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)

Endothelin-1 (ET-1) acts not only as a growth-promoting peptide but also as a potent survival factor against myocardial cell apoptosis. However, the signaling pathways leading to myocardial cell protection by ET-1 are poorly understood. Using a culture system of primary cardiac myocytes derived from neonatal rats, we show in the present study that ET-1 almost completely blocked the hydrogen peroxide-induced increase in the percentage of TdT-mediated dUTP-biotin nick-end labeling-positive myocytes. Apoptosis inhibition by ET-1 was confirmed by cytofluorometric analysis as well as by examination of the ladder formation, morphological features, and caspase-3 cleavage. We have found that ET-1 converts the nuclear factor of activated T lymphocytes (NFATc) in cardiac myocytes into high-mobility forms and translocates cytoplasmic NFATc to the nuclei. In addition, ET-1 stimulates the interaction between NFATc and the cardiac-restricted zinc-finger protein GATA4 in these cells. The immunosuppressants cyclosporin A and FK506, which antagonize calcineurin, negated the inhibitory effect of ET-1 on apoptosis. Calcineurin activation de novo was sufficient to inhibit hydrogen peroxide-induced apoptosis. ET-1 induced the expression of an antiapoptotic protein bcl-2 in cardiac myocytes in a cyclosporin A-dependent manner, but it did not alter the expression of bax. Cyclosporin A also attenuated the ET-1-stimulated transcription of the bcl-2 gene in these cells. These findings demonstrate that the calcineurin pathway is required for the inhibitory effect of ET-1 on oxidant stress-induced apoptosis in cardiac myocytes.
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PMID:Calcineurin pathway is required for endothelin-1-mediated protection against oxidant stress-induced apoptosis in cardiac myocytes. 1142 Feb 94

The immunosuppressant FK506 displays substantial neuroprotective and neuroregenerative effects. It is not fully understood to which extent these effects depend on the inhibition of the calcineurin phosphatase (PP2B). The present study has re-addressed this issue using Lie120, a novel highly specific inhibitor of calcineurin, which does not block the enzymatic activity of FKBPs or cyclophilins, respectively. We have determined the effect of FK506 (10-500 nM), V-10,367 (a FK506 derivative which does not block calcineurin; 1-5 microM) and Lie120 (a novel specific inhibitor of calcineurin, 0.1-5 microM) on the cellular survival and the pro-degenerative JNK activity of PC12 and Neuro2A cells following application of 200 microM H(2)O(2). FK506 and V-10,367, but not Lie120, protected both cell lines against H(2)O(2)-mediated death, whereas an increase in JNK1 activity was blocked by FK506 and Lie120, but not by V-10,367. Co-incubation of FK506 and V-10,367 with the mRNA synthesis inhibitor actinomycin D abolished the protective effect of FK506 and V-10,367. This antagonization was effective when actinomycin D was applied 30 min or 1 h, but not 2 or 4 h, after H(2)O(2) suggesting that FKBP-ligands confer their neuroprotection by rapid de novo synthesis of (functionally) anti-apoptotic proteins. The search for the corresponding effector genes revealed that the expression of FKBP25, FKBP38 and FKBP52 (analysis by reverse transcription-polymerase chain reaction (RT-PCR) did not change following H(2)O(2) or FK506, and this was also true for the expression of apoptosis-related genes caspase 3, bax, bcl-2 and bcl-xL (analysis by Multiplex-PCR). Summarizing, neuronal protection by FKBP-ligands is not mediated either by calcineurin or by JNK1 in this experimental set-up, whereas the FK506 mediated inhibition of JNK1 is realized by the inhibition of calcineurin, an effective activator of JNK1 in neurons.
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PMID:The neuroprotective actions of FK506 binding protein ligands: neuronal survival is triggered by de novo RNA synthesis, but is independent of inhibition of JNK and calcineurin. 1174 59

Protein phosphorylation plays an indispensable role in cellular regulation of mitosis, metabolism, differentiation, and death. We previously reported that the protein phosphatase inhibitor okadaic acid (OKA) induces apoptosis in renal epithelial cells in culture. In the present study, we examined the role of phosphotidylinositol 3 (PI3) kinase signaling in okadaic acid-induced apoptosis by pre-treating normal rat kidney renal epithelial cells expressing human bcl-2 with the PI3 kinase inhibitors, LY294002 and wortmannin, followed by apoptosis-inducing concentrations of okadaic acid. Given the reported cell survival activity of PI3 kinase signaling mostly attributed to Akt kinase activation, we hypothesized that inhibition of PI3 kinase would enhance okadaic-induced apoptosis. Surprisingly, our data show that pretreatment with LY294002, but not wortmannin, attenuated okadaic acid-induced apoptosis. In contrast, to LY294002, wortmannin enhanced apoptosis. Interestingly, we also found that LY294002 treatment increased bcl-2 protein levels in normal rat kidney epithelial cells expressing bcl-2 (NRK-bcl-2). In untreated cells, bcl-2 appeared to be mainly perinuclear, coincident with the nuclear membrane, or in the cytosol. In OKA treated cells that were pre-treated with Ly294002, bcl-2 was highly co-localized with mitochondria, but in cells treated with okadaic acid alone, bcl-2 was associated with fragmented chromatin. In this model, it appears that LY294002 may exert anti-apoptotic effects by a previously unreported treatment related increase in bcl-2. Although it is widely accepted that bcl-2 protein can inhibit apoptosis, we propose that the subcellular location of bcl-2 is an important determinant in whether bcl-2 effectively inhibits apoptosis.
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PMID:Phosphoinositol 3 kinase inhibitor, LY294002 increases bcl-2 protein and inhibits okadaic acid-induced apoptosis in Bcl-2 expressing renal epithelial cells. 1177 7

The cyclic AMP response element binding protein (CREB) has major roles in mediating adaptive responses at glutamatergic synapses and in the neuroprotective effects of neurotrophins. CREB has been implicated as a potential mediator of antidepressant actions. In vitro, chronic lithium treatment has been shown to promote neuronal cell survival. In the present study, we have used cultures of cerebellar granule neurons to analyze the effects of acute and chronic lithium treatment on the response to toxic concentrations of glutamate. Such concentrations of glutamate decrease the phosphorylation of CREB at serine(133) in an N-methyl-D-aspartate (NMDA) receptor-dependent manner. Chronic, but not acute, lithium treatment suppresses glutamate-induced decreases in phosphorylated CREB, and transfection studies indicate that chronic lithium, in the presence of a glutamate stimulus, markedly increases CRE-driven gene expression. Experiments with selected pharmacological reagents indicate that the glutamate-induced decreases in phosphorylated CREB are regulated primarily by protein phosphatase 1. Chronic lithium treatment not only decreases protein phosphatase 1 activity under these circumstances, but also augments glutamate-induced increases in MEK activity. PD 98059, a MEK inhibitor, prevents chronic lithium treatment from increasing phosphorylated CREB levels in glutamate-treated neurons. We conclude from these results that chronic lithium treatment is permissive for maintaining higher phosphorylated CREB levels in the presence of glutamate in part by decreasing protein phosphatase 1 activity and in part by increasing MEK activity. Higher levels of phosphorylated CREB and CRE-responsive genes such as bcl-2 may be responsible for lithium's reported effects on neuronal survival.
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PMID:Chronic lithium treatment antagonizes glutamate-induced decrease of phosphorylated CREB in neurons via reducing protein phosphatase 1 and increasing MEK activities. 1255 97

Accumulating evidence indicates that the mitochondrial cell-death pathway, which involves the release of cytochrome c from mitochondria, participates in neuronal cell death after transient cerebral ischemia. However, the upstream events, that induce cytochrome c release after transient global ischemia are not fully understood. Bad is a pro-apoptotic member of the bcl-2 gene family that promotes apoptosis by binding to and inhibiting functions of anti-apoptotic proteins Bcl-2 and Bcl-xL. We investigated the effects of transient (15 min) global ischemia on the intracellular localization of Bad and the interaction of Bad with calcineurin, Akt or Bcl-xL in the vulnerable CA1 and resistant CA3/dentate gyrus of the hippocampus. Immunoblotting analysis revealed that the amount of Bad in mitochondria significantly increased after ischemia. Co-immunoprecipitation studies showed decreased interactions of Bad with Akt and calcineurin in the cytosol and increased binding with Bcl-xL in the mitochondrial fraction of hippocampal CA1, but not in the CA3/dentate gyrus region. Further, we examined the effect of recombinant Bad on the cytochrome c release from isolated mitochondria. Treatment with both recombinant Bad and calcium, but not with recombinant Bad alone, induced cytochrome c release. These results suggest that changes in localization and complex formation by Bad are, at least in part, involved in the vulnerability of cells after transient global ischemia.
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PMID:Altered Bad localization and interaction between Bad and Bcl-xL in the hippocampus after transient global ischemia. 1512 May 93

Accumulating data support the idea that apoptosis in cardiac myocytes, in part, contributes to the development of heart failure. Since a number of neurohormonal factors are activated in this state, these factors may be involved in the positive and negative regulation of apoptosis in cardiac myocytes. Norepinephrine is one such factor and induces apoptosis in cardiac myocytes via a beta-adrenergic receptor pathway. beta-adrenergic agonist-induced apoptosis in cardiac myocytes is dependent on the activation of the cAMP/protein kinase A pathway. Interestingly, the activation of this pathway protects PC12 cells from apoptosis, suggesting that cAMP/protein kinase A regulates apoptosis in a cell type-specific manner. Another neurohormonal factor activated in heart failure is endothelin-1, which acts as a potent survival factor against myocardial cell apoptosis. Intracellular signaling pathways for endothelin-1-mediated protection include activation of MEK-1 /ERK1/2 and PI3 kinase. In addition to these protective pathways common among cell types, endothelin- activates the calcium-activated phosphatase calcineurin, which is necessary for the nuclear import of NFAT transcription factors. These factors interact with the cardiac-restricted zinc finger protein GATA-4 and induce transcription and expression of anti-apoptotic molecule bcl-2. Thus, myocardial cell apoptosis is regulated by pathways unique to cardiac myocytes as well as by those common among cell types. It should be further determined whether agents that specifically block myocardial cell apoptosis will attenuate the progression of heart failure.
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PMID:Intracellular signaling pathways for norepinephrine- and endothelin-1-mediated regulation of myocardial cell apoptosis. 1512 20

Endothelin-1 (ET-1) is a potent survival factor against myocardial cell apoptosis. This anti-apoptotic effect of ET-1 is mediated in part through calcineurin/NFATc-dependent induction of bcl-2 expression. Since it has been reported that peroxisome proliferator-activated receptor-gamma (PPARgamma) interacts with NFATc, we investigated the effects of PPARgamma ligands on anti-apoptotic effects of ET-1 in cardiac myocytes. In primary cardiac myocytes from neonatal rats, administration of PPARgamma activators (15-deoxy-delta12,14-prostaglandin J2 and troglitazone) attenuated the anti-apoptotic effects of ET-1. These activators abolished the ET-1-stimulated increase in bcl-2 expression and in binding of cardiac NFATc to the bcl-2 NFAT site. These findings demonstrate that activators of PPARgamma perturb the anti-apoptotic effects of ET-1 in cardiac myocytes and that this perturbation is, in part, based on functional transcriptional cross-talk between NFATc and PPARgamma.
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PMID:Activators of PPARgamma antagonize protection of cardiac myocytes by endothelin-1. 1535 82

We have previously demonstrated that the serine/threonine protein phosphatase-1 (PP-1) plays an important role in promoting cell survival. However, the molecular mechanisms by which PP-1 promotes survival remain largely unknown. In the present study, we provide evidence to show that PP-1 can directly dephosphorylate a master regulator of apoptosis, p53, to negatively modulate its transcriptional and apoptotic activities, and thus to promote cell survival. As a transcriptional factor, the function of p53 can be greatly regulated by phosphorylation and dephosphorylation. While the kinases responsible for phosphorylation of the 17 serine/threonine sites have been identified, the dephosphorylation of these sites remains largely unknown. In the present study, we demonstrate that PP-1 can dephosphorylate p53 at Ser-15 and Ser-37 through co-immunoprecipitation, in vitro and in vivo dephosphorylation assays, overexpression and silence of the gene encoding the catalytic subunit for PP-1. We further show that mutations mimicking constitutive dephosphorylation or phosphorylation of p53 at these sites attenuate or enhance its transcriptional activity, respectively. As a result of the changed p53 activity, expression of the downstream apoptosis-related genes such as bcl-2 and bax is accordingly altered and the apoptotic events are either largely abrogated or enhanced. Thus, our results demonstrate that PP-1 directly dephosphorylates p53, and dephosphorylation of p53 has as important impact on its functions as phosphorylation does. In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.
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PMID:Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities. 1650 11

In pulmonary arterial hypertension (PAH), antiapoptotic, proliferative, and inflammatory diatheses converge to create an obstructive vasculopathy. A selective down-regulation of the Kv channel Kv1.5 has been described in human and animal PAH. The resultant increase in intracellular free Ca(2+) ([Ca(2+)](i)) and K(+) ([K(+)](i)) concentrations explains the pulmonary artery smooth muscle cell (PASMC) contraction, proliferation and resistance to apoptosis. The recently described PASMC hyperpolarized mitochondria and increased bcl-2 levels also contribute to apoptosis resistance in PAH. The cause of the Kv1.5, mitochondrial, and inflammatory abnormalities remains unknown. We hypothesized that these abnormalities can be explained in part by an activation of NFAT (nuclear factor of activated T cells), a Ca(2+)/calcineurin-sensitive transcription factor. We studied PASMC and lungs from six patients with and four without PAH and blood from 23 PAH patients and 10 healthy volunteers. Compared with normal, PAH PASMC had decreased Kv current and Kv1.5 expression and increased [Ca(2+)](i), [K(+)](i), mitochondrial potential (Delta Psi m), and bcl-2 levels. PAH but not normal PASMC and lungs showed activation of NFATc2. Inhibition of NFATc2 by VIVIT or cyclosporine restored Kv1.5 expression and current, decreased [Ca(2+)](i), [K(+)](i), bcl-2, and Delta Psi m, leading to decreased proliferation and increased apoptosis in vitro. In vivo, cyclosporine decreased established rat monocrotaline-PAH. NFATc2 levels were increased in circulating leukocytes in PAH versus healthy volunteers. CD3-positive lymphocytes with activated NFATc2 were seen in the arterial wall in PAH but not normal lungs. The generalized activation of NFAT in human and experimental PAH might regulate the ionic, mitochondrial, and inflammatory remodeling and be a therapeutic target and biomarker.
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PMID:The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. 1759 40

The phosphorylation state of Retinoblastoma protein (Rb) plays a role in cell proliferation and apoptosis. Within cells, cyclin dependent kinases (cdks) phosphorylate Rb in response to growth stimulatory signals, whereas protein phosphatase 1 (PP1) dephosphorylates Rb when cells stop proliferating or undergo apoptosis in response to anti-proliferative or stress signals. Stimulation of PP1 activity via siRNA mediated knockdown of its interacting protein PNUTS (Phosphatase Nuclear Targeting Subunit) leads to Rb dephosphorylation and apoptosis in cancer cells. We utilized two separate methods to modulate the phosphorylation state of Rb in cancer cells. Kinase activity toward Rb is inhibited by the clinically relevant cdk inhibitor, Roscovitine. In addition, siRNA mediated PNUTS knockdown stimulates phosphatase activity toward Rb. Either of these treatments in cancer cells causes a 2-fold stimulation of apoptosis. When activation of phosphatase activity is combined with inhibition of cdk activity toward Rb, however, cells exhibit a 4-fold increase in apoptosis. The mechanism by which PNUTS knockdown mediated PP1 activation leads to apoptosis was determined to be dependent on the activity of the transcription factor E2F1. The Rb phosphorylation profiles resulting from each treatment were analyzed and found to be similar but not identical. In addition, the two treatments differentially effect the expression of bcl-2 family proteins. Thus inhibition of cdk activity and activation of PP1 activity toward pRb are functionally distinct processes that together increase the apoptotic effect in cells.
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PMID:PNUTS knockdown potentiates the apoptotic effect of Roscovitine in breast and colon cancer cells. 2037 2


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