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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of HL-60 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1-5 nM) induced inhibition of cell growth and the appearance of an adherent monocyte-like cell type in a dose- and time-dependent manner. The extent of TPA-induced monocytic differentiation was found to be markedly reduced by okadaic acid (OA) (35 nM). OA had to be present for the early 12 h during treatment with TPA to reduce the induction of monocytic differentiation. The majority of cells (80%) were non-adherent but morphologically resembled mature myelocytes or granulocytes after treatment with TPA (5 nM) in the presence of OA (35 nM). Vanadate (VD), on the other hand, enhanced the extent of monocytic differentiation induced by low-dose of TPA (1 nM). These results indicated that dephosphorylation by tyrosine protein phosphatase and serine-threonine protein phosphatase may play an important role in the induction of monocytic and granulocytic differentiation.
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PMID:Effects of okadaic acid and vanadate on TPA-induced monocytic differentiation in human promyelocytic leukemia cell line HL-60. 773 56

Activation pathways inducing the expression of the interferon (IFN)-gamma gene in a cytotoxic T lymphocyte (CTL) clone were studied for their effects on transcription and on mRNA stability. IFN-gamma was secreted by the CTL clone in response to the Ca2+ ionophore ionomycin when used in conjunction with either protein kinase C (PKC)-activating phorbol 12-myristate 13-acetate (PMA) or with agents increasing cAMP, including prostaglandin E2. We describe that ionomycin induced IFN-gamma gene transcription, which was totally inhibited in the presence of cyclosporin A (CSA), an immunosuppressant forming a calcineurin-inhibiting complex with cyclophilin. Ionomycin did not, however, permit accumulation of IFN-gamma mRNA. Activation of PKC by PMA or of cAMP-dependent protein kinase through increase in cAMP had no transcription-inducing effect, either alone or in conjunction with ionomycin, as measured in run on assays of the IFN-gamma gene. When transcription of the IFN-gamma gene, initiated in the presence of ionomycin and an agent increasing intracellular cAMP, was inhibited by CSA in the absence of PKC or cAMP-dependent protein kinase activation, the IFN-gamma mRNA was rapidly degraded (half-life = 30 min). When either PKC was activated or intracellular cAMP was increased at the time of inhibition with CSA, a stabilizing effect was observed on IFN-gamma mRNA, which led to an increase in secreted IFN-gamma. These effects were selective, they did not affect the rate of transcription of the actin gene, nor the accumulation of actin mRNA. These results show that (i) post-transcriptional events can be critical for IFN-gamma expression in activated lymphocytes, and (ii) specific stabilization of IFN-gamma mRNA can be mediated by activation of two different protein kinases involved in T cell activation.
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PMID:Regulation of interferon-gamma mRNA in a cytolytic T cell clone: Ca(2+)-induced transcription followed by mRNA stabilization through activation of protein kinase C or increase in cAMP. 773 90

Challenge of intact hepatocytes with insulin reduced the level of phosphorylated alpha-Gi-2 found under basal (resting) conditions. At maximally effective concentrations of insulin the steady-state labelling of alpha-Gi-2 was reduced by approximately 21%. Insulin achieved this in a time- and dose-dependent fashion, exhibiting an IC50 value of 109 +/- 22 pM. The increased labelling of alpha-Gi-2 seen after challenge of cells with phorbol 12-myristate 13-acetate was also attenuated by insulin. Treatment of hepatocytes with the protein phosphatase inhibitor okadaic acid increased the labelling of alpha-Gi-2 in a fashion which was insensitive to the action of insulin. It is suggested that insulin may reduce the level of phosphorylation of alpha-Gi-2 by stimulating intracellular protein phosphatase activity and that this action may offer a molecular explanation for the ability of insulin to inhibit adenylate cyclase activity in hepatocytes by increasing the level of non-phosphorylated alpha-Gi-2.
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PMID:Insulin inhibits the phosphorylation of alpha-Gi-2 in intact hepatocytes. 777 59

Thyrsiferyl 23-acetate (TF23A), a cytotoxic compound from marine red alga, has been shown to potently and specifically inhibit serine/threonine protein phosphatase 2A (PP2A) with IC50 values of 4-16 microM, depending on the enzyme concentration. TF23A did not affect activity of protein phosphatase 1 (PP1), 2B (PP2B), 2C (PP2C), or protein tyrosine phosphatases (PTP) up to 1 mM. It inhibited PP2A activity in a crude extract of a human T cell line, Jurkat cell, as well as the purified catalytic subunit. Thus, TF23A proved to be a novel useful probe for clearly distinguishing the activity of PP2A from those of the other protein phosphatases in crude cell extracts and identification of cellular processes that are regulated by PP2A.
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PMID:Thyrsiferyl 23-acetate is a novel specific inhibitor of protein phosphatase PP2A. 780 52

To investigate a possible relationship between apoptosis induction and protein phosphorylation in human breast carcinoma cells, we treated three such cell types, MB-231, MCF-7, and AU-565, with okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A, or phorbol 12 myristate 13-acetate, an activator of protein kinase C. We then examined these cells for the appearance of apoptosis markers. While OA caused multiplication arrest and cytotoxicity in all three cell lines, apoptosis was induced in MB-231 and MCF-7 cells but not in AU-565 cells. A similar cell-specific apoptosis induction was also observed after treatment with dinophysistoxin-1 (an active OA analogue) and with calyculin A (a structurally unrelated protein phosphatase inhibitor) but not with analogues that either are inactive or penetrate epithelial cells poorly. Phorbol 12-myristate 13-acetate also inhibited cell multiplication but was without effect in inducing apoptosis in these cells. Levels of the apoptosis-inhibitory protein BCL2 were examined in these cells, but they did not correlate with this differential susceptibility. We additionally treated the three cell types with 1-beta-D-arabinofuranosylcytosine and genistein to determine whether the AU-565 cell line would also be resistant to apoptosis induction by other chemical stimuli. Both of these agents led to the induction of apoptosis in all three cell lines. These results indicate that the AU-565 cells are specifically resistant to apoptosis induction by inhibitors of protein phosphatases 1 and 2A. This cell-specific resistance may thus allow one to identify cellular mediators of apoptosis by comparing protein phosphorylation patterns in these cells before and after treatment with OA or related inhibitors.
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PMID:Differential induction of apoptosis in human breast tumor cells by okadaic acid and related inhibitors of protein phosphatases 1 and 2A. 781 37

Our laboratory has recently demonstrated that 1,25-dihydroxyvitamin D3(1,25(OH)2D3) rapidly stimulated membrane polyphosphoinositide breakdown and increased intracellular calcium, as well as activated protein kinase C (PKC) in vitamin D-sufficient rat colonocytes. These effects of 1,25(OH)2D3 were, however, lost in vitamin D-insufficient rats and restored by the in vivo repletion of 1,25(OH)2D3. In the present studies we have examined the ability of 1,25(OH)2D3 to stimulate the phosphorylation of colonic membrane proteins in intact D-sufficient cells. In addition, we investigated the effects of vitamin D status on the phosphorylation of these membrane proteins in broken cell preparations. These studies demonstrated that 1,25(OH)2D3 increased the phosphorylation of at least two colonic membrane proteins with apparent molecular weights of 42,000 (pp42) and 48,000 (pp48) in intact cells of vitamin D-sufficient rats. Moreover, in vitamin D-sufficient rats, treatment of colonocytes with 1,25(OH)2D3 or 12-O-tetradecanoyl phorbol 13-acetate (TPA), a known activator of PKC, significantly increased the phosphorylation of pp42 and pp48 in broken cell preparations. The kinetics of these phosphorylations in response to 1,25(OH)2D3 were both rapid and transient. In addition, PKC19-36, a specific PKC inhibitor, decreased the phosphorylation of pp42 and pp48, whereas okadaic acid (OA), a type 1 and 2A protein phosphatase inhibitor, further augmented their phosphorylation in response to 1,25(OH)2D3. The isoelectric points of pp42 and pp48 were 5.79 and 5.97, respectively, and both were predominantly phosphorylated on threonine residues. In contrast to our findings in colonocytes from vitamin D-sufficient animals, basal phosphorylation of pp42 and pp48 were increased in membranes prepared from vitamin D-insufficient rats. Moreover, these phosphorylations failed to change in response to 1,25(OH)2D3-treatment of colonocytes from vitamin D-insufficient rats. The basal phosphorylation of each of these proteins was restored to control levels, as was their ability to respond to the direct addition of 1,25(OH)2D3 following the in vivo repletion of vitamin D-insufficient rats with this secosteroid. In summary, we have identified two acidic membrane proteins from rat colonocytes that are phosphorylated in both intact and broken cell preparations in response to 1,25(OH)2D3 treatment, an event modulated by vitamin D status and mediated, at least in part, by PKC.
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PMID:1,25-Dihydroxyvitamin D3 stimulates the phosphorylation of two acidic membrane proteins of 42,000 and 48,000 daltons in rat colonocytes: an effect modulated by vitamin D status. 782 28

Engagement of the T cell receptor for antigen activates phospholipase C resulting in an increase in intracellular free calcium concentration ([Ca2+]i) and activation of protein kinase C (PKC). Increased [Ca2+]i activates Ca2+/calmodulin-dependent kinases including the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM-K II), as well as calcineurin, a type 2B protein phosphatase. Recent studies have identified calcineurin as a key enzyme for interleukin (IL)-2 and IL-4 promoter activation. However, the role of CaM-K II remains unknown. We have used mutants of these kinases and phosphatases (gamma B*CaM-K and delta CaM-AI, respectively) to explore their relative role in cytokine gene transcription and their interactions with PKC-dependent signaling systems. gamma B*CaM-K and delta CaM-AI, known to exhibit constitutive Ca(2+)-independent activity, were cotransfected (alone or in combination) in Jurkat T cells with a plasmid containing the intact IL-2 promoter driving the expression of the chloramphenicol acetyltransferase reporter gene. Cotransfection of gamma B*CaM-K with the IL-2 promoter construct downregulated its transcription in response to stimulation with ionomycin and phorbol myristate acetate (PMA). The inhibitory effect of CaM-K II on IL-2 promoter was associated with decreased transcription of its AP-1 and NF-AT transactivating pathways. Under the same conditions, delta CaM-AI superinduced IL-2 promoter activity (approximately twofold increase). When both mutants were used in combination, gamma B*CaM-K inhibited the induction of the IL-2 promoter by delta CaM-AI. Similar results were obtained when a construct containing the IL-4 promoter also was used. gamma B*CaM-K also downregulated the activation of AP-1 in response to transfection with a constitutively active mutant of PKC or stimulation with PMA. These results suggest that CaM-K II may exert negative influences on cytokine gene transcription in human T cells, and provide preliminary evidence for negative cross-talk with the calcineurin- and PKC-dependent signaling systems.
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PMID:Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells. 786 38

Mechanisms of regulation of GABAA receptor function by intracellular calcium ([Ca2+]i) were examined in cell somata and apical dendrites of pyramidal cells, acutely dissociated from the CA1 hippocampal subfield of adult guinea-pigs. GABAA receptor-mediated currents were measured by whole-cell clamp recordings. N-methyl-D-aspartate receptor-mediated currents were used as conditioning source of calcium influx. Peak amplitudes of somatic GABAA whole-cell currents were reduced to about 15% of control values when net inward charge accumulation by N-methyl-D-aspartate currents reached 1.85 nC. A similar decline of GABAA currents was observed in dendritic recordings. The N-methyl-D-aspartate-mediated reduction of somatic and dendritic GABAA currents was accompanied by a well correlated decrease in peak and chord conductances. Pharmacological blockade of N-methyl-D-aspartate currents by 2-amino-5-phosphonopentanoic acid prevented the N-methyl-D-aspartate-mediated suppression of GABAA responses. The N-methyl-D-aspartate effect was mediated by the calcium component of N-methyl-D-aspartate receptor-mediated currents as demonstrated by a lack of effect in the absence of extracellular calcium and faster N-methyl-D-aspartate-mediated suppression of GABAA responses in lower intracellular 1,2-bis(2-aminophenoxy)ethane-N,N,N',N"-tetra-acetate. N-methyl-D-aspartate-mediated suppression of GABAA currents was significantly less expressed when intracellular ATP was replaced by its analog adenosine 5'-O-(3-thiotriphosphate) and when the specific phosphatase 2B inhibitor cypermethrin was added intracellularly. The reduction of GABAA responses persisted after cessation of N-methyl-D-aspartate-mediated calcium influx, indicating a long-term action of N-methyl-D-aspartate on GABAA responses. Voltage-activated calcium currents did not affect GABAA responses under the experimental conditions applied. In conclusion, the data presented show that calcium influxes through N-methyl-D-aspartate receptor channels result in long-term suppression of GABAA receptor function in CA1 pyramidal cells. Intracellular mechanisms of N-methyl-D-aspartate-mediated reduction of GABAA conductances involve activation of phosphatase 2B and consecutive dephosphorylation of the GABAA receptor or a closely associated GABAA receptor-regulating enzyme. Possible mechanisms of such a distinct N-methyl-D-aspartate-dependent calcium signalling pathway in the dephosphorylation-dependent suppression or GABAA receptor function are discussed.
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PMID:Impairment of GABAA receptor function by N-methyl-D-aspartate-mediated calcium influx in isolated CA1 pyramidal cells. 787 Mar 9

The effect of the tumor promoter okadaic acid on cell cycle progression and on vimentin expression in MPC-11 mouse plasmacytoma cells was compared with that of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Cell cycle progression of asynchronously grown MPC-11 cells was inhibited by both agents, but, in contrast to the G1 phase arrest caused by TPA, okadaic acid gave rise to G2/M phase and S phase arrest. This effect of okadaic acid was delayed significantly compared to the TPA-caused arrest. Furthermore, okadaic acid was able to induce vimentin expression to an extent comparable to the TPA response. However, vimentin expression was markedly delayed in okadaic acid-treated relative to TPA-treated cells. Another protein phosphatase inhibitor, calyculin A, also induced cell cycle changes and vimentin expression at concentrations at or above 1 x 10(-9) M. Based on these observations, we suggest an involvement of protein phosphatase 1 (possibly also phosphatase 2A and/or other phosphatases) in both the G2/M cell cycle block and the induction of vimentin expression in MPC-11 cells by okadaic acid.
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PMID:Okadaic acid Co-induces vimentin expression and cell cycle arrest in MPC-11 mouse plasmacytoma cells. 789 91

alpha 1-Adrenergic (alpha 1-AR) agents stimulate NaCl(K) cotransport and phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2]-specific phospholipase C in human trachea and nasal polyp epithelial cells. One second messenger generated by PtdIns(4,5)P2 degradation is inositol trisphosphate. We now show that diglycerides (DG) are also generated during alpha 1-AR stimulation. In cells prelabeled with [3H]arachidonic acid, alpha 1-AR agents produced a biphasic DG generation in normal and cystic fibrosis (CF) cells that is blocked by pertussis toxin. The early DG peak closely paralleled PtdIns(4,5)P2 degradation, stimulation of cotransport by phorbol 12-myristate 13-acetate (PMA), and inhibition of cotransport by the protein kinase C (PKC) inhibitor staurosporine. This suggests that cotransporter activation requires PKC-protein phosphorylation. This possibility was tested using the protein phosphatase inhibitor okadaic acid. Okadaic acid elevated bumetanide-sensitive Cl efflux. Staurosporine also blocked > 63% of okadaic-acid-stimulated Cl transport. The late DG peak did not support hormone-stimulated cotransport. The results demonstrate that DGs are a pivotal link between alpha 1-AR stimulation and NaCl(K) cotransport activation with a role for PKC and protein phosphorylation. alpha 1-AR intracellular signaling mechanisms apparently operate normally in CF cells.
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PMID:The role of protein kinase C in alpha-adrenergic regulation of NaCl(K) cotransport in human airway epithelial cells. 790 Aug 23


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