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)

Flow-microfluorimetric analysis has been carried out on populations of exponentially growing S49 mouse lymphoma cells treated with dibutyryl cyclic AMP. The drug produces a specific concentration-dependent block in the G-1 phase of the cell cycle while other phases of the cycle are not perceptibly altered. The cell cycle of a line of mutant cells lacking the cyclic AMP-dependent protein kinase is not affected by the drug. Since these mutant cells have been shown to maintain a normal cell cycle, even in the presence of high levels of cyclic AMP, periodic fluctuations in the levels of the cyclic nucleotide cannot be required for or determine progression through the cell cycle.
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PMID:Cyclic AMP, a nonessential regulator of the cell cycle. 16 91

Dibutyryl cyclic AMP and theophylline kill S49.1 mouse lymphoma tissue culture cells. When cells are grown in soft agar with these drugs, the few clones that survive are resistant to cytolysis. The rate of mutation to resistance is 1-3 times 10-7/cell/generation in both diploid and tetraploid cells. The incidence of mutants is increased by treatment with a chemical mutagen, ICR 191. The mutation is consistently associated with greatly reduced or absent cytoplasmic cyclic AMP binding protein. These results suggest that a somatic mutation leads to a defect of the protein kinase regulatory subunit and that activity of this kinase is required for induction of cell death by cyclic AMP.
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PMID:Somatic genetic analysis of cyclic AMP action: selection of unresponsive mutants. 16 36

A mouse lymphoma tissue culture line, S49, is killed by isoproterenol, choleratoxin, or prostaglandin E1, inducers of cyclic AMP (cAMP) in these cells, or by the analog dibutyryl (db) cAMP. Cell death follows arrest in the G1 phase of the cell cycle. Mutant subclones obtained by growing S49 with dbcAMP were resistant to killing. They were deficient in cAMP-dependent protein kinase. These results are discussed in relation to the possible physiologic role of cAMP-induced cell death in T-cell differentiation.
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PMID:Mechanism of lymphoma cell death induced by cyclic AMP. 17 Aug 34

Dibutyryl cyclic adenosine 3',5'-monophosphate (cyclic AMP) produces phosphodiesterase induction, growth arrest, and cytolysis in S49 lymphoma cells. The striking parallelism between protein kinase activity that is dependent on cytosol cyclic AMP and cellular responses to dibutyryl cyclic AMP in wild-type cells and three classes of clones resistant to cyclic AMP indicates that protein kinase mediates cyclic AMP regulation of growth and enzyme induction in S49 cells.
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PMID:Cyclic AMP-dependent protein kinase: pivotal role in regulation of enzyme induction and growth. 17 70

Compared to the wild-type parental line of S49 mouse lymphoma cells, intact cells of a mutant line (kin.A) are 10-fold less sensititive to biologic effects of exogenous cyclic adenosine 3':5'-monophophosphate (cAMP), such as induction of cAMP phosphodiesterase, cell cycle-specific growth inhibition, and cytolysis. The cAMP-dependent protein kinase (ATP:protein phosphotransferase; EC 2.7.1.37) activity of kin.A cells exhibits an apparent Ka for activation by cAMP 10-fold greater than that of wild type, and is much more resistant to inactivation by heat. These differences between the wild-type and mutant enzymes persist through a high degree of purification, suggesting a structural alteration in the kin.A holoenzyme. Heterologous reconstitution experiments, using separated R and C subunits of the wild-type and kin.A cAMP-dependent kinases, show that the altered cAMP affinity and thermolability are conferred by the R component of the kin.A enzyme. These results are most consistent with a structural mutation in the kin.A gene coding for the R subunit of cAMP-dependent protein kinase. Evidence for a structural mutation helps to define one mechanism of heritable variation in cultured somatic cells. The phenotype produced by the kin.A structural mutation also greatly strengthens the conslusion that cAMP-dependent protein kinase is essential for cAMP regulation of growth and enzyme induction in intact S49 cells.
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PMID:A structural gene mutation affecting the regulatory subunit of cyclic AMP-dependent protein kinase in mouse lymphoma cells. 17 91

The beta-adrenergic catecholamine isoproterenol produces a large, rapid, but often a transient, elevation in cellular content of cyclic AMP. We have used the S49 mouse lymphoma cell line, in which genetic variants with specific defects in the pathway of cyclic AMP generation and function have been isolated, to study the increase and subsequent decrease in cyclic AMP levels (termed refractoriness) following incubation of cells with isoproterenol. In wild type S49 cells, isoproterenol produces a peak response in the cellular content of cyclic AMP within 30 min, but the cyclic AMP level falls rapidly thereafter, approaching basal levels by 6 h. Neither inactivation of the drug nor secretion of a nonspecific inhibitor of adenylate cyclase appears to account for the refractoriness. Because isoproterenol refractory cells can still be stimulated by cholera toxin, refractoriness to isoproterenol does not represent a generalized decrease in cellular cyclic AMP response. Particulate preparations from refractory cells have a selective loss of isoproterenol-responsive adenylate cyclase activity, but their activation constants and stereoselectivity for (-)- and (+)-isoproterenol are unaltered. In addition, refractory cells have decreased specific binding of the beta-adrenergic antagonist [125I]iodohydroxybenzylpindolol. This decrease appears to represent a reduction in the number, but not the affinity, of beta-adrenergic receptor sites. Similar studies in an S49 clone that lacks the enzyme cyclic AMP-dependent protein kinase yield essentially identical findings. Because kinase-deficient cells do not induce the cyclic AMP-degrading enzyme phosphodiesterase after the cellular content of cyclic AMP is increased, induced of phosphodiesterase cannot account for refractoriness to isoproterenol. Cyclic AMP-dependent protein kinase does not appear to be required for either the decrease in beta-adrenergic receptors and isoproterenol-responsive adenylate cyclase, nor does it appear to be required for the development of refractoriness to isoproterenol. In contrast, an S49 clone lacking hormone-responsive adenylate cyclase activity but retaining beta-adrenergic receptors does not appear to lose receptors after being incubated with isoproterenol, either alone or together with dibutyryl cyclic AMP. Therefore, in this clone, receptor occupancy alone or in combination with elevated cyclic AMP levels is insufficient to cause refractoriness. Refractoriness thus appears to require intact adenylate cyclase. This suggests that adenylate cyclase may exert regulatory controls on beta-adrenergic receptors in addition to generation of cyclic AMP.
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PMID:Agonist-specific refractoriness induced by isoproterenol. Studies with mutant cells. 18 93

Two-dimensional polyacrylamide gel electrophoresis is used to visualize the regulatory subunit of cAMP-dependent protein kinase from cultured S49 mouse lymphoma cells and to demonstrate its in vivo phosphorylation. Regulatory subunits from mutant cells with altered kinases exhibit at least two patterns of charge shifts consistent with substitutions of single amino acids. The direct demonstration of structural alteration of this protein provides strong evidence for structural gene mutation in this cultured cell system. While mutant and wild-type gene products co-exist in the mutant cells, there is apparently preferential expression and phosphorylation of mutant subunit in these heterozygotes.
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PMID:Mutations causing charge alterations in regulatory subunits of the cAMP-dependent protein kinase of cultured S49 lymphoma cells. 19 Nov 96

We have previously selected and characterized mutant S49 mouse lymphoma cells that possess an adenosine 3':5'-cyclic monophosphate (cAMP)-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37) with an increased apparent affinity constant (Ka) for activation by cAMP. The Ka lesion in one such mutant clone has been shown to result from a structural mutation involving the kinase holoenzyme's regulatory (R) subunit. The present report examines the interaction of R and catalytic (C) subunits of the kinases in extracts of the mutant cells and the normal "wild type" (WT) parental line. Subunit recombination experiments were performed, by using purified WT and mutant R subunits, and C subunits purified from WT cells. As compared to WT R subunits, only 1/6 as much mutant R subunit was required to reassociate with and suppress 50% of C subunit activity, at equilibrium. NaSCN activates cAMP-dependent kinase of both cell types by causing the holoenzyme to dissociate. In comparison with WT, a 2-fold higher concentration of NaSCN is required to maximally activate the kinase in mutant extracts. Both the reassociation result and the increased resistance of the mutant enzyme to a nonspecific dissociating agent strongly suggest that the mutant R subunit binds C subunit more tightly than does the WT R subunit. This interpretation raises the possibility that increased R-C subunit binding affinity in the mutant cell is responsible for the increased Ka for activation by cAMP of the mutant holoenzyme, and thus for the decreased potency of cAMP in regulating intact mutant cells.
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PMID:Subunit interaction in cyclic AMP-dependent protein kinase of mutant lymphoma cells. 19 31

The ability of cyclic AMP to inhibit growth, cause cytolysis and induce synthesis of cyclic AMP-phosphodiesterase in S49.1 mouse lymphoma cells is deficient in cells selected on the basis of their resistance to killing by 2 mM dibutyryl cyclic AMP. The properties of the cyclic AMP-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37) in the cyclic AMP-sensitive (S) and cyclic AMP-resistant (R) lymphoma cells were comparatively studied. The cyclic AMP-dependent protein kinase activity or R cells cytosol exhibits an apparent Ka for activation by cyclic AMP 100-fold greater than that of the enzyme from the parental S cells. The free regulatory and catalytic subunits from both S and R kinase are thermolabile, when associated in the holoenzyme the two subunits are more stable to heat inactivation in R kinase than in S kinase. The increased heat stability of R kinase is observed however only for the enzyme in which the catalytic and cyclic AMP-binding activities are expressed at high cyclic AMP concentrations (10(-5)--10(-4) M), the activities expressed at low cyclic AMP concentrations (10(-9)--10(-6) M) being thermolabile. The regulatory subunit of S kinase can be stabilized against heat inactivation by cyclic AMP binding both at 2-10(-7) and 10(-5) M cyclic AMP concentrations. In contrast, the regulatory subunit-cyclic AMP complex from R kinase is stable to heat inactivation only when formed in the presence of high cyclic AMP concentrations (10(-5)M). The findings indicate that the transition from a cyclic AMP-sensitive to a cyclic AMP-resistant lymphoma cell phenotype is related to a structural alteration in the regulatory subunit of the cyclic AMP-dependent protein kinase which has affected the protein's affinity for cyclic AMP and its interaction with the catalytic subunit.
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PMID:Altered regulation of cyclic AMP-dependent protein kinase in a mouse lymphoma cell line. 19 71

Wild-type S49 lymphoma cells respond to cyclic adenosine 3', 5'-monophosphate (cAMP) by inducing cAMP phosphodiesterase, halting growth in the G1 phase of the cell cycle and subsequently dying. By using a counter selection procedure, we have isolated a new class of mutants of S49 cells termed "deathless" that are resistant to cytolysis, but otherwise respond like the wild-type cells to cAMP. Upon removal of the cyclic nucleotide, D-cells resume their normal growth. Unlike all other cAMP-resistant mutants of S49 cells isolated until now, the D- mutant has a functionally normal cAMP-dependent protein kinase and retains normal ability to induce phosphodiesterase and arrest cell growth in G1. It is probable that the altered gene product of the D- mutant is distal to protein kinase and in a biochemical pathway separate from that of cAMP induction of phosphodiesterase or growth arrest. The D- mutant may facilitate studies of the mechanism of cAMP-induced cytolysis and growth regulation in S49 cells.
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PMID:Cyclic AMP-induced cytolysis in S49 cells: selection of an unresponsive "deathless" mutant. 19 2


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