Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine aminotransferase (TAT) is a liver-specific enzyme whose activity is subject to positive regulation by several agents including insulin and agonists that increase the intracellular concentration of cAMP. To further characterize the mechanism of insulin action and the interaction between cAMP and insulin several types of experiments were performed in a rat hepatoma cell-line. In the presence of the transcriptional inhibitor 5,6-dichloro-1-beta-D-ribofuranoyslbenzimidazole, TAT enzyme activity remains inducible by insulin and to a lesser extent by the cAMP analog (Bu)2cAMP. This suggests that transcriptional events are not necessary for the insulin-mediated increase in TAT activity, and also suggests a dualistic mechanism for the cAMP-induced increase in TAT activity. Surprisingly, using a cDNA probe for mRNATAT, it was found that insulin causes a decrease in hybridizable mRNATAT, in addition to causing a partial inhibition of the increase of hybridizable TAT transcript caused by (Bu)2cAMP. Examination of the rate of transcription of the TAT gene by a nuclear run-off assay shows that insulin causes a decrease in the transcription of the TAT gene by greater than 50%, which is sufficient to account for the decrease in hybridizable mRNATAT. As expected (Bu)2cAMP increases the transcription of TAT, but combined with insulin a complete inhibition of the increase in TAT transcription caused by (Bu)2cAMP is observed. To address the possibility that insulin acts posttranslationally to increase TAT activity, the t1/2 of TAT protein was measured in the presence and absence of insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of tyrosine aminotransferase by insulin and cyclic AMP: similar effects on activity but opposite effects on transcription. 257 13

A patient with long lasting non-parathyroid hormone mediated hypercalcaemia occurring within the context of hepatitis B virus chronic hepatitis is reported. Hepatocellular carcinoma and bone malignancy were carefully excluded. The biological pattern associated hypercalcaemia with normal phosphataemia, low nephrogenic cAMP level and high level of tubular reabsorption of phosphate. The usual causes of hypercalcaemia were ruled out. Hypercalcaemia may represent a rare biological feature of some advanced liver disease. The underlying mechanisms remain to be elucidated.
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PMID:Hypercalcaemia associated with chronic viral hepatitis. 260 2

Apart from kidney, where renin synthesis takes place in all mammals, the submaxillary gland (SMG) of most mouse strains constitutes an important source of an isoenzyme, renin-2, that is highly homologous to renal renin, but unglycosylated [(1982) Nature 298, 90-92]. This unique phenotype is due to the presence of an extra copy of th renin gene. A puzzling observation is that (pro)renin-2 cannot be detected in the kidney of these animals, although both mRNAs accumulate at similar levels [(1985) Proc. Natl. Acad. Sci. USA 82, 6196-6200]. In order to investigate whether (pro)renin-2 expression is detectable in mouse heterologous cell lines we transfected the renin-2 cDNA into AtT20 (pituitary corticotrope) and BTG9A (hepatoma) cells. Stable clones expressing renin were obtained in both cases. BTG9A cells secreted only prorenin while AtT20 cells secreted prorenin and active renin. In addition, in AtT20 cells the secretion of active renin was stimulated by 8-Br cAMP. Our results show that unglycosylated (pro)renin-2 can be expressed and secreted in two murine cell lines. Moreover, it is correctly processed to active renin and secreted upon stimulation in AtT20 cells.
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PMID:Sta!le and transient expression of mouse submaxillary gland renin cDNA in AtT20 cells: proteolytic processing and secretory pathways. 264 24

The multihormonal regulation of phosphoenolpyruvate carboxykinase (PEPCK) was studied using chimeric genes composed of various regions of the PEPCK gene promoter region fused to the coding sequence of the chloramphenicol acetyltransferase (CAT) gene. These constructions, transfected into H4IIE hepatoma cells, are regulated like the endogenous PEPCK gene: dexamethasone and cAMP both stimulate PEPCK-CAT gene expression and their effects are additive; insulin inhibits the individual or combined effects of these stimulatory agents; and insulin inhibits dexamethasone-stimulated PEPCK-CAT fusion gene expression in a concentration-dependent fashion that is half-maximal at 10(-11) M. The induction by dexamethasone and the inhibition by insulin is specific for the DNA sequences that flank the 5' end of the PEPCK gene because similar effects were not observed for a plasmid in which the promoter and enhancer sequences of simian virus 40 (SV40) are fused to CAT. These results imply that the DNA adjacent to the transcription start site of the PEPCK gene contains the cis-acting hormone response elements responsible for the multihormonal regulation of this gene, including the insulin response.
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PMID:Multihormonal regulation of phosphoenolpyruvate carboxykinase-chloramphenicol acetyltransferase fusion genes. Insulin's effects oppose those of cAMP and dexamethasone. 282 6

At non-cytotoxic concentrations, actions of smooth muscle relaxants except for the action of isoproterenol (IPN) on the effect of vinblastine (VBL) and mitomycin C (MMC) in rat ascites hepatoma AH66 cells resistant to these antitumor agents clearly separated into two groups. IPN hardly influenced the effects of both VBL and MMC. Although verapamil, a calcium-antagonist, and W-7, a calmodulin inhibitor, enhanced the growth-inhibitory effect and uptake of VBL by inhibiting the VBL efflux, these drugs did not influence the effect and uptake of MMC. In contrast, forskolin, an adenylate cyclase activator, db-cAMP, a cAMP analog, and theophylline, a cyclic nucleotide phosphodiesterase inhibitor, potentiated the effect of MMC, but did not influence the effect of VBL. The combination effect of forskolin and db-cAMP might be elucidated from the increase of inward transport of MMC through the action of the intracellular cAMP elevated by these drugs. Theophylline, however, only slightly increased both intracellular cAMP level and MMC uptake into the cells, similar to the action of IPN. We thought that the combination effect of theophylline was effected through its other activity of repair inhibition against AH66 cells, which are resistant to MMC due to their high capacity to repair impaired DNA. Thus, the smooth muscle relaxants used in this study enhanced the growth-inhibitory effect of a distinct antitumor agent through their individual activity against tumor cells.
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PMID:Multiform combination effects of smooth muscle relaxants with antitumor agents in rat ascites hepatoma AH66 cells. 282 96

The purpose of this study was to determine whether changes in ADP-ribosylation affect expression of the gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) in H4IIE hepatoma cells. Treatment with 3-aminobenzamide, a specific inhibitor of poly(ADP ribose) synthetase, caused an 89% decrease of ADP-ribosylation in isolated nuclei, and resulted in a two- to threefold induction of immunoassayable PEPCK in cultured cells. In contrast, the structurally related compound p-aminobenzoic acid had no significant effect on either process. In vivo labeling of proteins with [35S]methionine, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography, showed that the induction of immunoreactive PEPCK by 3-aminobenzamide was due to a selective increase in the synthesis of the protein. The specific induction of PEPCK synthesis by 3-aminobenzamide was accounted for by a twofold increase of mRNAPEPCK which reached its maximal value 4 h after the addition of 3-aminobenzamide and returned to the basal level by 10 h. A possible role of ADP-ribosylation in cAMP or glucocorticoid induction of PEPCK was investigated in experiments in which H4IIE cells were treated with combinations of 3-aminobenzamide and either dexamethasone or a cAMP analog. In each case the effects on PEPCK induction were additive, indicating that glucocorticoids and cAMP induce PEPCK by pathways different from that used by 3-aminobenzamide.
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PMID:3-Aminobenzamide inhibits poly(ADP ribose) synthetase activity and induces phosphoenolpyruvate carboxykinase (GTP) in H4IIE hepatoma cells. 282 39

The chronic effect of cAMP-dependent regulation on adrenocortical steroidogenesis is known to be revealed in the stimulation of the biosynthesis of steroidogenic enzymes. P-450(SCC), one of the enzymes, catalyzes the first and the rate-limiting reaction in steroidogenesis from cholesterol and its synthesis is regulated by cAMP. In order to investigate cis-acting DNA elements of this gene in response to cAMP-dependent regulation, we have constructed a fusion gene (pSCC5.4k) by ligating the 5'-flanking and the upstream untranslated region (5.4 kb) of the human P-450(SCC) gene to the structural gene for chloramphenicol acetyltransferase (CAT) and transfected it into various culture cells including Y-1 (mouse adrenal tumor), L929 (mouse fibroblast), HTC (rat hepatoma) and Hepa-1 (mouse hepatoma). Only Y-1 cells transfected with pSCC5.4k were found to express transiently the enhanced CAT activity in response to the cAMP analogue, cyclic dibutyryl-AMP (Bt2cAMP). Primer-extension analysis of RNA prepared from the cells treated with or without Bt2cAMP showed that the enhanced CAT activity was due to an increase in the CAT mRNA and that the transcription start site, determined here with the human P-450 gene in the adrenal cortex, was correctly utilized with the fusion gene in the transient expression system. Forskolin and cholera toxin, activators of adenylate cyclase, also increased the expression of the CAT activity in the Y-1 cells. It has been demonstrated, therefore, that the cAMP-dependent regulation of the P-450(SCC) gene in adrenal cortex is faithfully reflected in the transient expression system using Y-1 cells and the fusion gene and that a cis-acting DNA element(s) in response to cAMP is present within the 5'-flanking sequence (5.4 kb) of the P-450(SCC) gene.
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PMID:The 5'-flanking region of the human P-450(SCC) gene shows responsiveness to cAMP-dependent regulation in a transient gene-expression system of Y-1 adrenal tumor cells. 283 Oct 49

Human urinary bladder carcinoma cells (JTC-32) retain a low alkaline phosphatase activity. Prednisolone or a hypertonic concentration of NaCl caused a moderate increase in the activity (10- to 15-fold of control), but dibutyryl cAMP or butyrate did not. Examination of the combined effect of these four agents revealed that they acted synergistically in any combination. When the cells were incubated with the four agents together, the enzyme activity increased 60- to 250-fold. Serum also contributed to this synergistic increase. These agents slightly inhibited cell growth and protein synthesis. The enzyme induction was completely inhibited by cycloheximide or actinomycin D. The synergistic effect of the four agents on the enzyme activity was also observed in other strains of carcinoma cells, human urinary bladder carcinoma cells (JTC-30) and monkey hepatocarcinoma cells (NCLP-6E). Thus, it is concluded that the coexistence of the four agents provides general and superior conditions for the induction of alkaline phosphatase in cultured carcinoma cells.
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PMID:Induction of alkaline phosphatase activity by synergistic action of dibutyryl cyclic adenosine monophosphate, prednisolone, butyrate and sodium chloride in cultured cells. 283 93

Nuclei isolated from H4IIE rat hepatoma cells were used in an in vitro run-on assay, with probes directed against various regions of the phosphoenolpyruvate carboxykinase [GTP: oxaloacetate carboxy-lyase (transphosphorylating); EC 4.1.1.32] gene, to analyze whether transcription proceeds uniformly across this gene in response to insulin and cAMP treatment. Fewer polymerase II complexes were associated with the phosphoenolpyruvate carboxykinase gene after insulin treatment, as compared with cAMP-treated cells, but they were distributed uniformly, so insulin does not block transcription at a discrete site, nor does it cause gradual, but progressive, premature termination. The phosphoenolpyruvate carboxykinase primary transcript was synthesized at a rate of about 2500 nucleotides per min in cAMP-treated cells and about 1000 nucleotides per min in insulin-treated cells. Thus insulin retards transcript elongation in comparison with cAMP, but this action does not account for the total effect insulin has on transcription. After insulin treatment, few, if any, nascent transcripts are associated with the first 69 nucleotides of the gene, whereas in cAMP-treated cells the opposite is true. These observations lead us to suggest that both insulin and cAMP exert their primary effects directly at the level of transcription initiation, but in opposite ways.
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PMID:Regulation of phosphoenolpyruvate carboxykinase gene transcription by insulin and cAMP: reciprocal actions on initiation and elongation. 283 22

It is now well established that cAMP induces the transcription rate of the gene for phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) and that this induction is dependent on a nucleotide domain located within the promoter-regulatory region of the gene (Short, J. M., Wynshaw-Boris, A., Short, H. P., and Hanson, R. W. (1986) J. Biol. Chem. 261, 9721-9726). We report here that cAMP also stabilizes phosphoenolpyruvate carboxykinase mRNA against degradation. Using two independent experimental approaches, we show that the half-life of the mRNA for phosphoenolpyruvate carboxykinase is extended when FTO-2B rat hepatoma cells are exposed to dibutyryl cyclic AMP (Bt2cAMP). In the first experiment, the rate of decay of phosphoenolpyruvate carboxykinase mRNA was determined in cells incubated in the presence of insulin, which has been shown to block the transcription rate of the gene for the enzyme. Under these conditions, the half-life of phosphoenolpyruvate carboxykinase mRNA was 30 min. However, in cells incubated in the presence of Bt2cAMP, the mRNA decayed with a half-life of 150 min. In the other experiment, mRNA stability was measured under steady state conditions, utilizing a "pulse-chase" approach. The apparent half-life of phosphoenolpyruvate carboxykinase mRNA increased from 40 min to over 250 min in Bt2cAMP-treated cells. No significant change in the stability of total cellular RNA was noted. Other experiments have shown that the transcription rate of the gene for phosphoenolpyruvate carboxykinase peaks within the first 20 min after exposing the cells to Bt2cAMP and then levels off, while the abundance of the mRNA reaches a maximum at about 90 min and remains at this level thereafter. Thus, the long term effect of cAMP on the expression of the gene coding for phosphoenolpyruvate carboxykinase occurs at least in part, through an alteration in the degradation rate of the mRNA for this enzyme.
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PMID:Cyclic AMP stabilizes the mRNA for phosphoenolpyruvate carboxykinase (GTP) against degradation. 283 95


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