UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic AMP treatment of hepatoma cells leads to increased protein binding at the cyclic AMP response element (CRE) of the tyrosine aminotransferase (TAT) gene in vivo, as revealed by genomic footprinting, whereas no increase is observed at the CRE of the phosphoenolpyruvate carboxykinase (PEPCK) gene. Several criteria establish that the 43 kDa CREB protein is interacting with both of these sites. Two classes of CRE with different affinity for CREB are described. One class, including the TATCRE, is characterized by asymmetric and weak binding sites (CGTCA), whereas the second class containing symmetrical TGACGTCA sites shows a much higher binding affinity for CREB. Both classes show an increase in binding after phosphorylation of CREB by protein kinase A (PKA). An in vivo phosphorylation-dependent change in binding of CREB increases the occupancy of weak binding sites used for transactivation, such as the TATCRE, while high affinity sites may have constitutive binding of transcriptionally active and inactive CREB dimers, as demonstrated by in vivo footprinting at the PEPCK CRE. Thus, lower basal level and higher relative stimulation of transcription by cyclic AMP through low affinity CREs should result, allowing finely tuned control of gene activation.
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PMID:Phosphorylation of CREB affects its binding to high and low affinity sites: implications for cAMP induced gene transcription. 135 12

Fatty acid metabolism has been studied in Fao rat hepatoma cells. In basal conditions of culture, [1-14C]oleate is mainly esterified (85% of oleate uptake) in Fao cells, phospholipids being the most important esterified products (60% of oleate esterified). Addition of N6,O2'-dibutyryl-adenosine 3',5'-monophosphate (0.1 mM) in Fao cells does not change the metabolic fate of oleate whereas it induces gluconeogenesis and phosphoenolpyruvate carboxykinase mRNA accumulation. It is shown that the limitation of oleate oxidation is located at the level of the entry into mitochondria since octanoate is actively oxidized in Fao cells. Neither the activities of carnitine palmitoyltransferase (CPT) I and II nor the CPT II protein amount are affected by cAMP addition. The limitation of oleate oxidation in Fao cells results from (a) a high rate of lipogenesis and a high malonyl-CoA concentration, (b) a CPT I very sensitive to malonyl-CoA inhibition. The presence of an active oleate oxidation in mitochondria isolated from Fao cells confirms that CPT I is the limiting step of oleate oxidation. Moreover, Fao cells are unable to perform ketogenesis. This particular feature results from a specific deficiency in mitochondrial hydroxymethylglutaryl-CoA synthase protein, activity and gene expression. The metabolic characteristics observed in Fao cells could be a common feature in hepatoma cell lines with regard to the low capacity for long-chain fatty acid oxidation and ketone body production observed in the rat H4IIE and the human HepG2 cells.
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PMID:Evidence for an impaired long-chain fatty acid oxidation and ketogenesis in Fao hepatoma cells. 135 69

Incubation of isolated hepatocytes from fasted rats with 20 mM LiCl for 1 h decreased glucose production from lactate, pyruvate, and alanine. In addition, phosphoenolpyruvate carboxykinase (PEPCK) gene expression in FTO-2B rat hepatoma cells was inhibited by treatment with LiCl. Lithium was also able to counteract the increased PEPCK mRNA levels caused by both Bt2cAMP and dexamethasone, in a concentration-dependent manner. A chimeric gene containing the PEPCK promoter (-550 to +73) linked to the amino-3-glycosyl phosphotransferase (neo) structural gene was transduced into FTO-2B cells using a Moloney murine leukemia virus-based retrovirus. In these infected cells, 20 mM LiCl decreased both the concentration of neo mRNA transcribed from the PEPCK-neo chimeric gene and mRNA from the endogenous PEPCK gene. Lithium also inhibited the stimulatory effect of Bt2cAMP and dexamethasone on both genes. The stability of neo mRNA was not altered by lithium, since in cells infected with retrovirus containing only the neo gene transcribed via the retroviral 5'-LTR and treated with 20 mM LiCl, no change in neo mRNA levels was observed. The intraperitoneal administration of LiCl to rats caused a decrease in hepatic PEPCK mRNA, indicating that lithium could also modify gene expression in vivo. The effects of lithium were not due to an increase in the concentration of insulin in the blood but were correlated with an increase in hepatic glycogen and fructose 2,6-bisphosphate levels. These results indicate that lithium ions, at concentrations normally used therapeutically for depression in humans, can inhibit glucose synthesis in the liver by a mechanism which can selectively modify the expression of hepatic phosphoenolpyruvate carboxykinase.
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PMID:Lithium inhibits hepatic gluconeogenesis and phosphoenolpyruvate carboxykinase gene expression. 137 Nov 8

The decreased synthesis of hepatic phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme of gluconeogenesis, that occurs during endotoxemia was shown previously in rats to occur at the transcriptional level. In the current study, the exogenous administration of human recombinant tumor necrosis factor (TNF), a proximal mediator of endotoxic shock, reduced the PEPCK transcription rate, mRNAPEPCK levels, and PEPCK enzyme activity in a time- and dose-dependent manner in CD-1 mice. Comparable amounts of circulating TNF were measured in mice 2 h after injection of human recombinant TNF (10(5) U) or a 50% lethal dose of Escherichia coli endotoxin (20 mg/kg). Direct action of TNF to decrease the PEPCK transcription rate was confirmed in vitro with H-4-II-E Reuber hepatoma cells, in which a dose-dependent inhibition of PEPCK transcription was observed with 1 to 100 U of TNF per ml. A role for TNF-elicited changes in PEPCK gene expression during endotoxemia was confirmed by the protective effect of rabbit polyclonal antibodies to recombinant murine TNF. C57BL/6 mice passively immunized with anti-TNF 4 h prior to endotoxin challenge exhibited normal PEPCK enzyme activity. Neutralization of circulating TNF with anti-TNF failed, however, to prevent the hypoglycemia commonly observed during endotoxemia, suggesting the participation of other mediators. Anti-TNF treatment reduced circulating interleukins 1 and 6 at 3 and 6 h after endotoxin treatment, respectively. These results suggest that during endotoxemia, the development of hypoglycemia is multifaceted and that several cytokines are most likely involved. The findings from the Reuber hepatoma cell model afford an opportunity in future work to map putative cytokine response elements in the PEPCK promoter responsible for perturbed hormonal regulation of the gene during endotoxemia.
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PMID:Identification of tumor necrosis factor as a transcriptional regulator of the phosphoenolpyruvate carboxykinase gene following endotoxin treatment of mice. 139 16

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

The ability of a retinoic acid (RA) response element (RARE) in the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter to mediate effects of either RA or thyroid hormone (T3) on gene expression was studied. Fusion gene constructs consisting of PEPCK promoter sequences ligated to the chloramphenicol acetyltransferase (CAT) reporter gene were used for this analysis. While T3 induced CAT expression to a small degree (about twofold) when such constructs were transiently transfected into H4IIE rat hepatoma cells, along with an expression vector encoding the alpha subtype of the T3 receptor (TR), this effect was mediated by promoter sequences distinct from the PEPCK RARE. Although TRs were capable of binding the PEPCK RARE in the form of putative monomers, dimers, and heterodimers with RA receptors (RARs), this element failed to mediate any positive effect of T3 on gene expression. In contrast, the PEPCK RARE mediated six- to eightfold induction of CAT expression by RA. When TRs were coexpressed along with RARs in transfected H4IIE cells, this RA induction was substantially blunted in a T3-independent manner. This inhibitory effect may be due to the binding of nonfunctional TRs or TR-RAR heterodimers to the PEPCK RARE. A model is proposed to explain the previously observed in vivo effects of T3 on PEPCK gene expression.
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PMID:Specificity of a retinoic acid response element in the phosphoenolpyruvate carboxykinase gene promoter: consequences of both retinoic acid and thyroid hormone receptor binding. 194 93

The present study investigates the effect of glucose on the gene expression of the hepatic glucoregulatory enzyme, phosphoenolpyruvate carboxykinase (PPrvck). By use of hepatocytes in culture and FAO hepatoma cells it could be demonstrated that glucose suppressed the effect of dibutyryl cyclic AMP (Bt2cAMP), glucocorticoids or both, to increase PPrvck mRNA and consequently PPrvck enzyme activity. Glucose had a dual effect; it reduced PPrvck gene transcription and it accelerated the rate of PPrvck mRNA degradation. The effect was specific for glucose, as glucose-related carbohydrates such as mannose, galactose and sorbitol were without effect on PPrvck mRNA. The repressive effect of glucose was limited to certain proteins; glucose had no effect on Bt2cAMP and glucocorticoid provoked induction of tyrosine aminotransferase (TAT). Also the pattern of mRNA in vitro translation products was virtually unaffected when FAO hepatoma cells were incubated either in the presence or absence of glucose, demonstrating the specificity of the effect of glucose on gene expression of selected proteins. In FAO hepatoma cells and in hepatocytes in culture, insulin, like glucose, also decreased PPrvck mRNA. While the effect of glucose and insulin was additive in FAO hepatoma cells, in primary hepatocytes in culture an effect of glucose by itself on PPrvck mRNA could only be demonstrated in the absence of insulin. Correspondingly also in vivo, the effect of glucose was demonstrated in the absence of insulin (provoked by streptozotocin diabetes); glucose application reduced the amount of hepatic PPrvck mRNA. To summarize, glucose is capable of suppressing the effect of glucocorticoids and Bt2cAMP on increasing the PPrvck mRNA level. The carbohydrate reduces the rate of PPrvck gene transcription and accelerates the rate of PPrvck mRNA degradation. While in FAO hepatoma cells the effect is evident in the presence of insulin, in hepatocytes in culture the effect of glucose cannot be demonstrated in the presence of insulin, questioning its role under physiological conditions.
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PMID:Transcriptional and post-transcriptional effects of glucose on liver phosphoenolpyruvate-carboxykinase gene expression. 166 21

The ability of an inositol phosphate-glycan (IPG) to mimic the effects of insulin on regulation of the expression of specific mRNAs was studied in isolated hepatocytes from normal and diabetic rats. Incubation of normal liver cells with IPG (10 microM) during 90 min produced a 5-fold decrease in phosphoenolpyruvate carboxykinase (PEPCK) mRNA levels, which had been previously increased about 10-fold by incubation with 8-bromo-cAMP (0.1 mM). The effect of IPG was dose dependent and could not be reproduced by galactose, glucosamine, or myo-inositol. IPG reduction of PEPCK mRNA is primarily due to a decrease in the rate of transcription of the gene, as judged by nuclear run-on transcription experiments performed in rat hepatoma H4IIE cells. In hepatocytes isolated from diabetic rats, treatment with 5 microM IPG for 15 min caused a 4-fold induction in the expression of alpha 2-microglobulin mRNA concomitantly with a 2.5-fold decrease in the level of PEPCK mRNA. Cleavage of IPG with nitrous acid abolished both the increase and the decrease in specific mRNAs levels. Glycosyl-phosphatidylinositol, the lipid precursor of IPG, did not modify either PEPCK or alpha 2-microglobulin mRNA levels. These data indicate that both positive and negative effects of insulin on the regulation of gene expression are mimicked by IPG.
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PMID:Insulin-like effects of inositol phosphate-glycan on messenger RNA expression in rat hepatocytes. 171 85

Ochratoxin A has a number of toxic effects in mammals, the most notable of which is nephrotoxicity. It is also immunosuppressive, teratogenic and carcinogenic. The biochemical and molecular aspects of its action were first studied in bacteria. The appearance of 'magic spots' (ppGpp and pppGpp) pointed to inhibition of the charging of transfer ribonucleic acids (tRNA) with amino acids. This suggestion was confirmed by the demonstration that ochratoxin A inhibits bacterial, yeast and liver phenylalanyl-tRNA synthetases. The inhibition is competitive to phenylalanine and is reversed by an excess of this amino acid. As a consequence, protein synthesis is inhibited, as shown with hepatoma cells in culture, with Madin Darby canine kidney cells (which are much more sensitive) and in vivo in mouse liver, kidney and spleen, the inhibition being more effective in the latter two organs. An excess of phenylalanine also prevents inhibition of protein synthesis in cell cultures and in vivo. Analogues of ochratoxin A in which phenylalanine has been replaced by other amino acids have similar inhibitory effects on the respective amino acid-specific aminoacyl tRNA synthetases. 4R-Hydroxyochratoxin A, a metabolite of ochratoxin A, has a similar action, whereas ochratoxin alpha (the dihydroisocoumarin moiety) and ochratoxin B (ochratoxin A without chlorine) have no effect. Ochratoxin A might act on other enzymes that use phenylalanine as a substrate. We showed recently that it inhibits phenylalanine hydroxylase. In addition, the phenylalanine moiety of ochratoxin A is partially hydroxylated to tyrosine by incubation with hepatocytes and in vivo. This competitive action with phenylalanine might explain why this amino acid prevents the immuno-suppressive effect of ochratoxin A and partially prevents its teratogenic and nephrotoxic actions. The effect of ochratoxin A on protein synthesis is followed by an inhibition of RNA synthesis, which might affect proteins with a high turnover. Ochratoxin A also lowers the level of phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis; this inhibition is reported to be due to a specific degradation of mRNA that codes for this enzyme. Recently, ochratoxin A was also found to enhance lipid peroxidation both in vitro and in vivo. This inhibition might have an important effect on cell or mitochondrial membranes and be responsible for the effects on mitochondria that have been shown by several authors. Finally, the recent results of Pfohl-Leszkowicz et al. (this volume), who showed the formation of DNA adducts mainly in kidney but also in liver and spleen, explain the DNA single-strand breaks observed previously in mice and rats after acute and chronic treatment.
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PMID:Mechanism of action of ochratoxin A. 182 Mar 32

The interaction of promoters contained in a Moloney murine leukemia virus (MoMLV)-based retroviral vector was studied after infection of FTO-2B rat hepatoma and NIH 3T3 mouse fibroblast cells. Segments of the phosphoenolpyruvate carboxykinase (PEPCK) promoter-regulatory region, which are known from previous studies to confer responsiveness to hormones, were linked to the structural genes for bovine growth hormone, amino-3'-glycosyl phosphotransferase (neo), and herpes-virus thymidine kinase and inserted into a MoMLV-based retroviral vector. In vectors in which PEPCK was the only internal promoter, it was the major site of gene transcription. This dominant effect was independent of the orientation of the PEPCK promoter relative to the 5' long terminal repeat of the provirus and was noted with as little as -174 base pairs of the 5'-flanking sequence. NIH 3T3 cells, which do not express the endogenous PEPCK gene, transcribed the transduced PEPCK-chimeric genes at the same high levels as was observed in hepatoma cells. When two promoters were present in the provirus, the expression of chimeric structural genes depended on the relative position and orientation of these genes as well as the type of cell infected by the retrovirus. Differential responses of proviral promoters in infected cells were also observed in the presence of hormones. Dibutyryl cyclic AMP increased the expression of genes linked to the PEPCK promoter in FTO-2B and NIH 3T3 cells, whereas glucocorticoids stimulated transcription from both the PEPCK promoter and the long terminal repeat in FTO-2B cells. The effect of these hormones on transcription of proviral promoters depended on their position relative to the 5' long terminal repeat. In contrast, insulin uniformly inhibited transcription from the PEPCK promoter in a position-independent manner but only in hepatoma cells and not in fibroblasts. In clonally isolated FTO-2B cells infected with a retrovirus, the site of proviral integration was also a major factor determining the expression and hormonal regulation from the internal promoters. The data suggest that the hormonal regulation of the expression of genes contained in retroviral vectors depends on the type and position of the regulatory elements present in the provirus and the lineage of the infected cell.
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PMID:Hormonal control of interacting promoters introduced into cells by retroviruses. 202 56

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