Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of wild-type S49 lymphoma cells with glucocorticoids, such as dexamethasone and hydrocortisone, inhibits the activity of ornithine decarboxylase (L-ornithine carboxylyase, EC 4.1.1.17), the rate-limiting enzyme in the pathway of polyamine biosynthesis. The kinetics of this inhibition are more rapid than the glucocorticoid-mediated growth arrest in the G1 phase of the cell cycle or in glucocorticoid-mediated cytolysis of these cells. The inhibition of ornithine decarboxylase activity by corticosteroids is specific for steroids of the glucocorticoid class. Results obtained with variant S49 cells having lesions in the pathways of glucocorticoid or cyclic AMP action indicate that cytoplasmic glucocorticoid receptors, as well as nuclear transfer of steroid--receptor complexes, are required for the inhibition of ornithine decarboxylase activity but that this inhibition does not require hormonal activation of adenylate cyclase or cyclic AMP-dependent protein kinase. Because glucocorticoid-mediated inhibition of ornithine decarboxylase occurs when cellular protein synthesis has decreased less than 20%, this inhibition may represent a specific glucocorticoid-mediated deinduction of ornithine decarboxylase in S49 cells. Inhibition of ornithine decarboxylase activity may offer a useful marker for suppression of growth and cell cycle progression in these and other lymphoma cells.
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PMID:Glucocorticoid-mediated inhibition of ornithine decarboxylyase activity in S49 lymphoma cells. 627 11

When crude preparations of protein kinase inhibitor (PKI) are added to homogenates of S49 lymphoma cells, protein kinase activity increases rather than decreases. This is not an increase in the activity of cyclic AMP-dependent protein kinase, which is completely inhibited by PKI, nor an increase in either cyclic GMP-dependent or Ca ++-dependent kinases. The increased kinase activity is not due to PKI itself but to one or more protein contaminants which serve as substrates for an S49 cell kinase which is cyclic nucleotide- and Ca ++ -independent. These contaminating substrates can be readily separated from PKI by DEAE cellulose chromatography. Although the crude PKI preparations sold by the major biochemical supply houses may be satisfactory for some purposes, we suggest that crude PKI be further purified when used to assess kinase activity in systems as complex as homogenates of whole cells. Otherwise, the presence of contaminating proteins in crude preparations of PKI can lead to erroneous conclusions about the type and quantity of protein kinase in the cell.
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PMID:Cautions on the use of the heat stable inhibitor of protein kinase: studies with S49 lymphoma cells. 627 9

We have examined the regulation of two key enzymes that control polyamine biosynthesis-L-ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) - by agents increasing cAMP in S49 lymphoma cells. Incubation of wild type S49 cells with beta-adrenergic agonists (terbutaline or isoproterenol) inhibited ODC and SAMDC activities rapidly (less than 2 hr). more quickly than these agents arrested the cells in the G1 phase of the cell cycle. The beta-adrenergic antagonist propranolol blocked inhibition of ODC activity produced by isoproterenol, but only if added simultaneously or less than 4 hr after the agonist. Incubation of wild type S49 cells with cholera toxin or PGE1 also inhibited ODC activity. Decreases in ODC activity produced by beta-adrenergic agonists, cholera toxin, PGE1 or dibutyryl cAMP were all enhanced by the phosphodiesterase inhibitor Ro 20-1724. Results of studies of ODC and SAMDC activity in S49 variants having lesions in the pathway of cAMP generation and action were as follows: kin- cells (which lack cAMP-dependent protein kinase activity) showed no inhibition of ODC by any agent; AC- cells (which have absent nucleotide coupling units in their adenylate cyclase system) only demonstrated inhibition in response to dibutyryl cAMP; UNC cells (which have deficient coupling of hormone receptors and adenylate cyclase) only demonstrated inhibition in response to dibutyryl cAMP and cholera toxin, and beta-depleted cells (which have a decreased number of beta-adrenergic receptors) responded as did wild type cells except for absent response to isoproterenol. We conclude that inhibition of ODC and SAMDC activity in S49 cells is an early response to agents that increase cAMP and that this action occurs via the "classical" pathways of activation of adenylate cyclase and protein kinase. These results in S49 cells contrast with evidence in other systems in which cAMP has been suggested to enhance polyamine biosynthesis, perhaps through alternative mechanisms.
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PMID:Inhibition of ornithine decarboxylase and S-adenosylmethionine decarboxylase activities of S49 lymphoma cells by agents increasing cyclic AMP. 628 19

The human cell lines HL-60 (acute promyelocytic leukemia) and U-937 (histiocytic monoblast-like lymphoma) differentiate to functionally mature cells by incubation with retinoic acid (RA). This differentiation is potentiated by agents known to increase intracellular cyclic adenosine 3':5'-monophosphate (cAMP) levels. The present study shows that these cells can be primed for differentiation by treatment for approximately one day with RA followed by exposure to a cAMP-inducing agent. The reverse sequence was ineffective. Thus, HL-60 could be primed by incubation for less than 20 hr with 10 nM RA to respond by differentiation to the addition of 10 nM prostaglandin E2 or 1 nM cholera toxin, whereas 10 nM RA alone was almost inactive. RA-primed HL-60 also responded with differentiation to a concentration of T-lymphocyte-derived differentiation-inducing factor which alone was inactive. U-937 primed by incubation for 24 hr with 100 nM RA responded to cAMP-inducing agents and differentiation-inducing factor, which alone were inactive on this cell line. Priming of these cell lines does not depend on the normal rate of protein synthesis, as it occurs even better in the presence of a concentration of cycloheximide that inhibits growth completely, suggesting that a decrease in synthesis of some protein(s) favors RA-induced differentiation. Cycloheximide alone produced some priming of HL-60 but not of U-937. HL-60, but not U-937, primed with RA responded to adenosine triphosphate and other nucleoside triphosphates, consistent with the notion that modulation of the RA effect may be mediated through protein kinase activity at the plasma membrane. The finding that myeloid cell lines, like HL-60 and U-937, blocked at a late stage of maturation can be primed by RA to respond to cAMP-inducing agents and differentiation-inducing factor may improve our understanding of the arrest in maturation typical of some forms of leukemia.
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PMID:Priming of human myeloid leukemic cell lines HL-60 and U-937 with retinoic acid for differentiation effects of cyclic adenosine 3':5'-monophosphate-inducing agents and a T-lymphocyte-derived differentiation factor. 628 1

Tubuloreticular structures (TRS) occur spontaneously in S49 mouse lymphoma cells grown in suspension culture. These structures appear in approx. 20% of the cells in electron microscopical cross-sections. Cloning of S49 cells in semi-solid agarose reveals that TRS are potentially present in all S49 cells. An increase of 60% in the frequency of TRS was observed following exposure of S49 cells to 2 X 10(-4) db-cAMP. This increase was not observed in mutant S49 cells lacking cAMP-dependent protein kinase activity. The data suggest that one possibility for the regulation of TRS is through a pathway involving cAMP-dependent protein kinase. In addition, TRS also appear in tumors derived from S49 cells and therefore serve as an ultrastructural cytoplasmic marker for these cells, both in culture and in syngeneic hosts. We suggest the S49 cells as a model system for studying the regulation and function of tubuloreticular structures in vitro and in vivo in malignant lymphoid cells.
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PMID:Tubuloreticular structures in S49 cells. Relation to cAMP-dependent protein kinase. 629 64

Treatment of mouse lymphoma S49 cells with D,L-alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, depleted cellular polyamine levels and stopped cell growth. The cells were arrested predominantly in G1. Thus, polyamine depletion may lead to a regulatory growth arrest in S49 cells. We tested two hypotheses regarding the relationship of growth arrest mediated by polyamine limitation to that mediated by cyclic AMP (cAMP). The hypothesis that cAMP-induced arrest results from polyamine depletion is not tenable, because the arrest could not be reversed by addition of exogenous polyamines, and because cellular polyamine levels do not drop in dibuturyl cyclic AMP (Bt2cAMP)-arrested cells. The hypothesis that polyamine-mediated growth arrest is effected via modulation of cAMP levels or cAMP-dependent protein kinase activity was also shown to be incorrect, because a S49 variant deficient in cAMP-dependent protein kinase was arrested by DFMO. The activities of the polyamine-synthesizing enzymes ornithine decarboxylase (ODC) and S-adenosyl methionine decarboxylase (SAMD) are both reduced in Bt2cAMP-treated cells to about 10% of that in control populations, as shown previously. DFMO diminishes ODC activity and augments SAMD activity in both untreated and Bt2cAMP-treated cells, leading to polyamine depletion in both cases.
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PMID:Growth regulatory effects of cyclic AMP and polyamine depletion are dissociable in cultured mouse lymphoma cells. 630 Jan 39

The regulatory subunits of cyclic AMP (cAMP)-dependent protein kinase from a dibutyryl cAMP-resistant S49 mouse lymphoma cell mutant, clone U200/65.1, and its revertants were visualized by two-dimensional polyacrylamide gel electrophoresis. Clone U200/65.1 co-expressed electrophoretically distinguishable mutant and wild-type subunits (Steinberg et al., Cell 10:381-391, 1977). In all 48 clones examined, reversion of the mutant to dibutyryl cAMP sensitivity was accompanied by alterations in regulatory subunit labeling patterns. Some spontaneous (3 of 11) and N-methyl-N'-nitro-N-nitrosoguanidine-induced (2 of 11) revertants retained mutant subunits, but these were altered in charge, degree of phosphorylation, or both. The charge alterations were consistent with single amino acid substitutions, suggesting that reversion was the result of second-site mutations in the mutant regulatory subunit allele that restored wild-type function, although not wild-type structure, to the gene product. The majority of spontaneous (8 of 11) and N-methyl-N'-nitro-N-nitrosoguanidine-induced (9 of 11) revertants and all of the revertants induced by ethyl methane sulfonate (14 of 14) and ICR191 (12 of 12) displayed only wild-type subunits. Dibutyryl cAMP-resistant mutants isolated from several of these revertants displayed new mutant but not wild-type subunits, suggesting that the revertant parent expresses only a single, functional regulatory subunit allele. The mutant regulatory subunit allele can, therefore, be modified in two general ways to produce revertant phenotypes: (i) by mutations that restore its wild-type function, and (ii) by mutations that eliminate its function.
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PMID:Reversion of an S49 cell cyclic AMP-dependent protein kinase structural gene mutant occurs primarily by functional elimination of mutant gene expression. 630 Jun 60

A novel peptide mapping approach has been used to map sites of charge modification to major structural domains of regulatory subunit (R) of type I cAMP-dependent protein kinase from S49 mouse lymphoma cells. Proteolytic fragments of crude, radiolabeled R were purified by cAMP affinity chromatography and displayed by two-dimensional polyacrylamide gel electrophoresis. [35S]methionine-labeled peptides containing sites of mutation or phosphorylation exhibited charge heterogeneity attributable to the modification. Phosphate-containing fragments were also labeled with [32P]orthophosphate to confirm their phosphorylation. Major fragments from [35S]methionine-labeled S49 cell R corresponded in size to carboxyterminal cAMP-binding fragments reported from proteolysis of purified type I Rs from various mammalian species; additional fragments were also visualized. End-specific markers in Rs from some mutant S49 sublines confirmed that cAMP-binding fragments extended to the carboxyterminus of R. Aminoterminal endpoints of fragments could be deduced, therefore, from peptide molecular weights. Clustering of proteolytic cleavage sites within the "hinge-region" separating aminoterminal and carboxyterminal domains of R permitted high resolution mapping in this region: the endogenous phosphate and a "phenotypically-silent" electrophoretic marker mutation fell within a 2.5-kdalton interval at its aminoterminal end. On the other hand, Ka mutations that increase the apparent constant for activation of kinase by cAMP mapped within the large cAMP-binding region of R. A map of charge density distribution within the hinge-region of R was constructed to facilitate structural comparisons between Rs from S49 cells and from other mammalian sources.
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PMID:Sites of phosphorylation and mutation in regulatory subunit of cyclic AMP-dependent protein kinase from S49 mouse lymphoma cells: mapping to structural domains. 631 40

Studies of beta-adrenergic receptors on several types of intact target cells indicate that agonists, but not antagonists, show prominent KD/Kact discrepancies--lower affinities (KD) in equilibrium binding studies (i.e. in competition with antagonist radioligands) than in functional assays (Kact). In this report we show that intact S49 lymphoma cells initially bind beta-adrenergic agonists in a high affinity manner but that this high affinity binding rapidly converts to a low affinity state. This time course is similar to that of agonist-mediated desensitization in S49 cells. In competitive binding studies conducted with [125I]iodocyanopindolol or [125I]iodohydroxybenzylpindolol, IC50 values for beta-adrenergic agonists increased 13-200-fold between 1 and 60 min, whereas antagonists yielded similar IC50 values at the two time points. The binding of antagonists, but not agonists, could be simulated by a computer model based on the law of mass action. In contrast with results in intact S49 cells, crude membrane fractions yielded similar IC50 values for agonists in 1- and 60-min incubations with [125I]iodocyanopindolol. Moreover, time-dependent decreases in apparent affinity of the agonist (-)-isoproterenol were observed not only in wild type S49 cells but also in several S49 variants (UNC, cyc-, H21a) having defects in Ns, the guanine nucleotide binding protein that couples receptors to activation of adenylate cyclase, and in Kin-, an S49 variant with absent cAMP-dependent protein kinase activity. These results show that beta-adrenergic receptors of intact S49 cells demonstrate a prominent time-dependent decrease in apparent affinity for agonists and that this decrease in affinity does not require cAMP generation, the Ns components defective in several S49 variants or cAMP-dependent protein kinase. The rapid conversion of agonist binding from high to low affinity can account for the rapid desensitization of intact cells to catecholamines and probably explains previously reported KD/Kact discrepancies of intact cells.
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PMID:Time-dependent decreases in binding affinity of agonists for beta-adrenergic receptors of intact S49 lymphoma cells. A mechanism of desensitization. 631 5

Several sarcoma-inducing viruses encode protein kinases that phosphorylate tyrosine residues. Such enzymatic activities can be detected within the detergent-insoluble matrix of transformed fibroblasts. We have analysed the protein kinase activities in two murine lymphoma cell lines ( MBL2 and LSTRA) induced by Moloney murine leukemia virus (Mo-MuLV). After incubation of the detergent-insoluble matrix of these cells with [gamma-32P]ATP, several alkali-resistant phosphoproteins, including a very heavily labelled 55 000 mol. wt. protein ( p55 ), have been detected in LSTRA, reflecting the activity of a protein kinase specific to this cell line. This protein kinase activity shares some of the distinctive properties of the protein kinases of transforming viruses, i.e., specificity for tyrosine residues, association with membranous and/or cytoskeletal structures, and inhibition by a synthetic peptide derived from the phosphorylation site of pp60src. In view of the absence of a transforming gene in MoMuLV , it is likely that the high level of protein kinase detected in the LSTRA cell line arises from the expression of a cellular gene.
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PMID:High level of tyrosine protein kinase in a murine lymphoma cell line induced by Moloney leukemia virus. 632 81


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