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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Keyhole limpet hemocyanin was injected into the hind foot pads of rabbits. Six days later cell suspensions were prepared from the popliteal lymph nodes. Various amounts of hemocyanin (1 ng to 100 mug) were added to 1 times 10-7 cells to induce an anamnestic antibody response. Various amounts of cholera enterotoxin, which stimulates the enzyme adenylate cyclase, or dibutyryl cyclic adenosine 3'5'-monophosphate (AMP), were added to the cultures with or without hemocyanin. De novo synthesis of antibody, protein, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) from radioactive precursors was assayed. The addition of cholera toxin or dibutyryl cyclic AMP for the first 24 hr with optimal (1 mug) or supraoptimal (100 mug) amounts of hemocyanin enhanced antibody synthesis by at least 100 to 200%. Addition of the toxin or dibutyryl cyclic AMP for the same period to cells minus hemocyanin or with suboptimal amounts (1 to 100 ng) of antigen failed to enhance antibody synthesis. Addition of these agents for 72 to 120 hr to hemocyanin-induced cultures consistently inhibited antibody synthesis. These agents slightly inhibited DNA and RNA synthesis. The increase in protein synthesis caused by the toxin or dibutyryl cyclic AMP was almost totally accounted for by the increase in antibody synthesis. Neither toxin nor cyclic nucleotide promoted the antibody response in the presence of antibody to rabbit thymus-derived lymphocytes; these lymphocytes as well as bursa-equivalent lymphocytes were required for potentiation of the response. Macrophages were not required either for induction of the anamnestic response or for enhancement of this synthesis by cyclic nucleotide or cholera toxin. Both IgM and IgG antibody synthesis were regulated by exogenous cholera toxin and dibutyryl cyclic AMP. A number of possible cellular mechanisms of regulation of the antibody response through the cyclic AMP pathway were discussed. These included the effects of modifications of this pathway on the activities of T lymphocytes early (0 to 24 hr) and B lymphocytes late (72 to 120 hr) in the response and on the apparent reversal of high zone tolerance.
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PMID:Regulation of the in vitro early anamnestic antibody response by exogenous cholera enterotoxin and cyclic AMP. 16 58

The concentration of cyclic AMP (cAMP) and its metabolites (5'-AMP and adenosine) as well as the adenyl cyclase, cAMP phosphodiesterase, and 5'-nucleotidase activities were determined in lymphocytes of thymus, spleen, and lymph nodes of control and protein-deficient rats. The values of these parameters, when expressed as per milligran DNA and as per 10-8 cells, but not always when expressed as per milligran protein, were much lower in the thymus as compared with the spleen and the lymph nodes in the control rats. The protein-deficient diet increased the nucleotide concentrations in the thymus and spleen lymphocytes on a per milligram DNA basis except those of thymic cAMP, which did not change. The same diet also increased the activities of the enzymes involved in the cAMP metabolism in thymic, splenic, and lymph node lymphocytes. Such a peculiarity could be related to the reduction of the mitotic activity of lymphocytes caused by protein deficiency since an inverse relationship has been reported between this activity and the synthesis of cAMP. On the other hand, it was noted that purified lymphocyte suspensions contained paradoxically higher amounts per cell of DNA, RNA, and protein in the thymus, spleen, and lymph nodes of protein-deficient rats as compared with those of the control rats. However, when the cell preparations were not purified, only the lymph node cells displayed a strong increase in their DNA content. Prolongation of the S phase of the cell cycle in these lymphocytes is suggested.
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PMID:Cyclic AMP metabolism and nucleic acid content in the lymphocytes of the thymus, spleen, and lymph nodes of protein-deficient rats. 16 50

Cyclic adenosine 3':5'-monophosphate (cyclic AMP) levels were slightly increased in preleukemic AKR mouse thymus cells, compared with nonleukemic thymus cells, but were markedly reduced in leukemic cells. Adenylate cyclase activity rose during the preleukemic and leukemic phases of leukemogenesis. Although the drop of epinephrine-induced stimulation of thymus adenylate cyclase in the preleukemic phase was probably age related, there was an additional decrease of adenylate cyclase activation by epinephrine in leukemic cells. Cyclic AMP phosphodiesterase activity was slightly higher in preleukemic cells and more than fourfold AKR thymus. These observations suggest that cyclic AMP phosphodiesterase is largely responsible for the low levels of cyclic AMP in leukemic cells. Significant changes in cyclic AMP metabolism are already detectable before neoplastic cells may be found in the thymus.
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PMID:Changes in lymphoid cyclic adenosine 3':5'-monophosphate metabolism during murine leukemogenesis. 16 59

Studies with chemically modified cholera toxin derivatives showed that all treatments that decreased the ability of toxin to bind to mouse thymus cells or to polystyrene-coupled GM1 ganglioside caused a concomitant reduction in the toxin's ability to increase adenosine 3':5'-cyclic phosphate (cyclic AMP) in thymus cells and skin vascular permeability in rabbits. Dissociation of the H (heavy) and L (light) subunits abolished the biologic activity without inhibiting receptor binding, as did treatment with arginyl-specific reagents (which did not change the aggregation state of the toxin). When thymus cells were incubated with 125I-labelled toxin at 37C,only about 1% of the total cell-bound radioactivity was recovered in the cytosol supernate. Similar values were found for cells incubated with toxin at 0C, and with 125I-labelled choleragenoid at 37C or 0C. Thymus cells rapidly bound less than or equal to equal to 5 X 10(4) cholera toxin molecules per cell at both 0C and 37C. Much less, however, of the radioactive toxin bound at 37C than of that bound at 0C was displaced by addition of unlabelled toxin or choleragenoid. Similar temperature-related irreversible binding was noted with 125I-labelled choleragenoid. The relative amounts of H and L subunits in the irreversibly cell-bound and in the displaced 125I-labelled toxin were indistinguishable. Treatment of thymus cells at 37C, but not at 0C, with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide caused a 10-fold reduction of adenylate cyclase stimulation by cholera toxin without inhibiting activation by epinephrine or prostaglandin E1, or appreciably altering the basal, unstimulated enzyme activity. The carbodiimide inhibited the cyclic AMP response to cholera toxin when added shortly after the toxin had bound to the cells (early in the lag phase).
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PMID:Cholera toxin and the adenylate cyclase-activating signal. 17 82

Cholera toxin activates plasma membrane adenylate cyclase in all mammalian cell types. The structure-function relationship of the toxin has recently been clarified, and the cell membrane receptor identified. This information has made cholera toxin the "agent of choice" for studies in many biological systems of the possible regulatory role of adenylate cyclase/cyclic AMP. This article describes briefly our current knowledge about the toxin and its receptor. It then reviews recent research which has revealed that cholera toxin has strong modulating influences on the proliferation of normal and malignant lympocytes as well as on the initiation and expression of immune responses. The toxin has been found to inhibit DNA synthesis of B and T lymphocytes in vitro without inducing cell death and also to inhibit seems to decrease antibody secretion from plasma cells in vitro, and might also interfere with the release of other soluble immunological mediator subtances. In vivo cholera toxin induces a transient involution of the spleen and a more prolonged lymphocyte depletion of the thymus in mice; these effects appear to be mediated through the adrenal glands. The toxin inhibitors allograft rejection, and either stimulates or suppresses antibody formation depending on the timing of the toxin in relation to the antigen administration. It increases the capacity of the spleen cells to induce graft-vs-host reactions and the "allogeneic effect" on antibody production. An inhibitory effect on a normal suppressor population among the spleen cells has been identified. The findings illustrate the complex effects induced on the immune system by the probably most discriminative investigative tool available for stimulation of the adenylate cyclase/cyclic AMP system.
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PMID:Cholera toxin, ganglioside receptors and the immune response. 19 68

Lymphocytes were purified from peripheral blood of normal donors and patients with chronic lymphocytic leukemia (CLL) by Ficoll-Hypaque centrifugation. Adenylate cyclase activity, expressed as picomoles [(32)P]cyclic AMP generated per milligram protein per minute, was 57+/-4 in normals and 26+/-4 in CLL patients. Enzyme activity, expressed as picomoles [(32)P]cyclic AMP generated per 10(6) lymphocytes per minute, was 2.09+/-0.19 for normal lymphocytes and 1.10+/-0.16 for CLL lymphocytes. The differences between normal and CLL peripheral lymphocytes are highly significant (P < 0.001) with either method of calculating activity. Cyclic AMP levels (picomoles per 10(6) lymphocytes) also differed significantly: 1.38+/-0.29 for normals and 0.45+/-0.08 for CLL lymphocytes. Adenylate cyclase was assayed in lymphocytes enriched for bone marrow-derived (B) cells by removing E-rosetted thymus-derived (T) cells, and enriched for T cells by harvesting E-rosetted lymphocytes or by removing B cells with nylon wool absorption. Solutions to simultaneous equations gave the following calculated enzyme activities for pure B- and T-cell subpopulations (in picomoles [(32)P]cyclic AMP generated per milligram mg protein per minute): normal B, 196+/-22; normal T, 30+/-10; CLL B, 34+/-6; CLL T, 19+/-4. Thus. normal B-lymphocyte adenylate cyclase exceeds normal T-lymphocyte activity by more than sixfold, whereas in the case of CLL the enzyme activity in B lymphocytes is markedly reduced to levels comparable to T lymphocytes. The responses of lymphocytes to stimulation with the hormones prostaglandin E(1) and isoproterenol, and with NaF, were assessed. Compared with normal lymphocytes, enzyme activities were reduced in CLL lymphocytes incubated with these agents, but to a degree paralleling the reduced basal activities. Thus, the ratios between stimulated and basal adenylate cyclase levels in Ficoll-Hypaque-purified, normal lymphocytes were 2.3+/-0.1 after incubation with 10 muM isoproterenol, and 3.9+/-0.2 with 10 mM NaF, values which did not differ significantly from those obtained with CLL lymphocytes. When the enzyme activities calculated for purified T- and B-lymphocyte subpopulations were used to derive the stimulation ratios, the responses of normal and CLL T and B cells to these agents were also indistinguishable. The simplest explanation for these findings is a reduced number of normally responsive enzyme sites on the surface membranes of CLL lymphocytes, although alternative explanations are possible.
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PMID:Adenylate cyclase in thymus-derived and bone marrow-derived lymphocytes from normal donors and patients with chronic lymphocytic leukemia. 22 34

Prostaglandins (PG) of the E series, PGE(1) and PGE(2) (PGEs), can induce elevations of intracellular cyclic AMP (cAMP) among thymus-derived (T) lymphocytes (T cells) and inhibit their reactivity. For example, 0.1 muM of PGEs induces a two- to threefold increase of intracellular cAMP among human peripheral blood T cells and a 20-30% suppression of their blastogenic response to phytohemagglutinin. However, this suppression actually represents the net reactivity of T-cell populations demonstrating quite different responses to PGEs. Fractionation of T-enriched populations on a discontinuous density gradient yields a population of high density cells whose phytohemagglutinin-induced blastogenic response is suppressed 60%; a population of intermediate density cells whose response is suppressed 20%; and a population of low density T cells whose response is not suppressed, but is enhanced 20% by both of the PGEs. The diametrically opposite responses of low and high density T cells to the PGEs is not related to any difference in their intrinsic mitogen reactivity nor is it influenced by interactions with other T cells, bone marrow-derived (B) cells, or monocytes. Moreover, the distinct blastogenic response of low and high density T cells to PGEs does not simply correlate with PGE-mediated activation of adenylate cyclase. PGE(2) induced comparable absolute and identical relative increases of intracellular cAMP among the low and high density T cells. Cholera toxin, a potent activator of adenylate cyclase, and exogenous 8-bromo cAMP mimicked the effects of the PGEs on these two T-cell populations. These data demonstrate that T cells are heterogeneous with regard to their response to the PGEs. Thus, PGEs should be considered as potential regulators rather than as universal suppressors for T-cell reactivity. Moreover, the effect of PGEs on the blastogenic response of a given T-cell population depends upon intracellular events which occur subsequent to elevations of cAMP.
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PMID:Prostaglandin E modulation of the mitogenic response of human T cells. Differential response of T-cell subpopulations. 22 26

The thymus produces several polypeptides, which induce lymphocyte differentiation in vitro and in vivo. Several of these polypeptides have been chemically characterized, and three of them have been sequenced and synthesised (alpha 1 thymosin, thymopoietin and the serum thymic factor). Thymic hormones do not act identically on all T-cell subsets: they alter preferentially post-thymic precursor cells, and among mature T cells cytotoxic cells and suppressor cells. Their mode of action at the cellular level involves binding to specific cellular receptors and interaction with adenyl cyclase. Preliminary clinical trials with crude extracts have provided promising results in immunodeficient and cancer patients. The differentiation of T cells from stem cells has been the matter of considerable investigation over the last two decades, since it has been realized that the thymus and its products, the thymus-derived cells (T cells) play a central role in the generation of effector cells in cell-mediated immunity and in the regulation of the various categories of immune responses. That the thymus could act by the intermediate of humoral substances was precociously suggested by MILLER and OSOBA before the observation that thymuses grafted within a cell-impermeable Millipore diffusion chamber restored the immunocompetence of neonatally thymectomized (Tx) mice (1). However, although this experiment was ultimately confirmed by using chambers with well-controlled impermeability (2), MILLER did not pursue the idea of the humoral function of the thymus. Probably, the striking results obtained by DAVIES (3) and other workers, indicating direct migration of functional T cells from the thymus and the poor results initially obtained in trying to reconstitute the immune system of neonatally Tx mice by cell-free thymic extracts contributed to this disappointment. A new impetus was given to the subject in the early 70's when in vitro tests of lymphocyte function became available and when purified extracts of the thymus proved capable of restoring antigen-specific and non-specific immunocompetence of Tx mice. More recently, completely defined synthetic thymic hormones have been obtained. The question is no longer to decide whether thymic hormones exist, but rather to elucidate their biological significance and potential clinical applications. The multiplicity of available factors has created some confusion. It will be the aim of these few pages to review critically the various factors reported in the literature, giving particular emphasis to their pharmacology and their potential use in the modulation of immune responses.
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PMID:Thymic hormones. 23 13

A humoral factor extracted from calf thymus (THF) restores the immunocompetence of spleen cells from neonatally thymectomized (NTx) mice to induce an in vitro graft-vs-host (GVH) response. This acquistion of immunocompetence consists of a series of biochemical events, the first of which involves an obligatory rapid increase in adenyl cyclase acitivity and in intracellular levels of cyclic AMP. Protein synthesis occurs as a further step in the events leading to induction of immunocompetence by THF and could be blocked by cycloheximide with the consequent abolishment of the immunocompetence of the lymphoid cells tested. The induction of competence by THF is accompanied by a simultaneous reduction in DNA synthesis resulting from the increase in intracellular cyclic AMP levels. These steps have been studied in the absence of antigenic stimulation which is not required for the induction of competence by THF. Spleen extracts prepared by a similar procedure as THF were found to be devoid of the properties described above.
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PMID:Intracellular events involved in the induction of immune competence in lymphoid cells by a thymus humoral factor. 23 96

A polypeptide of 8500 molecular weight is described that induces the differentiation of T (thymus-derived) cell and B (bone-marrow-derived) cell immunocytes in vitro, apparently via beta-adrenergic receptors and adenylate cyclase activation. This polypeptide shows a high degree of evolutionary conservation, exhibiting close structural, functional, and immunological similarity when isolated from such diverse origins as cells of mammals and higher plants. This polypeptide was detected in animal cells, yeast, bacteria, and higher plants, and so may well be a universal constituent of living cells.
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PMID:Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. 107 92


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