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)

Selective glucose-free media have been used to study the reexpression of liver-specific gluconeogenic enzymes in rat hepatoma X mouse lymphoblastoma somatic hybrids. The utilization for gluconeogenesis of dihydroxyacetone or oxaloacetate requires two enzymes: fructose diphosphatase as well as either triokinase for the former or phosphoenolpyruvate carboxykinase for the latter. By sequential selection with these substrates, the reexpression of the three gluconeogenic enzymes has been dissociated. The reexpression of these enzymes is correlated with the loss of mouse chromosomes. In addition, the characterization of the parental forms of aldolase B, another liver-specific enzyme, shows that reexpression corresponds to the simultaneous production of the rat and mouse enzymes. These results demonstrate the chromosomal origin of extinction and suggest that activation of mouse silent genes which accompanies reexpression can occur without loss of the parental determinations. The hypothesis that determination involves regulatory rather than structural genes is discussed.
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PMID:Expression of differentiated functions in hepatoma cell hybrids: selection in glucose-free media of segregated hybrid cells which reexpress gluconeogenic enzymes. 20 53

New hepatocyte-like cell lines (mhAT) were derived from the liver of a transgenic mouse expressing SV40 early genes under the direction of the liver-specific antithrombin III gene promoter (ATIII-TSV40). Their differentiated phenotypes were improved and stabilized by the use of liver-specific growth media (arginine-free, glucose-free, or low-fructose/glucose-free medium). The best differentiated lines display a very high level of albumin, transferrin, and L-type pyruvate kinase (L-PK) gene expression that is comparable to that observed in the mouse liver. Abundance of the aldolase B and phosphoenolpyruvate carboxykinase (PEPCK) transcripts varied from 5 to 35% of the in vivo concentrations while abundance of the alpha-fetoprotein and phenylalanine hydroxylase transcripts remained very low. Hormonal (cAMP and insulin) and nutritional (glucose) gene controls of PEPCK and L-PK were, at least partially, conserved. mhAT cells are readily transfectable by the calcium phosphate coprecipitation technique and exhibit a liver-specific pattern of expression of exogenous genes. Thus, mhAT cells seem suitable for the analysis of the regulatory regions involved in the tissue-specific transcription of genes. This work demonstrates, therefore, the great efficiency of targeted carcinogenesis in transgenic mice to create new differentiated cell lines. The availability of various lines of liver-specific cells with different phenotypes will constitute useful tools to establish correlations between expression of trans-acting factors and control of the phenotype.
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PMID:Gene expression in hepatocyte-like lines established by targeted carcinogenesis in transgenic mice. 137 87

The expression and regulation of the phosphoenolpyruvate carboxykinase gene were not grossly modified by feeding rats a 3'-methyl-4-(dimethylamino)azobenzene-containing diet despite maximum expression of the L-type pyruvate kinase gene being dramatically reduced as early as the 24th hour of the carcinogenic diet. Inhibition of aldolase B mRNA synthesis occurred more slowly, being maximum at the 3rd day. After stopping administration of the carcinogen, a very rapid, but transient increase of the L-type pyruvate kinase mRNA was observed at the 24th hour, whereas aldolase B mRNA increased only slowly. The amount of aldolase A mRNA fell quickly after termination of carcinogen administration, levels being normal at the 2nd-3rd day. At this time, the histological structure of the liver was indistinguishable from that of animals still receiving the azo-dye diet. It appears, therefore, that in the rat both administration and withdrawal of the azo-dye carcinogen induce rapid modifications of the expression of some genes, before any cellular modification is distinguishable.
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PMID:Early modifications of gene expression induced in liver by azo-dye diet. 309 78

Transcription of hepatocyte-specific genes requires the interaction of their regulatory regions with several nuclear factors. Among them is the hepatocyte nuclear factor 3 (HNF3) family, composed of the HNF3 alpha, HNF3 beta, and HNF3 gamma proteins, which are expressed in the liver and have very similar fork head DNA binding domains. The regulatory regions of numerous hepatocyte-specific genes contain HNF3 binding sites. We examined the role of HNF3 proteins in the liver-specific phenotype by turning off the HNF3 activity in well-differentiated mhAT3F hepatoma cells. Cells were stably transfected with a vector allowing the synthesis of an HNF3 beta fragment consisting of the fork head DNA binding domain without the transactivating amino- and carboxy-terminal domains. The truncated protein was located in the nuclei of cultured hepatoma cells and competed with endogenous HNF3 proteins for binding to cognate DNA sites. Overproduction of this truncated protein, lacking any transactivating activity, induced a dramatic decrease in the expression of liver-specific genes, including those for albumin, transthyretin, transferrin, phosphoenolpyruvate carboxykinase, and aldolase B, whereas the expression of the L-type pyruvate kinase gene, containing no HNF3 binding sites, was unaltered. Neither were the concentrations of various liver-specific transcription factors (HNF3, HNF1, HNF4, and C/EBP alpha) affected. In partial revertants, with a lower ratio of truncated to full-length endogenous HNF3 proteins, previously extinguished genes were re-expressed. Thus, the transactivating domains of HNF3 proteins are needed for the proper expression of a set of liver-specific genes but not for expression of the genes encoding transcription factors found in differentiated hepatocytes.
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PMID:Overproduction of a truncated hepatocyte nuclear factor 3 protein inhibits expression of liver-specific genes in hepatoma cells. 756 96

We investigated whether the multiple pathophysiological signals generated in a peritonitis septic model alter the mRNA levels of glycolytic and gluconeogenic enzymes, and whether these alterations are associated with glucose dyshomeostasis. Rats were sham-operated in the control group, and peritonitis sepsis was produced by a 1 cm cecal incision in the septic group. At 2, 4, and 6 hr post-surgery, total cellular RNAs were isolated from livers, and Northern blots performed to measure mRNA levels of aldolase B (ADL), lactate dehydrogenase (LDH), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), and glucokinase (GK). Hepatic PEPCK enzymatic activity was measured by condensing 14CO2 with phosphoenolpyruvate (PEP) to form malate. Serum glucose concentrations were also measured. We found the following: At 2 hr of peritonitis sepsis, serum glucose concentrations, mRNA levels of all enzymes, and PEPCK enzymatic activity increased over control levels. At 4 hr of peritonitis sepsis, serum glucose concentrations and mRNA levels of GK and PK continued to increase; mRNA levels of all other enzymes, as well as PEPCK enzymatic activity decreased to or below control levels. At 6 hr of peritonitis sepsis, serum glucose concentrations, mRNA levels of all enzymes, and PEPCK enzymatic activity decreased to or below control levels. We concluded that sepsis affects mRNA levels of glycolytic and gluconeogenic enzymes at the transcriptional level, and that these alterations are associated with glucose dyshomeostasis.
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PMID:Altered levels of mRNA encoding enzymes of hepatic glucose metabolism in septic rats. 840 44

Expression of the serum albumin gene is extinguished in rat hepatoma microcell hybrids that retain mouse chromosome 1. These data define a trans-dominant extinguisher locus, Tse-2, on mouse chromosome 1. To localize the human TSE2 locus, we prepared and characterized rat/human microcell hybrids that contained either human chromosome 1 or chromosome 2, the genetic homologues of mouse chromosome 1. Rat hepatoma microcell hybrids retaining a derivative human chromosome 1 [der 1 t(1;17)(p34.3;q11.2)] expressed their serum albumin genes at levels similar to those of parental hepatoma cells. In contrast, microcell transfer of human chromosome 2 into rat hepatoma recipients produced karyotypically heterogeneous collections of hybrid clones, some of which displayed dramatic albumin extinction phenotypes. For example, albumin mRNA levels in several extinguished microcell hybrids were reduced at least 500-fold, similar to albumin mRNA levels in hepatoma x fibroblast whole-cell hybrids. Expression of several other liver genes, including alpha 1-antitrypsin, aldolase B, alcohol dehydrogenase, and phosphoenolpyruvate carboxykinase, was also affected in some of the microcell hybrids, but expression of these genes was not concordant with expression of albumin. Hybrid segregants were prepared from the albumin-extinguished hybrids, and reexpression of albumin mRNA and protein was observed in sublines that had lost or fragmented human chromosome 2. Finally, expression of mRNAs encoding the liver-enriched trans activators HNF-1, HNF-4, HNF-3 alpha, and HNF-3 beta was not affected in any of the chromosome 2-containing hybrids. These data define and map a genetic locus on human chromosome 2 that extinguishes albumin gene expression in trans, and they suggest that TSE2-mediated extinction is independent of HNF-1, -4, -3 alpha, and -3 beta expression.
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PMID:Extinction of albumin gene expression in a panel of human chromosome 2 microcell hybrids. 883 17

Gene expression of aldolase B, an important enzyme for glucose and fructose metabolism, is regulated by hormones. We examined direct effects of major hormones on aldolase B gene expression in rat primary cultured hepatocytes, in comparison with those on the gene expression of phospho(enol)pyruvate carboxykinase (PEPCK), a key enzyme for gluconeogenesis. Insulin, dexamethasone, and high concentration of glucose increased aldolase B mRNA abundance in the hepatocytes. Glucagon strongly suppressed aldolase B gene expression, and this hormone canceled the stimulative effects of insulin, dexamethasone, and high concentration of glucose. Epinephrine and thyroxine slightly reduced aldolase B mRNA abundance, but these hormones did not cancel the stimulative effects of insulin and dexamethasone. To the contrary, expression of PEPCK gene was suppressed by insulin, dexamethasone, and high concentration of glucose, and remarkably induced by glucagon. Glucagon rapidly suppressed aldolase B gene expression at the transcriptional level. Forskolin and dibutyryl cAMP mimicked the suppressive effect of glucagon on aldolase B gene expression. These results suggest that glucagon may be a key regulator of aldolase B gene transcription through a cAMP/protein kinase A-signaling pathway.
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PMID:Hormonal regulation of aldolase B gene expression in rat primary cultured hepatocytes. 947 4

Although p53 regulates the cell cycle and apoptosis, gross embryonic development is normal in the p53 knockout (-/-) mouse. In this study, we comprehensively assessed liver development in p53 -/- mice (from embryonic day 15 to adult) for evidence of a cell cycle-induced perturbation in differentiation. Liver cell proliferation in the embryo and newborn is similar in p53 -/- and +/+ mice; in contrast, -/- adult hepatocytes divide at twice the rate of wild types. Developmental expression patterns of liver-specific markers that are up-regulated (e.g., phosphoenolpyruvate carboxykinase and aldolase B) and down-regulated (e.g., alpha-fetoprotein) are similar. Therefore, embryonic and perinatal liver development is normal in the absence of p53. However, the p53 -/- adult liver displays small blast-like cells, the majority being hepatic and some lymphoid. These cells appear in periportal regions and can infiltrate the parenchyma. The hepatic blast-like cells express both mature and immature liver markers, suggesting that differentiation of the liver stem cell compartment is blocked.
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PMID:Hepatoblast-like cells populate the adult p53 knockout mouse liver: evidence for a hyperproliferative maturation-arrested stem cell compartment. 1137 69

Our laboratory has shown previously that recombinant rainbow trout Ea4 (rtEa4)-peptide of pro-insulin-like growth factor-I (pro-IGF-I) exhibited antitumor activities against cancer cell lines derived from various human cancer tissues (Chen et al., 2002; Kuo and Chen, 2002). To confirm that rtEa4-peptide can exhibit the same spectrum of antitumor activities in fish tumor cells, we had developed permanent single-cell clones (RTH1B1A, RTH1B1D, RTH1B2A, and RTH1B2C) from a rainbow trout liver tumor induced by dibenzo[a,l]pyrene treatment. At 135 passages, the doubling time of these single-cell clones in CO2-independent medium at 20 degrees C was 3.9, 3.5, 3.0, and 4.5 d, respectively. Reverse transcription-polymerase chain reaction analysis showed that the expression of liver signature genes (e.g., aldolase B, glucose-6-phosphatase [G-6-Pase], phosphoenolpyruvate carboxykinase [PEPCK], hepatic nuclear factor-1 [HNF-I], IGF-I, IGF-II, and growth hormone [GH] receptor-2 genes) and CYP1A1 and CYP1A3 genes was detected in these four single-cell clones. Furthermore, results of in vitro colony formation assay in a soft-agar medium showed different degrees of colony formation activities among them. These results confirmed that the single-cell clones were derived from the rainbow trout liver. Treatment of RTH1B1D with recombinant trout Ea4-peptide resulted in the induction of a dose-dependent morphological change and the suppression of colony formation in a soft-agar medium. In addition, both morphological change and reduction of colony formation were also observed in permanent transfectants of RTH1B1D cells carrying a trout Ea4-peptide gene or its human counterpart, hEb-peptide gene. These results confirm our earlier observations that trout pre-IGF-I Ea4-peptide and hEb possess activities counteracting malignant properties of cancer cells in vitro.
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PMID:Development of rainbow trout hepatoma cell lines: effect of pro-IGF-I Ea4-peptide on morphological changes and anchorage-independent growth. 1531 63

Posttransplantation diabetes mellitus (PTDM) is a frequent complication in immunosuppressive therapy. To better understand the molecular events associated with PTDM we investigated the effect of cyclosporine on expression and activity of hepatic nuclear factor (HNF)1alpha and 4alpha and on genes coding for glucose metabolism in cultures of the rat insulinoma cell line INS-1E, the human epithelial cell line Caco-2 and with Zucker diabetic fatty (ZDF) rats. In the pancreas of untreated but diabetic animals expression of HNF4alpha, insulin1, insulin2 and of phosphoenolpyruvate carboxykinase was significantly repressed. Furthermore, cyclosporine treatment of the insulinoma-1E cell line resulted in remarkable reduction in HNF4alpha protein and INS1 as well as INS2 gene expression, while transcript expression of HNF4alpha, apolipoprotein C2, glycerolkinase, pyruvatekinase and aldolase B was repressed in treated Caco-2 cells. Furthermore, with nuclear extracts of cyclosporine treated cell lines protein expression and DNA binding activity of hepatic nuclear factors was significantly repressed. As cyclosporine inhibits the calcineurin dependent dephosphorylation of nuclear factor of activated T-cells (NFAT) we also searched for binding sites for NFAT in the pancreas specific P2 promoter of HNF4alpha. Notably, we observed repressed NFAT binding to a novel DNA binding site in the P2 promoter of HNF4alpha. Thus, cyclosporine caused inhibition of DNA binding of two important regulators for insulin signaling, i.e. NFAT and HNF4alpha. We further investigated HNF4alpha transcript expression and observed >200-fold differences in abundance in n = 14 patients. Such variability in expression might help to identify individuals at risk for developing PTDM. We propose cyclosporine to repress HNF4alpha gene and protein expression, DNA-binding to targeted promoters and subsequent regulation of genes coding for glucose metabolism and of pancreatic beta-cell function.
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PMID:HNF4alpha and HNF1alpha dysfunction as a molecular rational for cyclosporine induced posttransplantation diabetes mellitus. 1925 40


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