Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genes for tryptophan oxygenase (TO) and tyrosine aminotransferase (TAT) are expressed in a tissue- and development-specific manner and are regulated by glucocorticoids (TO and TAT) and glucagon or its intracellular mediator cAMP (TAT) in rat liver. We have analyzed the chromatin structure of these genes in the vicinity of the 5' ends with regard to DNaseI hypersensitivity and have found DNaseI hypersensitive sites upstream of each of the promoters. Mapping of this region reveals three closely spaced cleavage sites near the TO promoter and a doublet of sites near the TAT promoter. In both genes additional cleavage sites are found further upstream. All hypersensitive sites of both genes are absent in kidney nuclei and therefore appear to be specific for the tissue expressing the genes. A correlation of expression and modified chromatin structure was also observed in a hepatoma cell line expressing TAT but not TO: hypersensitive sites are present in TAT but not in TO chromatin. Upon glucocorticoid induction an additional hypersensitive site is detected approximately 2 kb upstream of the TAT promoter in liver and hepatoma cells.
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PMID:Tissue-specific DNaseI hypersensitive sites in the 5'-flanking sequences of the tryptophan oxygenase and the tyrosine aminotransferase genes. 614 20

The studies described in this paper demonstrate rather conclusively the efficacy of the study of the regulation of gene expression in primary cultures of adult rat hepatocytes. The utilization of these cells in completely defined medium allows one to determine the exact environmental conditions for the regulation of the expression of specific genes. In the studies described in this work, we have demonstrated that the regulation of glucokinase involved three hormones, insulin, corticosteroids, and T3. In contrast, the regulation of an enzyme involved primarily in fatty acid metabolism, ATP-citrate lyase, required only insulin and T3 for its full expression. Cyclic GMP appeared to be involved in the regulation of glucokinase, but not ATP-citrate lyase, a fact that would be extremely difficult to demonstrate clearly in vivo. The regulation of the gluconeogenic enzyme, ornithine aminotransferase, in vitro involved only a single hormone, glucagon, the inhibition of induction by corticoid steroids demonstrable in vivo being absent in cell culture. However, the repressive effect of glucose on the induction of this enzyme was quite comparable to that seen in vivo and was not mediated through cyclic AMP or insulin, based on findings in cell culture. Thus, the requirements for and the mechanisms involved in enzyme induction and repression by hormones and glucose may be much more easily studied in primary cultures of rat hepatocytes than in vivo, or even in hepatoma cell lines, where relatively few genes are expressed as compared with adult liver. In addition to the regulation of enzyme levels, the characteristics of protein secretion may be investigated in primary cultures of rat hepatocytes and compared with the biochemical and physiological parameters in the whole organism. This was exemplified by the study of the synthesis and secretion of alpha 2u-globulin that was secreted into the culture medium in both glycosylated and nonglycosylated forms but was maintained in the circulation in vivo, principally as the glycosylated form. Furthermore, the function of glycosylation in this particular instance may be deduced from a combination of the in vivo and in vitro approaches. The advantages of the use of primary hepatocyte cultures for the study of the regulation of gene expression in mammalian tissue has only recently been explored. Future investigations of the regulation of a variety of enzymes in these cultures as well as a study of the regulation of the synthesis of their messenger RNA are now possible and should provide an exciting system in which to understand at a molecular level the regulation of the expression of a number of genes.
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PMID:Regulation of gene expression in primary cultures of adult rat hepatocytes on collagen gels. 616 26

The study was prompted by the apparent detection of insulin antibodies in a black patient with HCC and recurrent hypoglycemia who had never received insulin. It consisted of two parts. Initially the sera of 30 individuals (six normoglycemic HCC patients, three with HCC and recurrent hypoglycemia, 11 patients with noncancerous liver diseases, and 10 healthy black controls) were analyzed for the presence of insulin (and glucagon) antibodies by precipitating the bound, labeled hormone with ethanol and also by the technique of radioimmunoelectrophoresis. In the nine HCC patients, binding of 125I-insulin averaged 13% by ethanol separation and 0.018 mU/ml with radioimmunoelectrophoresis, levels that were similar to those of patients with noncancerous liver disease and significantly higher than those of the healthy controls. Mean binding of 125I-glucagon was 11% in HCC sera. Serum binding of labeled hormones correlated significantly with IgG concentrations in the patients. The second part of the study attempted to define the nature of insulin binding in HCC and other forms of liver disease. After confirmation of the increased serum binding of labeled insulin by another method of precipitation, PEG, an attempt was made to compete with the labeled insulin for its serum binding sites by adding a large amount of unlabeled insulin. This binding was not displaceable, however, and was therefore considered nonspecific. When the same procedures were repeated using normal serum to which increasing amounts of gamma globulin were added, the nonspecific binding of insulin increased in a linear fashion. Furthermore, a similar degree of high nonspecific insulin binding occurred in six patients with multiple myeloma and raised serum IgG concentrations. We therefore conclude that in the many clinical situations where hypergammaglobulinemia exists, false positive tests for the detection of antibodies against insulin (and probably other peptide hormones) will emerge unless appropriate methods are used to check for nonspecific peptide binding.
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PMID:Nonspecific blinding of insulin to gamma globulin in the serum of black patients with hepatocellular carcinoma and other forms of liver disease. 618 Jan 12

Key enzymes of gluconeogenesis in the liver, phosphoenolpyruvate carboxykinase [EC 4.1.1.32] and glucose-6-phosphatase [EC 3.1.3.9], were studied in patients with primary or metastatic hepatic cancer. Liver specimens for enzyme assay were obtained by necropsy performed within four hours after death. It was confirmed that both enzyme activities in rat liver preserved at 4 degrees C remained unchanged within nine hours after the removal of the tissue. Activities of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase decreased to below ten per cent of the control in neoplastic liver tissue of patients with hepatocellular carcinoma accompanied with liver cirrhosis. These two enzyme activities in cirrhotic tissue of patients with hepatocellular carcinoma were lower than those in patients merely with cirrhosis. In patients with metastatic hepatic cancer both two enzyme activities further decreased and were scarcely detected not only in neoplastic tissue but also in non-neoplastic tissue. These results show that hepatic gluconeogenesis markedly decreases in patients with primary or metastatic hepatic cancer. The biochemical analysis of the blood in hepatic cancer, decreased in blood glucose and release in immunoreactive glucagon, also suggested the suppression of gluconeogenesis.
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PMID:Hepatic gluconeogenic key enzymes in patients with hepatic cancer. 625 51

Adenylate cyclase activity was measured in plasma membranes isolated form Morris Hepatomas (44 and 47C) and from their host livers. We found that the enzyme activity in the tumours was very low, approx. 5% of the level in control and host livers. The amount of cAMP and cGMP in the tumours was also lower than in the host livers but the ratio of cGMP to cAMP in the tumours was increased by a factor of 4-5. The membrane binding capacities for the pancreatic hormones insulin and glucagon were measured. Hepatoma membranes bound less glucagon than those of livers. A decrease in the number of the glucagon receptors was found but there were no changes in the affinity constant. For insulin, we found the same binding capacity as the host and control livers; thus there was an increase in the ratio of insulin bound/glucagon bound in tumours as compared to controls. The plasma levels of insulin in the tumour bearing animals were approximately half of those in control, whereas the glucagon levels in plasma were 60-62% higher in tumour bearing animals. These results are discussed in terms of the characterization of normal, foetal and regenerating liver, in comparison with slow growing hepatomas. The levels of cAMP and cGMP are discussed with respect to control mechanisms of cell proliferation.
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PMID:Some enzyme and hormonal attributes of hepatoma cell membranes. 625 69

The levels of the five enzymes of the urea cycle were measured in normal 5-week-old rats, in a transplantable hepatoma, and in the livers of tumor-bearing rats (host livers). The levels of all five enzymes were much lower in the hepatoma, although there was no exact correlation of the decrease in levels. In host livers, the levels were higher than in the tumors, but lower than in normal liver. The levels of all five urea cycle enzymes were positively correlated with dietary protein content in normal livers, in hepatomas, and in host livers. In fact, the hepatomas showed the greatest changes in response to diet. On all diets, the levels in host liver remained below those in normal liver, indicating that the decreased level was probably not due to preferential utilization of nutrients by the tumor. The levels of urea cycle enzymes in normal liver were not altered by a single injection of glucocorticoid, glucagon, or dibutyryl cyclic adenosine 3':5'-monophosphate. By contrast, in hepatoma, the levels were usually significantly elevated by the same treatment. In addition, the levels in host livers were always significantly elevated and were usually above those in normal animals, whether the latter were hormone treated or not. Injection of plasma from tumor-bearing rats into normal animals produced a decrease in the levels of all five enzymes; if glucagon was injected together with the plasma, large increases in levels were observed. This result supports the concept of a humoral factor produced by the tumor which affects the levels and the inducibility of urea cycle enzymes in host livers. Autopsied human primary hepatomas also showed levels of urea cycle enzymes below those in normal livers with host livers having intermediate values. A cell line derived from a human hepatoma showed induction of arginase by glucocorticoid in culture; in this, it resembled a cell line of the rat hepatoma. Tyrosine aminotransferase in human hepatoma cells was not induced by glucocorticoid; in this, it differed from the rat hepatoma cells where induction of this enzyme was observed.
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PMID:Regulation of urea cycle enzymes in transplantable hepatomas and in the livers of tumor-bearing rats and humans. 626 64

The activation of cyclic AMP-dependent protein kinase has been found to be the predominant mode by which cyclic AMP (cAMP) leads to alterations of a large variety of cellular functions. The activation of the kinase results in the release of the catalytic subunit which as the free enzyme possesses phosphotransferase activity for a variety of specific protein substrates. Using a sensitive and specific cytofluorometric technique we monitored the appearance of free catalytic subunit in Reuber H35 hepatoma cells in culture after incubation with N6-1'-O-dibutyryl-cyclic AMP (DBcAMP), 8-bromoadenosine-3':5'-cyclic monophosphate (8-BrcAMP), and glucagon. The cytochemical method employs the heat-stable inhibitor of the free catalytic subunit which has been conjugated to fluorescein isothiocyanate (F:PKI) and was validated as described in the companion paper (Fletcher and Byus. 1982. J. Cell Biol. 93:719-726). Here we studied the temporal and spatial kinetics of the free catalytic subunit following activation of cAMP-dependent protein kinase by increasing concentrations of DBcAMP,8-BrcAMP, and glucagon. Under similar conditions protein kinase activation was also assessed biochemically in H35 cell supernatants by assaying the protein kinase activity ratio. Incubation of the hepatoma cells with DBcAMP (0.1 mM) led to an increase in the activity ratio from 0.2 in control cultures to a value of nearly 1.0 within a 1- to 2-h period. During this same period using the F:PKI probe, a significant increase in cytoplasmic and nucleolar fluorescence indicative of the release of the free catalytic subunit was coincidentally observed. In contrast to the rapid appearance of catalytic subunit in the cytoplasm and nucleolus of the cell within 5-15 min of the addition of DBcAMP, discernible nucleoplasmic fluorescence did not occur until after 1 h. H35 cell cultures incubated with 8-BrcAMP (0.01-1.0 mM) exhibited a more rapid activation of the protein kinase measured cytochemically compared to the cells treated with DBcAMP. Cultures incubated with 8-BrcAMP had significantly increased cytoplasmic and nucleolar fluorescence compared to unstimulated cells within 1 min of the addition of the analogue and reached a maximal level within 15 min. By employing a microspectrophotometer a distinct dose-dependent increase in cellular fluorescence (i.e., free catalytic subunit) was observed as the concentration of 8-BrcAMP was increased from 0.01 to 1.0 mM at 1, 5, 15, and 60 min following stimulation. The addition of glucagon (10(-6) M) to the culture also led to the activation of cAMP-dependent protein kinase as determined by an increase in the activity ratio. This increase was paralleled throughout the incubation period by a marked elevation in cytoplasmic and nucleolar fluorescence. The results reported herein suggest that both cyclic nucleotide analogues and a polypeptide hormone lead to the activation of cAMP-dependent protein kinase in similar intracellular compartments in Reuber H35 hepatoma cells...
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PMID:Direct cytochemical localization of catalytic subunits dissociated from cAMP-dependent protein kinase in Reuber H-35 hepatoma cells. II. Temporal and spatial kinetics. 628 33

Reuber hepatoma H-35 was found to retain the activity of carbamoyl-phosphate synthetase I. The content of this enzyme in H-35 grown in Eagle's minimal essential medium was about half that in rat liver. The enzyme from H-35 was the same as that from rat liver in molecular weight estimated by SDS-polyacrylamide gel electrophoresis, specific enzyme activity, kinetic parameters for ATP and N-acetyl-L-glutamate, and immunological crossreactivity. The enzyme in H-35 was induced by dexamethasone (1.4-fold) but not by glucagon or dibutyryl cAMP. Incorporation of [35S] methionine into the enzyme indicated that the effect of dexamethasone was due to increased synthesis of the enzyme protein (2.1-fold). By labeling with [35S]methionine, the precursor and the mature forms of carbamoyl-phosphate synthetase I were observed in the post-mitochondrial and mitochondrial fractions, respectively. By chasing the labeled cells with unlabeled methionine and cycloheximide, it was observed that the rate of translocation of the precursor into mitochondria is not affected by dexamethasone.
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PMID:Induction of carbamoyl-phosphate synthetase I in Reuber hepatoma H-35 by dexamethasone. 630 26

In contrast to the changes seen in membrane transport systems for other neutral, anionic, and cationic amino acids, System N for glutamine, histidine, and asparagine in the rat hepatocytes shows nearly constant properties at the fetal, differentiated, and cultured hepatoma stages. These properties were tested by measuring the Na+-dependent transport of glutamine. This approximate constancy applies not only to the transport selectivity of the system among neutral amino acids, but also to its tolerance of Li+ as a substitute for Na+, its characteristic sensitivity to pH lowering, its relative sensitivity to N-ethylmaleimide, its stimulation by amino acid deprivation, and its failure to respond to insulin or glucagon. The properties of histidine as a substrate for System N were also examined. Inhibition studies with different cell types suggest that the Na+-dependent glutamine and histidine uptake is more restricted to System N in the hepatoma line H35 (H4-11-EC,3) and in the fetal hepatocyte than in hepatoma line HTC and the Ehrlich cells. The Na+-independent component of glutamine and histidine uptake was greater in the hepatoma cells in continuous culture than in fetal and adult hepatocytes in primary culture. Trans-stimulation of glutamine and histidine influx into H35 cells occurs predominantly by the Na+-independent route.
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PMID:Comparison of system N in fetal hepatocytes and in related cell lines. 630 40

Peripancreatic venous abnormalities were demonstrated angiographically in 10 patients with islet cell tumor: six nonfunctioning, two gastrin-producing, one glucagon-producing, and one pancreatic polypeptide-producing. Venous involvement recognized included venous occlusion, venous encasement, and intraportal tumor growth. Seven patients had islet cell carcinoma with hepatic metastases while the other three had benign tumors. Three patients had arteriographic evidence of intraportal tumor growth with the "thread and streaks" sign, similar to that of portal venous extension of hepatocellular carcinoma.
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PMID:Venous involvement in islet cell tumors of the pancreas. 632 Jun 13


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