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)

T cell activation initiates signals that control gene expression of molecules important for T cell function. The focal adhesion kinase Pyk2 has been implicated in T cell signaling. To further analyze the involvement of Pyk2 in T cell processes, we examined the effect of T cell stimulation on the expression of Pyk2. We found that TCR ligation or PMA increased Pyk2 expression in Jurkat T cells and in normal T cells. In contrast, TCR ligation and PMA failed to induce any detectable increase in the expression of the other member of the focal adhesion kinase family, Fak, in Jurkat T cells and induced only a weak increase in Fak expression in normal T cells. The serine/threonine kinases, protein kinase C and mitogen-activated protein/extracellular signal-related kinase kinase (MEK), regulated Pyk2 expression, as inhibitors of these kinases blocked stimulus-induced Pyk2 expression. Cyclosporin A, FK506, and KN-62 did not block Pyk2 expression; thus, calcineurin and Ca2+/calmodulin-activated kinases are not critical for augmenting Pyk2 expression. TCR ligation increased Pyk2 mRNA, and the transcriptional inhibitor actinomycin D blocked Pyk2 expression. Strikingly, Ca2+ ionophores, at concentrations that in combination with other stimuli induced IL-2 expression, blocked TCR- and PMA-induced up-regulation of Pyk2 expression. Thus, the increase in Ca2+ has opposing effects on IL-2 and Pyk2 expression. Cyclosporin A and FK506, but not KN-62, blocked Ca2+ ionophore-mediated inhibition of Pyk2 expression, implicating calcineurin in down-regulating Pyk2 expression. These results show that TCR-triggered intracellular signals increase Pyk2 expression and shed light on the molecular mechanisms that regulate Pyk2 expression in T cells.
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PMID:T cell activation up-regulates the expression of the focal adhesion kinase Pyk2: opposing roles for the activation of protein kinase C and the increase in intracellular Ca2+. 1058 59

Incubation of cultured astrocytes in Ca(2+)-containing medium after exposure to Ca(2+)-free medium causes Ca2+ influx followed by delayed cell death. Here, we summarize the mechanisms underlying the Ca(2+)-mediated injury of cultured astrocytes and the protective effects of drugs against Ca(2+)-reperfusion injury. Our results show that Ca(2+)-reperfusion injury of astrocytes appears to be mediated by apoptosis as evidenced by DNA fragmentation and nuclear condensation. Calpain, reactive oxygen species (ROS) production, calcineurin, caspase-3, and NF-kappa B activation are involved in Ca(2+)-reperfusion injury. Several drugs including T-588 and idebenone protect astrocytes against Ca(2+)-reperfusion injury. The protective effect of idebenone is mediated by nerve growth factor production, whereas that of T-588 is mediated mainly by the mitogen-activated protein/extracellular signal-regulated kinase signal cascade.
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PMID:[Cell injury and its protection in astrocytes]. 1062 41

Brain-derived neurotrophic factor contributes profoundly to modulate activity-dependent synaptic plasticity in adult brain areas such as the hippocampus, but the mechanisms underlying this important role still remain unclear. Recently, we have shown that two serine/threonine kinases, calcium/calmodulin-dependent protein kinase-2 and casein kinase-2, are capable of mediating brain-derived neurotrophic factor responses in adult rat hippocampus. In the present study, using hippocampal slices from adult rat, we show that phospholipase C-regulated calcium signals couple the brain-derived neurotrophic factor receptor to two distinct pathways: a pathway in which calcium/calmodulin-dependent protein kinase-2 stimulates a signalling module involving the p38 subfamily of mitogen-activated protein kinases and its downstream target, usually named mitogen-activated protein kinase-activated protein kinase-2; and a pathway in which the extracellular signal-regulated kinase subfamily of mitogen-activated protein kinases activates casein kinase-2. Our results suggest that: (i) extracellular signal-regulated kinase is activated by B-Raf in response to a calcium-sensitive adenylate cyclase; and (ii) extracellular signal-regulated kinase activates casein kinase-2 via a protein phosphatase(s) that may be of the PP1 and/or PP2A type. Interestingly, we also show that neurotrophin-induced activation of the two signalling cascades promotes a sustained activation of mitogen-activated protein kinase-activated protein kinase-2 and casein kinase-2 in slices. Considering the ability of these two kinases to be persistently activated, and that most of the protein kinases which lie in these pathways are believed to be important for multiple events underlying neuronal plasticity, it is suggested that the mechanisms described here might contribute both to rapid synaptic changes through local effects and to long-lasting synaptic responses through new gene transcription in the hippocampus.
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PMID:Identification of two persistently activated neurotrophin-regulated pathways in rat hippocampus. 1067 Apr 37

Various signaling molecules have been implicated in the oocyte G2/MII transition, including protein kinase C (PKC), cAMP and mitogen-activated protein (MAP) kinases. However, the cross-talk among these signaling pathways has not been elucidated. The present study demonstrates that both germinal vesicle break down (GVBD) and MAP kinase phosphorylation (activation) are inhibited when intraoocyte cAMP is increased by treating the GV-intact oocytes with dibutyryl cyclic AMP (dbcAMP), forskolin, or isobutylmethylxanthine (IBMX). Okadaic acid, a specific inhibitor of protein phosphatase-1 and -2A, completely overcame this effect. Calphostin C, a specific inhibitor of PKC, accelerated both GVBD and MAP kinase phosphorylation, and this effect was attenuated by increased intraoocyte cAMP, whereas PKC activation inhibited these events. Once GVBD occurred, the progression of oocyte maturation and MAP kinase phosphorylation were independent of cAMP These results indicate that an increase in intraoocyte cAMP, in synergy with PKC activation, initiates a cascade of events resulting in inhibition of MAP kinase phosphorylation and GVBD in the mouse oocyte.
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PMID:CAMP inhibits mitogen-activated protein (MAP) kinase activation and resumption of meiosis, but exerts no effects after spontaneous germinal vesicle breakdown (GVBD) in mouse oocytes. 1073 51

We examined the mechanism of atrial natriuretic factor (ANF) transcription by isoproterenol (ISO), an agonist for the beta-adrenergic receptor (betaAR), in cardiac myocytes. ISO only modestly activated members of the mitogen-activated protein kinase family. ISO-induced ANF transcription was not affected by inhibition of mitogen-activated protein kinases, whereas it was significantly inhibited by KN93, an inhibitor of Ca(2+)/calmodulin-dependent kinase (CaM kinase II). Production of 3'-phosphorylated phosphatidylinositides (3 phosphoinositides) was also required for ISO-induced ANF transcription. ISO caused phosphorylation (Ser-473) and activation of Akt through CaM kinase II- and 3 phosphoinositides-dependent mechanisms. Constitutively active Akt increased myocyte surface area, total protein content, and ANF expression, whereas dominant negative Akt blocked ISO-stimulated ANF transcription. ISO caused Ser-9 phosphorylation and decreased activities of GSK3beta. Overexpression of GSK3beta inhibited ANF transcription, which was reversed by ISO. ISO failed to reverse the inhibitory effect of GSK3beta(S9A), an Akt-insensitive mutant. Kinase-inactive GSK3beta increased ANF transcription. Cyclosporin A partially inhibited ISO-stimulated ANF transcription, indicating that calcineurin only partially mediates ANF transcription. These results suggest that both CaM kinase II and 3 phosphoinositides mediate betaAR-induced Akt activation and ANF transcription in cardiac myocytes. Furthermore, betaAR-stimulated ANF transcription is predominantly mediated by activation of Akt and subsequent phosphorylation/inhibition of GSK3beta.
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PMID:The Akt-glycogen synthase kinase 3beta pathway regulates transcription of atrial natriuretic factor induced by beta-adrenergic receptor stimulation in cardiac myocytes. 1079 29

Cardiac hypertrophy is a well known response to increased hemodynamic load. Mechanical stress is considered to be the trigger inducing a growth response in the overloaded myocardium. Furthermore, mechanical stress induces the release of growth-promoting factors, such as angiotensin II, endothelin-1, and transforming growth factor-beta, which provide a second line of growth induction. In this review, we will focus on the primary effects of mechanical stress: how mechanical stress may be sensed, and which signal transduction pathways may couple mechanical stress to modulation of gene expression, and to increased protein synthesis. Mechanical stress may be coupled to intracellular signals that are responsible for the hypertrophic response via integrins and the cytoskeleton or via sarcolemmal proteins, such as phospholipases, ion channels and ion exchangers. The signal transduction pathways that may be involved belong to two groups: (1) the mitogen-activated protein kinases (MAPK) pathway; and (2) the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. The MAPK pathway can be subdivided into the extracellular-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and the 38-kDa MAPK (p38 MAPK) pathway. Alternatively, the stress signal may be directly submitted to the nucleus via the cytoskeleton without the involvement of signal transduction pathways. Finally, by promoting an increase in intracellular Ca2+ concentration stretch may stimulate the calcium/calmodulin-dependent phosphatase calcineurin, a novel hypertrophic signalling pathway.
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PMID:Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. 1086 27

Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca(2+)/calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.
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PMID:Calcineurin blockade prevents cardiac mitogen-activated protein kinase activation and hypertrophy in renovascular hypertension. 1101 40

In this study, we examined whether the production of hepatocyte growth factor (HGF) in fibroblasts is regulated by protein phosphatase(s). Inhibitors of the enzymes okadaic acid and calyculin A were used for this purpose. Both inhibitors markedly stimulated HGF production in human skin fibroblasts in a dose-dependent manner. The effects of okadaic acid and calyculin A were maximal at 25-37.5 and 1.25 nM, respectively. Highly active HGF production in MRC-5 human embryonic lung fibroblasts was also promoted by both inhibitors. The effect of okadaic acid was accompanied by an up-regulation of HGF gene expression. The stimulating effect of okadaic acid on HGF production was synergistic with that of phorbol 12-myristate 13-acetate (PMA) and epidermal growth factor (EGF), whereas it was additive to the effect of cholera toxin. The protein kinase C (PKC) inhibitor GF 109203X inhibited the effect of PMA, but not of okadaic acid and EGF. The effect of okadaic acid as well as EGF was not inhibited, but rather enhanced in human skin fibroblasts pretreated for 24 hr with a high dose of PMA to deplete PKC, as compared with its effect in untreated cells. PD 98059, an inhibitor of mitogen-activated protein (MAP) kinase kinase, suppressed the effects of okadaic acid and EGF, but not those of cholera toxin and 8-bromo-adenosine 3',5'-cyclic monophosphate (cAMP). These results suggest that HGF production in human skin fibroblasts is down-regulated by protein phosphatase(s) and that HGF production stimulated by okadaic acid is, at least in part, dependent on the activation of the MAP kinase cascade.
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PMID:Stimulation of hepatocyte growth factor production in human fibroblasts by the protein phosphatase inhibitor okadaic acid. 1102 Apr 56

In response to increased ventricular wall tension or neurohumoral stimuli, the myocardium undergoes an adaptive hypertrophy response that temporarily augments pump function. Although initially beneficial, sustained cardiac hypertrophy can lead to decompensation and cardiomyopathy. Recent studies have focused on characterizing the molecular mechanisms that underlie cardiac hypertrophy. An increasing number of signal transduction pathways have been identified as important regulators of the hypertrophic response, including the low-molecular weight GTPases (Ras, RhoA, and Rac), mitogen-activated protein kinases, protein kinase C, and calcineurin. This review will discuss an emerging body of evidence that implicates the calcium-calmodulin-activated protein phosphatase calcineurin as a physiological regulator of the cardiac hypertrophic response. Although the sufficiency of calcineurin to promote cardiomyocyte hypertrophy in vivo and in vitro is established, its overall necessity as a hypertrophic mediator is currently an area of ongoing debate. The use of the calcineurin-inhibitory agents cyclosporine A and FK506 have suggested a necessary role for calcineurin in many, but not all, animal models of hypertrophy or cardiomyopathy. The evidence implicating a role for calcineurin signaling in the heart will be weighed against a growing body of literature suggesting necessary roles for a diverse array of intracellular signaling pathways, highlighting the multifactorial nature of the hypertrophic program.
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PMID:Calcineurin and beyond: cardiac hypertrophic signaling. 1105 75

The gene pzl-1 from the filamentous fungus Neurospora crassa encodes a putative Ser/Thr protein phosphatase that is reminiscent of the Ppz1/Ppz2 and Pzh1 phosphatases from Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. The entire PZL-1 protein, as well as its carboxyl-terminal domain, have been expressed in Escherichia coli as active protein phosphatases. To characterize its cellular role, PZL-1 was also expressed in Sz. pombe and in S. cerevisiae. Expression of PZL-1 in S. cerevisiae from the PPZ1 promoter was able to rescue the altered sensitivity to caffeine and lithium ions of a ppz1 strain. Furthermore, high copy number expression of PZL-1 alleviated the lytic phenotype of a S. cerevisiae slt2/mpk1 mitogen-activated protein (MAP) kinase mutant, similarly to that described for PPZ1, and mimicked the effects of high levels of Ppz1 on cell growth. Expression of PZL-1 in fission yeast from a weak version of the nmt1 promoter fully rescued the growth defect of a pzh1Delta strain in high potassium, but only partially complemented the sodium-hypertolerant phenotype. Strong overexpression of the N. crassa phosphatase in Sz. pombe affected cell growth and morphology. Therefore, PZL-1 appears to fulfil every known function carried out by its S. cerevisiae counterpart, despite the marked divergence in sequence within their NH(2)-terminal moieties.
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PMID:Functional analysis of the Neurospora crassa PZL-1 protein phosphatase by expression in budding and fission yeast. 1116 54


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