein kinase B (PKB) sites in FKHR are mutated, reduced insulin inhibition of basal expression of IGFBP-1 but not PEPCK. Mutation of the IGFBP-1 IRSs abolished insulin inhibition in the presence of T/S/S. Mutation of the PEPCK IRS had no effect on insulin inhibition in the presence of T/S/S, indicating that insulin inhibits PEPCK transcription independently of the IRS or of the putative PKB phosphorylation sites in FKHR. Mutations in the IRS or FKHR had no effect on insulin inhibition of glucocorticoid-induced transcription of either the PEPCK or IGFBP-1 gene. Thus, insulin uses gene- and activation-specific mechanisms to regulate the basal and glucocorticoid-induced activity of these genes.
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PMID:Gene- and activation-specific mechanisms for insulin inhibition of basal and glucocorticoid-induced insulin-like growth factor binding protein-1 and phosphoenolpyruvate carboxykinase transcription. Roles of forkhead and insulin response sequences. 1144 61

Insulin rapidly and completely inhibits expression of the hepatic insulin-like growth factor binding protein-1 (IGFBP-1), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. This inhibition is mediated through a phosphatidyl inositol 3-kinase-dependent regulation of a DNA element, termed the thymine-rich insulin response element, found within the promoters of each of these genes. This has led to the conclusion that these three promoters are regulated by insulin using the same molecular mechanism. However, we recently found that the regulation of the IGFBP1 but not the PEPCK or G6Pase genes by insulin was sensitive to rapamycin, an inhibitor of mTOR. Here, we present further evidence that different regulatory pathways mediate the insulin regulation of these promoters. Importantly, we identify a protein phosphatase activity in the pathway connecting mTOR to the IGFBP-1 promoter. These data have major implications for the development of molecular therapeutics for the treatment of insulin-resistant states such as diabetes and hypertension.
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PMID:Different mechanisms are used by insulin to repress three genes that contain a homologous thymine-rich insulin response element. 1291 28

GSK3 (glycogen synthase kinase-3) regulation is proposed to play a key role in the hormonal control of many cellular processes. Inhibition of GSK3 in animal models of diabetes leads to normalization of blood glucose levels, while high GSK3 activity has been reported in Type II diabetes. Insulin inhibits GSK3 by promoting phosphorylation of a serine residue (Ser-21 in GSK3alpha, Ser-9 in GSK3beta), thereby relieving GSK3 inhibition of glycogen synthesis in muscle. GSK3 inhibition in liver reduces expression of the gluconeogenic genes PEPCK (phosphoenolpyruvate carboxykinase), G6Pase (glucose-6-phosphatase), as well as IGFBP1 (insulin-like growth factor binding protein-1). Overexpression of GSK3 in cells antagonizes insulin regulation of these genes. In the present study we demonstrate that regulation of these three genes by feeding is normal in mice that express insulin-insensitive GSK3. Therefore inactivation of GSK3 is not a prerequisite for insulin repression of these genes, despite the previous finding that GSK3 activity is absolutely required for maintaining their expression. Interestingly, insulin injection of wild-type mice, which activates PKB (protein kinase B) and inhibits GSK3 to a greater degree than feeding (50% versus 25%), does not repress these genes. We suggest for the first time that although pharmacological inhibition of GSK3 reduces hepatic glucose production even in insulin-resistant states, feeding can repress the gluconeogenic genes without inhibiting GSK3.
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PMID:Analysis of hepatic gene transcription in mice expressing insulin-insensitive GSK3. 1617 84