Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:040116 (histone)
 44,835 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three protein kinases (EC 2.7.1.37) were detected in Blepharisma and partially purified. The enzymes were most active with histone as substrate protein. The stability of the bond between phosphate and protein acceptor showed the characteristics of seryl- or threonylphosphate. Protein kinase I was solubilized by ultrasonication or freezing and thawing, while the enzymes II and III were readily solubilized by mild homogenization. Protein II and III were noticeably activated by cAMP and cGMP, while protein kinase I was inhibited by cAMP. Associated with protein kinase II and III activity was the ability to bind labeled cAMP. The following molecular weights were determined: 90000 for enzyme I, 280000 for enzyme II, and 95000 for enzyme III. Various apparent Michaelis constants were estimated.
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PMID:Characterization of protein kinases from Blepharisma intermedium. 0 34

Adenosine 3',5'-cyclic monophosphate (cAMP) may be one of the important factors in regulating the expression of many differentiated functions in neuroblastoma cells, but some of these functions can be induced by agents that do not increase the intracellular level of cAMP. An elevation of the intracellular level of guanosine 3',5'-cyclic monophosphate (cGMP) neither induced differentiation nor antagonized the effects of cAMP. Neuroblastoma cells increased the level of cAMP-binding proteins during differentiation, whereas glial cells and L-cells did not. This might have accounted in part for an increase in the intracellular level of cAMP even in the presence of high phosphodiesterase activity in neuroblastoma cells, since the protein-bound with the same proteins, but cAMP had about 10 times higher affinity than did cGMP. cAMP promoted the organization of microtubules and microfilaments necessary for the expression of differentiated phenotypes. The extension of neurites required the synthesis of new protein, but it did not need the synthesis of new RNA. cAMP induced differentiation in neuroblastoma cells by increasing the expression of some genetic information while suppressing the expression of others; e.g., the activities of neural enzymes increased, whereas the synthesis of histone and the phosphorylation of H1-histone markedly decreased in differentiated cells. A hypothesis was offered: An increase in cAMP phosphodiesterase activity as a result of mutation in the regulatory gene for phosphodiesterase in a single, or group of, dividing nerve cell(s) is the primary lesion that leads to malignancy. Based on the concept that selective cytocytoxic drugs should be used with agents that cause differentiation, a new therapeutic approach was suggested for the treatment of neuroblastoma. This involved administration of sodium butyrate followed by L-DOPA or prostaglandin E1 in the presence of cAMP phosphodiesterase inhibitor followed by the less immunosuppressive vincristine and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide.
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PMID:Cyclic nucleotides in the regulation of expression of differentiated functions in neuroblastoma cells. 1 Apr 49

The examination of the regulation of the system of 3'-5' cyclic nucleotide monophosphates has only begun in cancer tissues. In human cancers, these studies are notably non-existent. However, in animal cancers, especially the Morris hepatomas, enough data has been gathered that, while risky, certain trends seem to begin to appear. Cyclic AMP is constant or lowered, while cyclic GMP is elevated in the fast growing hepatomas. Regulation of adenylate cyclase by protein hormones is reduced, while regulation by epinephrine may be increased. Binding of glucagon is decreased in the fast growing hepatomas. Guanylate cyclase, while being predominantly cytoplasmic in the normal liver, is predominantly membrane bound in the tumors. The liver enzyme is also readily stimulated by several chemical carcinogens. The cyclic GMP phosphodiesterases are decreased in these tumors; while the cAMP phosphodiesterases are increased. Although the cyclic nucleotide dependent protein kinases (histone as substrate) are altered in the hepatomas, observations of unique cyclic nucleotide binding proteins or cAMP independent protein kinases in cancer tissues may be of even greater significance for the development of or the maintenance of the neoplastic state of cells.
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PMID:Cyclic nucleotide metabolism in solid tumor tissues. 2 89

Exposure of neuroblastoma cells (NBD-2) to 8-bromo-adenosine 3',5'-cyclic monophosphate (0.2-1.0 mM) (8-Br-cAMP) for 15 min caused a long term increase in the Vmax of tyrosine-3-monooxygenase activity (TH) beginning about 1 day after 8-Br-cAMP application. Cyclic AMP-dependent histone kinase was maximally activated in about 30 min and stayed activated above pretreatment levels for one hour. In cells exposed to 8-Br-cAMP for 15 min, separation of soluble and particle bound histone kinase showed that the total histone kinase activity in the soluble fraction decreased by 40%. This decrease was accompanied by an increase in protein kinase activity in the particulate fraction, suggesting enzyme translocation. After translocation, the enzyme appears to acquire a different substrate affinity because it prefers as a PO43- acceptor, acidic protein rather than histone. In NBD-2 cells this kinase appears to precede, and may be related to, the delayed increase in TH Vmax.
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PMID:Translocation of cytosol protein kinase into nuclei and the induction of tyrosine hydroxylase in NBD-2 neuroblastoma cells. 3 81

Non-histone chromosomal proteins are phosphorylated and dephosphorylated within the intact nucleus by two independent sets of reactions, a protein kinase reaction which transfers the terminal phosphate group of a variety of nucleoside and deoxynucleoside triphosphates to serine and threonine residues in the proteins, and a phosphatase reaction which cleaves these phosphoserine and phosphothreonine bonds and releases inorganic phosphate. Several lines of evidence are consistent with the hypothesis that the phosphorylation and dephosphorylation of these proteins is involved in gene control mechanisms, including the findings that phosphorylated non-histone proteins are highly heterogeneous and their phosphorylation patterns are tissue specific, changes in their phosphorylation correlate with changes in chromatin structure and gene acticity, addition of phosphorylated non-histone proteins increases RNA synthesis in vitro. and phosphorylated non-histone proteins bind specifically to DNA. Cyclic AMP has both stimulatory and inhibitory properties on non-histone protein phosphorylation, depending on the enzyme fraction and substrate employed A specific protein component whose phosphorylation is inhibited by cyclic AMP has been found to be associated with RNA polymerase. The cyclic AMP-induced decrease in the phosphorylation of this protein correlates with an enhancement of RNA synthesis in vitro. These results suggest that both phosphorylation and dephosphorylation of chromatin-associated proteins may be involved in the control of gene readout.
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PMID:Phosphorylation of non-histone proteins in the regulation of chromosome structure and function. 16 80

There appear to be two classes of protein kinases in rat heart and adipose tissue, types I and II. Type I elutes from DEAE-cellulose at smaller than 0.1 M NaCl and type II at greater than 0.1 M NaCl. The type I enzyme is more readily dissociated by salt or histone than is the type II enzyme. If the type I kinase is first dissociated by cAMP, the subunits reassociate very slowly at 0 degrees C on removal of the cAMP by Sephadex G-25 chromatography, whereas those of type II reassociate very rapidly. Rat heart contains mostly type I and a small amount of type II enzyme, whereas adipose tissue contains almost exclusively the type II enzyme. The adipose tissue enzyme resembles the heart type II kinase in all of the above properties, although the two enzymes are not identical as indicated by slight differences in elution patterns from DEAE-cellulose columns. Incubation of rat epididymal adipose tissue with low concentrations of epinephrine (0.11 muM) increases glycerol production and the fraction of the protein kinase in the active form (activity ratio). The change in cAMP under these conditions is not statistically significant. The presence of insulin inhibits the epinephrine effect on glycerol production and protein kinase but has no measurable effect on cAMP levels. Incubation of adipose tissue with high epinephrine concentrations (11 muM) increases the cAMP level, the protein kinase activity ratio, and glycerol production. Under these conditions insulin decreases the cAMP level and kinase activity ratio but does not reduce glycerol production. The data suggest that very small changes in the tissue cAMP level, undetectable by the assay method, are magnified during the stepwise activation of glycerol output aided possibly by cooperative effects between cAMP and protein kinase. The procedure developed for determining the state of activation of the cAMP-dependent protein kinase in adipose tissue must be modified by reducing the salt concentration of the buffers in order to carry out similar studies in the heart. This reflects the different types of protein kinase in the two tissues. The addition of charcoal to crude extracts of heart prevents protein kinase activation by added cyclic AMP. Charcoal should therefore prevent any activation that could occur if any sequestered cAMP were released during homogenization. Charcoal addition thereby provides a means to distinguish intracellular cAMP activation of the kinase from that which might occur following cell rupture. If epinephrine-perfused hearts are homogenized in the presence of charcoal, epinephrine stimulation of the protein kinase is only slightly decreased. This indicates that the protein kinase is activated intracellularly by cAMP and suggests that all of the cAMP in the cell is available to the protein kinase; i.e., cAMP is not released during homogenization.
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PMID:Hormonal regulation of adenosine 3',5'-monophosphate-dependent protein kinase. 16 70

1. Extracts from rat mammary gland nuclei contain cyclic AMP -independent protein kinases which phosphorylate casein rather than histone. 2. A major increase in nuclear protein kinase activity occurred during late pregnancy and was maintained with the onset of lactation. 3. Two major peaks of activity were resolved by chomatography of nuclear extracts on DEAE-Sephadex; the first (NI) appeared in the void volume and the second (NII) was eluted by 0.05-0.12 M ammonium sulfate. Several other regions of lesser activity were also present. 4. Protein kinases in the cytosol 105,000 times g supernatant, precipitated by 70 percent ammonium sulfate, dialyzed against buffer, and chromatographed on DEAE-Sephadex, yielded a major components phosphorylated histone in preference to casein, and this was stimulated by cyclic AMP if histone was the substrate, but only the first (void volume) fraction was cyclic AMP-dependent when casein was used. 5. Most of RNA polymerases Ib and II, derived from the nucleolus and nucleoplasm, respectively, appeared in column fractions distinct from those containing the major NI and NII protein kinases. 6. Cyclic AMP altered the amount of RNA product synthesized by polymerases Ib and II, but the explanation for this is unknown. Due to their elution profiles and cyclic AMP-independence, protein kinases NI and NII are excluded from playing a catalytic role in these effects; participation of quantitatively minor protein kinases which co-elute with polymerase Ib and II is not yet excluded.
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PMID:Relationship between RNA polymerase and protein kinase activities in rat mammary gland nuclei. 16 36

In crude extracts of adipose tissue the protein kinase dissociates slowly at 30 degrees into regulatory and catalytic subunits in the presence of 700 mug per ml of histone or 0.5 M NaCl. If the kinase is first dissociated by adding 10 muM adenosine 3':5'-monophosphate (cAMP), reassociation occurs instantaneously after removal of the cAMP by Sephadex G-25 chromatography. In contrast, in crude xtracts of heart, the protein kinase dissociates rapidly in the presence of 700 mug per ml of histone or 0.5 M NaCl and reassociates slowly after removal of cAMP. These differences are accounted for by the existence of two types of protein kinases in these tissues, referred to as types I and II. DEAE-cellulose chromatography of extracts of adipose tissue produces only one peak of cAMP-dependent protein kinase activity (type II) which elutes between 0.15 and 0.25 M NaCl. Similar chromatography of heart extracts resolves enzyme activity into two peaks; a type I enzyme which elutes between 0.05 and 0.1 M and predominates (greater than 75% of total activity), and a type II enzyme which elutes between 0.15 and 0.25 M NaCl. The dissociation properties of the types I and II enzymes from heart and adipose tissue are retained after partial purification by DEAE-cellulose and Sepharose 6B chromatography. Rechromatography of the separated peaks of the cardiac enzymes does not change the elution pattern. Sucrose density gradient centrifugation and gel filtration studies indicate that the molecular weights of these enzymes are very similar. The type II enzyme isolated by DEAE-cellulose chromatography of heart extracts resembles the adipose tissue enzyme, i.e. it undergoes slow dissociation at 30 degrees in the presence of histone or 0.5 M NaCl. The adipose tissue kinase and the heart type II kinase are not identical, however, since they do not elute at exactly the same point on DEAE-cellulose columns. A survey of several tissues indicates the presence of type I and II protein kinases similar to the enzymes in adipose tissue and heart as determined by DEAE-cellulose chromatography of crude extracts and by dissociation of the enzymes with histone. The presence of MgATP prevents dissociation of type I enzyme from heart by 0.5 M NaCl or histone. The profile of the enzyme on DEAE-cellulose, however, is not changed...
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PMID:The distribution and dissociation of cyclic adenosine 3':5'-monophosphate-dependent protein kinases in adipose, cardiac, and other tissues. 16 86

Specific adenosine-binding proteins from homogenates of rat liver have been fractionated on a DEAE-cellulose column. Three major peaks have been identified with respect to histone phosphokinase and cAMP and adenosine-binding activities. Peak I contains only histone phosphokinase activity not stimulated by cAMP. Peak II contains histone phosphokinase slightly stimulated by cAMP. Both cAMP- and adenosine-binding activities are found in this fraction. The major adenosine-binding protein is associated with Peak III. Histone phosphokinase in Peak III which also binds cAMP is stimulated 2-fold by 2.5 muM cAMP whereas adenosine at 2.5 X 10(-4)M inhibits these enzymes equally well in each of three peaks. The specificity of adenosine binding is discussed.
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PMID:Specific adenosine binding proteins from rat liver. 16 80

The effects of epinephrine, glucagon, insulin and 1-methyl-3-isobutylxanthine on adenosine 3:5-monophosphate (cAMP)-dependent protein kinase activity were investigated in the perfused rat heart. The conditions for homogenization of heart tissue and assay of protein kinase are described. The activation state of the enzyme is expressed as the ratio of the rate of phosphorylation of histone in the absence to that in the presence of 2 mu-M cAMP. This activity ratio is stable in crude homogenates over 15 min of incubation; it is not affected by up to 30-fold dilution of the tissue volume. The ratio is elevated to a variable degree in hearts taken immediately from the animal but falls to a stable, basal level of 0.15 to 0.20 after 15 min of perfusion in vitro. An optimal concentration of epinephrine (10 mu-M) in the perfusate elevates cAMP from 0.5 to 1.3 nmol per g of tissue and increases the protein kinase activity ratio from 0.20 to 0.65. When hearts are perfused with a steady, submaximal concentration of epinephrine (0.4 mu-M), the level of cAMP and the protein kinase activity ratio rise in parallel within 15 s and remain elevated for at least 10 min. When epinephrine is removed from the perfusion medium, the level of cAMP and enzyme activity ratio decline rapidly to basal levels. Both glucagon and the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine also increase the cardiac cAMP levels and protein kinase activity ratio in a dose-dependent manner. Glucagon acts as rapidly as does epinephrine whereas 1-methyl-3-isobutylxanthine requires at least 30 s before any effect can be observed. Insulin by itself does not significantly affect the cyclic nucleotide level or enzyme activity. The hormone has not been observed to lower the cAMP level or protein kinase activity in the heart under any conditions tested. In concentrations of 10 microunits per ml or greater, it does, however, cause a slight rise in the tissue level of cAMP and the protein kinase activity when these have been elevated to intermediate levels by exposure to epinephrine. This effect could only be observed when hearts were treated with catecholamine and could not be detected with glucagon or 1-methyl-3-isobutylxanthine. In all cases tested, slight increases in the protein kinase activity ratio (from 0.2 to 0.3) were accompanied by much greater increases in the amount of phosphorylase in the a form (20% to 70%). It was observed that at perfusion times greater than 3 min, there was a significant reduction in phosphorylase activity even though both the cAMP level and protein kinase activity remained elevated. In these studies, changes in the protein kinase activity correlate well with the tissue cAMP levels under all conditions tested.
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PMID:Regulation of adenosine 3:5-monophosphate-dependent protein kinase. 16 93


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