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)

The effect of the tumor promoter phorbol 12-myristate 13-acetate (PMA) on expression of the P-enolpyruvate carboxykinase gene was studied in rat hepatoma H4IIE cells. Like insulin, PMA provokes a concentration and time-dependent decrease of mRNA coding for that enzyme that is due to an inhibition of P-enolpyruvate carboxykinase gene transcription. This effect of PMA is rapid, reversible, specific for phorbol esters known to be active in other systems, and it does not require on-going protein synthesis. PMA overrides the stimulatory effects cAMP and glucocorticoid analogs have on the transcription of this gene. A synthetic diacylglycerol, sn-1,2-dioctanoylglycerol, also inhibits P-enolpyruvate carboxykinase gene transcription. These effects of PMA and synthetic diacylglycerol are specific, since neither affected total mRNA synthesis. We conclude that diacylglycerol and phorbol esters, specific stimulators of protein kinase C, inhibit the transcription of P-enolpyruvate carboxykinase gene in H4IIE cells. The findings support the hypothesis that diacylglycerols generated in the plasma membrane can act as an intracellular signal that regulates specific gene expression.
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PMID:The effect of phorbol esters and diacylglycerol on expression of the phosphoenolpyruvate carboxykinase (GTP) gene in rat hepatoma H4IIE cells. 302 68

The role that protein kinase C (PKC) may play on insulin regulation of glucose metabolism was investigated in rat adipocytes and Zajdela hepatoma cultured (ZHC) cells which are two cell types highly responsive to insulin. In rat adipocytes, 4 beta-phorbol 12 beta-myristate, 13 alpha-acetate (PMA, 0.1-1,000 ng/ml), a potent tumor promoter acting as a substitute for diacylglycerol which directly activates PKC, stimulated basal 2-deoxyglucose (2-DG) transport in a time- and dose-dependent manner, but decreased the activation of this process elicited by submaximal concentrations of insulin. PMA (0.1-1,000 ng/ml) also stimulated basal lipogenesis from [3-3H] glucose in a dose-dependent manner. Maximal PMA and insulin effects on both processes were not additive. The specificity of the insulin-like effects of PMA was assessed by the finding that 4 beta-phorbol 12, 13 dibutyrate (PDBu), mezerein, 1-oleyl-2-acetyl glycerol (OAG) and 1, 2 diolein, know as PKC activators, also markedly stimulated glucose metabolism whereas 4 alpha-phorbol 12, 13 didecanoate (4 alpha-PDD) and 4 beta-phorbol 13-monoacetate, shown not to activate PKC, were ineffective. PMA and insulin biological effects exhibited several similarities: both agents stimulated glucose transport and lipogenesis in a calcium-dependent manner, both activated glucose transport through an energy-requiring process, and the effects of both were markedly decreased by mellitin, a PKC inhibitor. Finally, fat cells made PKC-deficient by a chronic treatment with PMA exhibited a marked decrease in insulin responsiveness for stimulation of glucose transport and lipogenesis, with no change in either the hormone sensitivity or the insulin receptor affinity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Regulation of glucose metabolism by insulin: dual role of protein kinase C]. 305 80

PLC/PRF/5 hepatoma cells cultured with a tumor promoter teleocidin showed polygonal cellular appearance with many vacuole-like structures, and reduced both c-myc mRNA level and growth rate. These teleocidin effects were partly mimicked by sodium butyrate but not by a protein kinase C stimulant 1-oleoyl-2-acetylglycerol(OAG). Protein kinase C inhibitor 1-(5-isoquinolinyl-sulfonyl)-2-methyl-piperazine(H7), calmodulin-dependent protein kinase antagonist N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide(W7) and topoisomerase II inhibitor novobiocin failed to inhibit the effects of teleocidin. These results may suggest the presence of still unknown biochemical pathways which mediate the actions of teleocidin.
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PMID:Effects of teleocidin on the morphology and c-myc expression of hepatoma cells which are not inhibited by protein kinase antagonists. 310 17

We have compared the effect of phorbol 12-myristate 13-acetate (PMA) with that of insulin on three targets of insulin action in H4IIEC3 (H4) rat hepatoma cells. These parameters are the phosphorylation state and tyrosine kinase activity of the insulin receptor, the activation state of glycogen synthase, and the accumulation of p33 mRNA. Under conditions where insulin treatment of H4 cells clearly activated receptor serine and tyrosine phosphorylation on the insulin receptor beta-subunit in situ, activated receptor tyrosine kinase activity in vitro, and activated glycogen synthase and p33 mRNA accumulation in situ, PMA alone did not influence the insulin receptor phosphorylation state or tyrosine kinase activity and did not affect glycogen synthase activity, but markedly increased p33 mRNA accumulation. When PMA was added in the presence of insulin, particularly if PMA was preincubated, the receptor phosphorylation state and the tyrosine kinase activity again were not affected, but insulin-activated glycogen synthase was significantly diminished or abolished. In contrast, increased p33 mRNA accumulation by PMA was additive with that of insulin. Thus, under conditions where no effect was observed on the insulin receptor phosphorylation state or the tyrosine kinase activity, PMA acted in an insulin-antagonistic manner on glycogen synthase and in an insulin-like manner on p33 mRNA accumulation, indicating that these actions of PMA are unrelated to early events in the pathway of the insulin action. Effects on glycogen synthase are most readily explained by an effect of protein kinase C-activated phosphorylation of glycogen synthase.
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PMID:Contrasting interactions between phorbol ester and insulin on the regulation of glycogen synthase activity and p33 mRNA accumulation in rat hepatoma cells. 312 51

The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the function of the insulin receptor was examined in intact hepatoma cells (Fao) and in solubilized extracts purified by wheat germ agglutinin chromatography. Incubation of ortho[32P]phosphate-labeled Fao cells with TPA increased the phosphorylation of the insulin receptor 2-fold after 30 min. Analysis of tryptic phosphopeptides from the beta-subunit of the receptor by reverse-phase high performance liquid chromatography and determination of their phosphoamino acid composition suggested that TPA predominantly stimulated phosphorylation of serine residues in a single tryptic peptide. Incubation of the Fao cells with insulin (100 nM) for 1 min stimulated 4-fold the phosphorylation of the beta-subunit of the insulin receptor. Prior treatment of the cells with TPA inhibited the insulin-stimulated tyrosine phosphorylation by 50%. The receptors extracted with Triton X-100 from TPA-treated Fao cells and purified on immobilized wheat germ agglutinin retained the alteration in kinase activity and exhibited a 50% decrease in insulin-stimulated tyrosine autophosphorylation and phosphotransferase activity toward exogenous substrates. This was due primarily to a decrease in the Vmax for these reactions. TPA treatment also decreased the Km of the insulin receptor for ATP. Incubation of the insulin receptor purified from TPA-treated cells with alkaline phosphatase decreased the phosphate content of the beta-subunit to the control level and reversed the inhibition, suggesting that the serine phosphorylation of the beta-subunit was responsible for the decreased tyrosine kinase activity. Our results support the notion that the insulin receptor is a substrate for protein kinase C in the Fao cell and that the increase in serine phosphorylation of the beta-subunit of the receptor produced by TPA treatment inhibited tyrosine kinase activity in vivo and in vitro. These data suggest that protein kinase C may regulate the function of the insulin receptor.
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PMID:Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity. 312 81

The heterogeneity of protein kinase C (PKC) derived from rat liver and the Zajdela hepatoma was studied by sodium dodecyl sulfate electrophoresis in polyacrylamide gel. Proteins with PKC-activity of molecular weight equal to 67,000 Da and 80,000 Da and an active fragment of 50,000 Da were detected in samples from the normal rat liver. The samples from the Zajdela hepatoma contained PKC with molecular weight equal to 67,000 Da and the active fragment of 50,000 Da. PKC with molecular weight of 80,000 Da was absent.
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PMID:[Comparative study of protein kinase C in the normal rat liver and in Zajdela's hepatoma. I. Electrophoretic analysis]. 324 94

Insulin stimulation of glycogen synthesis was nearly abolished in hepatoma cells shortly treated with 4 beta-phorbol 12 beta-myristate, 13 alpha-acetate (protein kinase C activation) but remained unmodified in cells chronically treated with the phorbol ester (protein kinase C depletion). Thus, although exogenous activation of protein kinase C results in an inhibition of insulin action, protein kinase C depletion has no influence on this process. The results suggest that, in hepatoma cells, no endogenous activation of protein kinase C may occur in response to the signal triggered by insulin.
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PMID:Effect of protein kinase C activation and depletion on insulin stimulation of glycogen synthesis in cultured hepatoma cells. 328 Mar 35

Insulin and tumor-promoting phorbol esters such as phorbol 12-myristate 13-acetate (PMA) share some biological activities in normal hepatocytes and in some lines of cultured hepatoma cells. To investigate the possibility that some of these common effects might involve a common pathway, we examined the effects of insulin and PMA on several biological processes in normal and protein kinase C-deficient H4IIE rat hepatoma cells. Protein kinase C deficiency was achieved by preincubating the cells in high concentrations of PMA, and was documented by direct enzyme measurement in soluble and particulate cellular fractions, and by analysis of immunoreactive protein kinase C concentrations in whole cellular homogenates. In the protein kinase C-deficient cells, the following actions of insulin remained at near normal levels: stimulated phosphorylation of the ribosomal protein S6; activation of a ribosomal S6 protein kinase; and increases in ornithine decarboxylase activity and mRNA accumulation. PMA stimulated all of these responses in the normal cells, but none of them in the PMA-pretreated cells. We conclude that insulin can exert some of its actions in a normal manner in protein kinase C-deficient H4IIE hepatoma cells (ATCC CRL 1548) and that some of the actions insulin holds in common with PMA may be due to common activation of one or more distal pathways. A candidate for such a distal step is activation of the ribosomal protein S6 protein kinase.
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PMID:Insulin action in normal and protein kinase C-deficient rat hepatoma cells. Effects on protein phosphorylation, protein kinase activities, and ornithine decarboxylase activities and messenger ribonucleic acid levels. 333 10

The role protein kinase C plays in the regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by insulin and phorbol esters was studied in H4IIE hepatoma cells (ATCC CRL 1548). The combined effects of phorbol 12-myristate 13-acetate (PMA) and insulin on the suppression of mRNA coding for PEPCK (mRNAPEPCK) synthesis were additive. A potent inhibitor of both cyclic nucleotide-dependent protein kinases and protein kinase C, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, inhibited the cAMP and PMA-mediated regulation of mRNAPEPCK synthesis, but did not affect the action of insulin. Desensitization of the protein kinase C pathway by exposure to PMA for 16 h abolished the subsequent action of the phorbol ester, but did not affect insulin- or cAMP-mediated regulation of PEPCK gene expression. We conclude that insulin suppresses PEPCK gene expression independently from the protein kinase C-mediated pathway used by phorbol esters.
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PMID:The inhibition of phosphoenolpyruvate carboxykinase (guanosine triphosphate) gene expression by insulin is not mediated by protein kinase C. 333 12

Activated c-raf(-1) gene was found in three transformants obtained by transfecting DNAs from rat hepatocellular carcinoma, metastasis of human colon cancer in mesocolon and normal mucosa from a different colon cancer patient. Rat and human activated c-raf(-1) genes were cloned into cosmid vectors; restriction enzyme mapping revealed both activated c-raf(-1) genes to have rearrangement in the center of the normal form of the gene, and the upstream sequences were replaced by unrelated sequences. Using genomic DNA fragments located immediately downstream of the recombination points, the activations of all these c-raf(-1) were shown to have occurred during the transfection process. The recombination points in both the rat and human clones isolated were located in the intron between exons 7 and 8, and nucleotide sequencing around these recombination points showed there to be an inverted repeat which could be involved in inducing in vitro recombination. Nucleotide sequencing of rat and human c-raf(-1) cDNAs revealed the upstream sequences, recombined to the 3' half of c-raf(-1), to be expressed as fusion mRNAs; the production of fused proteins was predicted from a long open reading frame, which is in-frame with the kinase domain encoded from the 3' half of the c-raf(-1) gene. There is a cysteine clustering region in an N-terminal region of the c-raf(-1) product deduced from the nucleotide sequence, and this cysteine clustering region was found to be highly homologous to that present in an N-terminal region of protein kinase C, although, in the latter cysteine clusters are present in duplicate. From analogy with the activation mechanism of protein kinase C, the N-terminal region of serine/threonine kinase coded by the c-raf(-1) gene is suggested to be a regulatory part of the enzyme activity, and it proposed that the replacement or truncation of this regulatory part could be the mechanism whereby c-raf(-1) is activated.
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PMID:Activation of rat and human c-raf(-1) by rearrangement. 333 22


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