Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoietin is a glycoprotein factor which specifically regulates the proliferation and differentiation of erythroid progenitor cells. We have investigated here the biochemical mechanisms of erythroid differentiation on mouse erythroleukemia SKT6 cells which can be induced to differentiate either with erythropoietin or dimethyl sulfoxide (Me2SO). cAMP-elevating agents, such as forskolin and 3-isobutyl-1-methyl-xanthine, caused spontaneous erythroid differentiation, and these agents showed the stimulatory effects on erythropoietin- or Me2SO-induced differentiation. An adenylate cyclase inhibitor, 2',5'-dideoxyadenosine, blocked erythropoietin-induced differentiation. The intracellular cAMP level was rapidly increased by addition of erythropoietin but not by Me2SO. These observations suggest that erythroid differentiation induced by erythropoietin is mediated, at least in part, through the cAMP-dependent pathway. When the effect of erythropoietin and Me2SO on the intracellular Ca2+ level was examined using fura 2, no acute change was observed. Measurements of the levels of inositol 1,4,5-trisphosphate and diacylglycerol following stimulation with erythropoietin or Me2SO showed that phosphatidylinositol turnover did not change significantly after erythropoietin stimulation but decreased gradually after Me2SO induction. Taken together, these results indicate that a complex signaling network including the cAMP-dependent pathway is involved in the erythroid differentiation process.
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PMID:Transmembrane signaling during erythropoietin- and dimethylsulfoxide-induced erythroid cell differentiation. 217 31

The review provides a survey of current knowledge about the changes in hormone-sensitive adenylate cyclase complex of erythroid cells. The basal enzyme activity decreases continuously during differentiation and maturation. Guanine nucleotides (GTP and GMP-P (NH)P) increase the adenylate cyclase activity of both early and late rabbit bone marrow erythroblasts. The stimulating effect of the beta 2-adrenergic drugs such as L-isoprenaline is limited to the immature cells. L-noradrenaline, a beta 1-agonist is inactive. The lack of response of non-dividing rabbit erythroblasts to beta-adrenergic stimuli is not due to loss of beta-receptors during differentiation, but to a decrease in the effectiveness of the coupling between the components of the system: receptor-guanine nucleotide regulatory protein-catalytic subunit. Prostaglandins E1 and E2 consistently enhance adenylate cyclase activity of erythroblasts on different stages of development. Erythropoietin (0.2 U/ml) causes a transient increase in the activity of adenylate cyclase, which is maximal by 20 min incubation of the cells in the presence of the hormone and disappears within 4 hours. The magnitude of the response to erythropoietin depends on the stage of erythroid cell development and is inverse related to the extent of previous hormonal stimulation of the cell.
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PMID:Adenylate cyclase system of differentiating erythroid cells. 228 99

We have presented a model for the role of external messenger substances in hypoxic stimulation of kidney production of erythropoietin. These autacoids probably act in concert to activate the adenylate cyclase system to enhance production and/or secretion of erythropoietin. The phosphoproteins generated in this system could act at the level of transcription and translation of erythropoietin as well as at the level of release of erythropoietin from the cell. Even though eicosanoids and beta-2-adrenergic agonists may be involved in mild to moderate hypoxia, it seems more likely that adenosine is more involved in erythropoietin production with increasing severity of hypoxia. Adenosine may play a very early role in hypoxia following the decrease in ATP to trigger erythropoietin production, and hydrogen peroxide may be generated from hypoxanthine, a metabolite of adenosine, during reoxygenation and regional changes in blood flow in the normal kidney and perhaps in certain renal and hepatic tumors. Further work is necessary in vivo to completely clarify the role of adenosine and oxygen free radicals in regulating kidney production of erythropoietin.
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PMID:External messengers and erythropoietin production. 254 24

The possibility that catecholamines modulate the erythropoietin-induced increase in production of cyclic AMP was investigated by examining the effect of erythropoietin and/or L-isoprenaline on the activity of the plasma membrane adenylate cyclase of anaemic rabbit bone marrow erythroblasts. Membranes isolated from cells cultured in the presence of both hormones exhibited both the transient stimulation of basal activity characteristic of erythropoietin action and the loss of the in vitro response to L-isoprenaline, concomitant with the loss of beta-adrenergic receptors, characteristic of L-isoprenaline stimulation. The presence of erythropoietin during cell culture with L-isoprenaline had no effect on the desensitization or number of beta-adrenergic receptors. The stimulation of adenylate cyclase by erythropoietin was observed also in the presence of the beta-antagonist propranolol, when both were added either to whole cells or to isolated membranes. We conclude that these two hormones activate adenylate cyclase independently of each other, via different receptors, with little evidence of cross-modulation.
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PMID:Independent activation of adenylate cyclase by erythropoietin and isoprenaline. 283 45

The role of prostaglandins in the mediation of hypoxia-stimulated erythropoietin (Ep) production by cultured rat renal mesangial cells was examined. It was found that an increase in prostaglandin E2 (PGE2) production accompanied the rise in Ep due to hypoxia (2% O2). The hypoxia-stimulated increase in Ep production was abolished in the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M). When PGE2 (10(-6) M was added simultaneously with indomethacin, however, no diminution in hypoxia-stimulated Ep production was observed. Addition of arachidonic acid (AA, 10(-5) M), PGE2 (10(-6) M), or PGI2 (10(-4) M) enhanced Ep production under normoxic conditions (20% O2), while PGF2 alpha (10(-6) M) had no effect on Ep production. AA, PGE2, and PGI2 were found to stimulate adenosine 3',5'-cyclic monophosphate formation by the cultured mesangial cells. Enhancement of adenylate cyclase activity by forskolin (10(-5) M) also increased Ep production in the cell cultures. Our results suggest that hypoxia-stimulated Ep production by cultured mesangial cells is mediated by prostaglandins with subsequent stimulation of adenylate cyclase activity.
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PMID:Role of prostaglandins in hypoxia-stimulated erythropoietin production. 299 Feb 27

This study was done to investigate aspects of control of extrarenal erythropoietin (Ep) production. To this end we studied the effects of three stimuli of renal Ep production in the adult, i.e. hypoxia, cobalt, and activation of adenylate cyclase on Ep generation by cultured fetal mouse liver cells. The fetal liver was taken as a model for extrarenal Ep production because this organ is considered the predominant site of extrarenal Ep production. We found that Ep production by the cells increased as the oxygen concentration was decreased in the incubation atmosphere from 20% to 1%. Cobalt (10(-4)-10(-5) M) had no effect on Ep production. Activation of adenylate cyclase by forskolin (10(-5) M) or isoproterenol (10(-5) M) greatly enhanced Ep production. These findings indicate that the Ep-stimulating effect of cobalt is specific for the kidney. However, oxygen depletion and activation of adenylate cyclase seem to be more general stimuli in Ep-producing cells. Furthermore we found that Ep production in hypoxia correlated with lactate formation in the cultured liver cells. This finding suggests that Ep production in fetal livers under hypoxic conditions parallels the shift from aerobic to anaerobic cellular energy metabolism.
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PMID:Erythropoietin production by fetal mouse liver cells in response to hypoxia and adenylate cyclase stimulation. 300 55

A model for the regulation of erythropoietin production has been presented. This model proposes that a primary O2-sensing reaction in the kidney is initiated by a decrease in ambient PO2, a rapid decrease in gas exchange in the lung, a diminished oxygen-carrying capacity of hemoglobin, a molecular deprivation of oxygen, or a decrease in renal blood flow. It is proposed that the primary oxygen-sensing reaction may trigger the release of several mediators that stimulate adenylate cyclase through a receptor-activated stimulation of a G protein in the renal cell membrane. Some of the agents that are thought to be released during hypoxia, which may trigger this cascade, are adenosine (A2 activation), eicosanoids (PGE2, PGI2, and 6-keto PGE1), oxygen-free radicals (superoxide and H2O2), and catecholamines with beta-2 adrenergic receptor agonist properties. The activation of adenylate cyclase generates cyclic AMP, which activates protein kinase A, leading to the production of a phosphoprotein that, in turn, activates a nuclear protein involved in transcription and/or translation for erythropoietin biosynthesis and/or secretion. A second part of this model concerns the effect of hypoxia on a renal cell membrane phosphodiesterase and the generation of inositol triphosphate and diacylglycerol. Diacylglycerol may interact with diacylglycerol lipase to generate arachidonic acid, which, together with arachidonic acid generated by the interaction of phospholipase A2 on membrane phospholipids, produces eicosanoids. Eicosanoids may play a secondary role in Ep production/secretion. The model further proposes that calcium levels in both renal and liver cells may be important in regulating erythropoietin biosynthesis and/or secretion. It is proposed that an increase in intracellular calcium leads to the inhibition of erythropoietin biosynthesis and/or secretion and a decrease in intracellular calcium increases erythropoietin production. The specific mechanism by which calcium regulates erythropoietin biosynthesis and secretion is not well understood. However, a good correlation is seen with several agents that decrease intracellular calcium and increase erythropoietin production as well as with other agents that increase intracellular calcium and decrease erythropoietin production. When inositol triphosphate levels are increased, an increase in the mobilization of intracellular calcium from the endoplasmic reticulum or another intracellular pool occurs. This increased intracellular calcium probably activates a calcium calmodulin kinase and produces a phosphoprotein that inhibits erythropoietin production/secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacologic modulation of erythropoietin production. 328 82

The involvement of adenylate cyclase in the response elicited by erythropoietin was investigated in fractionated erythroblasts obtained from anaemic rabbit bone marrow. Addition of 0.2 U/ml erythropoietin to cell cultures caused a transient increase in the activity of plasma membrane adenylate cyclase, which was observed within 5 minutes, was maximal by 20 minutes and disappeared within 4 hours. The magnitude of the response to hormonal stimulation depended on the stage of erythroid cell development and was greater in the more immature cells. Erythropoietin could also stimulate the basal activity of adenylate cyclase in an in vitro assay containing plasma membranes of immature, but not mature, erythroid cells. The degree of activation was hormone-concentration dependent, was maximal at 0.2-0.5 U/ml erythropoietin (5-12 nM) and was observed in the absence of exogenous guanine nucleotides. The in vitro effect of erythropoietin, however, was abolished by GDP (S) and extensive washing of the membranes made hormone action GTP-dependent. The ability of the hormone to stimulate adenylate cyclase activity in vitro was inversely related to the extent of hormonal stimulation in vivo. This desensitization was observed within 20 minutes and persisted for many hours. It is suggested that erythropoietin activates the adenylate cyclase of immature erythroblasts via a receptor and a guanine nucleotide-binding protein with high affinity for GTP.
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PMID:The effect of erythropoietin on the adenylate cyclase activity of rabbit bone marrow erythroblasts. 359 94

The effect of two agents of erythroid cell differentiation on the adenylate cyclase activity of fractionated rabbit bone marrow erythroblasts has been investigated. Addition of 0.2U/ml erythropoietin to cell cultures causes a transient increase in the activity of plasma membrane adenylate cyclase, which is maximal by 20 min and disappears within 4 h. The magnitude of the response to hormonal stimulation depends on the stage of erythroid cell development and is greater in the more immature cells. Addition of 50 microM haemin to cultures of erythroblasts also causes an increase in the activity of adenylate cyclase, which differs from the effect of erythropoietin in kinetics and specificity of target cells. With immature cells the haemin-induced stimulation starts after the first hour and continues to increase up to 20 h of culture. Erythropoietin but not haemin can stimulate the basal activity of adenylate cyclase in an in vitro assay containing plasma membranes of immature erythroid cells. The degree of activation depends on the concentration of erythropoietin and is maximal with 0.2-0.5 U/ml hormone (5-12 nM). In the presence of guanine nucleotides the activation of adenylate cyclase by erythropoietin is increased further but the effect is not additive. With respect to the basal and the guanine-nucleotide-stimulated activities of adenylate cyclase erythropoietin acts differently from the beta-agonist l-isoprenaline. The in vitro effect of erythropoietin is abolished by the beta-thio analogue of GDP, GDP[beta S], and extensive washing of membranes makes hormone action GTP-dependent. The stimulation of adenylate cyclase by the addition of erythropoietin to the reaction mixture is inversely related to the extent of previous hormonal stimulation of the cells from which the membranes were prepared. This loss of hormonal responsiveness is due to desensitization or receptor down-regulation and persists for up to 20 h. We conclude that in immature erythroblasts erythropoietin acts via a receptor and a guanine nucleotide-binding protein with high affinity for GTP (EC50 less than 10 nM), whereas haemin appears to activate adenylate cyclase indirectly, as a consequence of progressive perturbations of the plasma membrane.
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PMID:Stimulation of the adenylate cyclase activity of rabbit bone marrow immature erythroblasts by erythropoietin and haemin. 395 92

The formation of erythroid colonies from bone marrow and spleen cells infected with the polycythemic strain of the Friend virus (FV-P) was characterized in an in vitro methyl cellulose colony-forming system in response to prostaglandin E1 and the beta-2 adrenergic agonist, albuterol. Both drugs markedly inhibited the formation of CFU-E colonies of FV-P-infected bone marrow and spleen in the absence or presence of erythropoietin. The albuterol-mediated inhibition of CFU-E colonies (FV-P-infected) was selectively blocked by butoxamine, a beta-2 antagonist. Adenylate cyclase (AC) activity was also determined in FV-P spleen membrane preparations in response to albuterol and PGE1. Both agents stimulated enzyme activity, and butoxamine blocked the stimulation seen with albuterol. The ability of albuterol and PGE1 to stimulate AC activity in the FV-P-infected cells suggests that the effects of these agents on CFU-E formation may be mediated by specific beta-2 adrenergic and PG receptors through the adenylate cyclase-cyclic AMP system.
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PMID:Effects of beta adrenergic agents and prostaglandin E1 on erythroid colony (CFU-E) growth and cyclic AMP formation in Friend erythroleukemic cells. 625 32


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