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)

Calpain, a Ca(2+)-dependent cysteine protease, in vitro converts calcineurin (CaN) to constitutively active forms of 45 kDa and 48 kDa by cleaving the autoinhibitory domain of the 60 kDa subunit. In a mouse middle cerebral artery occlusion (MCAO) model, calpain converted the CaN A subunit to the constitutively active form with 48 kDa in vivo. We also confirmed increased Ca(2+)/CaM-independent CaN activity in brain extracts. The generation of constitutively active and Ca(2+)/CaM-independent activity of CaN peaked 2 h after reperfusion in brain extracts. Increased constitutively active CaN activity was associated with dephosphorylation of dopamine-regulated phosphoprotein-32 in the brain. Generation of constitutively active CaN was accompanied by translocation of nuclear factor of activated T-cells (NFAT) into nuclei of hippocampal CA1 pyramidal neurons. In addition, a novel calmodulin antagonist, DY-9760e, blocked the generation of constitutively active CaN by calpain, thereby inhibiting NFAT nuclear translocation. Together with previous studies indicating that NFAT plays a critical role in apoptosis, we propose that calpain-induced CaN activation in part mediates delayed neuronal death in brain ischemia.
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PMID:Generation of constitutively active calcineurin by calpain contributes to delayed neuronal death following mouse brain ischemia. 1680 17

The past few decades have revealed that cell death can be precisely programmed with two principal forms, apoptosis and necrosis. Besides pathophysiological alterations, physiologic processes, such as the pruning of neurons during normal development and the involution of the thymus, involve apoptosis. This review focuses on the role of inter- and intracellular signaling systems in cell death, especially in the nervous system. Among neurotransmitters, glutamate and nitric oxide have been most extensively characterized and contribute to cell death in excitotoxic damage, especially in stroke and possibly in neurodegenerative diseases. Within cells, calcium, the most prominent of all intracellular messengers, mediates diverse forms of cell death with actions modulated by many proteins, including IP3 receptors, calcineurin, calpain, and cytochrome c.
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PMID:Cell signaling and neuronal death. 1687 82

Reactive oxygen species are believed to be the central mediators of beta-cell destruction that leads to type 1 and 2 diabetes, and calcium has been reported to be an important mediator of beta cell death. In the present study, the authors investigated whether Ca(2+) plays a role in hydrogen peroxide (H(2)O(2))-induced MIN6N8a mouse beta cell death. Treatment with low concentration H(2)O(2) (50 microM) was found to be sufficient to reduce MIN6N8a cell viability by 55%, largely via apoptosis. However, this H(2)O(2)-induced cell death was near completely blocked by pretreatment with BAPTA/AM (5 microM), a chelator of intracellular Ca(2+). Moreover, the intracellular calcium store channel blockers, such as, xestospongin c and ryanodine, significant protected cells from 50 microM H(2)O(2)-induced cell death and under extracellular Ca(2+)-free conditions, 50 microM H(2)O(2) elicited transient [Ca(2+)](i) increases. In addition, pharmacologic inhibitors of calpain, calcineurin, and calcium/calmodulin-dependent protein kinase II were found to have a protective effect on H(2)O(2)-induced death. Moreover, H(2)O(2)-induced apoptotic signals, such as c-JUN N-terminal kinase activation, cytochrome c release, caspase 3 activation, and poly (ADP-ribose) polymerase cleavage were all down-regulated by the intracellular Ca(2+) chelation. These findings show that [Ca(2+)](i) elevation, possibly due to release from intracellular calcium stores and the subsequent activation of Ca(2+)-mediated apoptotic signals, critically mediates low concentration H(2)O(2)-induced MIN6N8a cell death. These findings suggest that a breakdown of calcium homeostasis by low level of reactive oxygen species may be involved in beta cell destruction during diabetes development.
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PMID:Involvement of calcium-mediated apoptotic signals in H2O2-induced MIN6N8a cell death. 1693 99

The mu- and m-calpains are major members of the calpain family that play an essential role in regulating cell motility. We have recently discovered that nicotine-activated protein kinase C iota enhances calpain phosphorylation in association with enhanced calpain activity and accelerated migration and invasion of human lung cancer cells. Here we found that specific disruption of protein phosphatase 2A (PP2A) activity by expression of SV40 small tumor antigen up-regulates phosphorylation of mu- and m-calpains whereas C2-ceramide, a potent PP2A activator, reduces nicotine-induced calpain phosphorylation, suggesting that PP2A may function as a physiological calpain phosphatase. PP2A co-localizes and interacts with mu- and m-calpains. Purified, active PP2A directly dephosphorylates mu- and m-calpains in vitro. Overexpression of the PP2A catalytic subunit (PP2A/C) suppresses nicotine-stimulated phosphorylation of mu- and m-calpains, which is associated with inhibition of calpain activity, wound healing, cell migration, and invasion. By contrast, depletion of PP2A/C by RNA interference enhances calpain phosphorylation, calpain activity, cell migration, and invasion. Importantly, C2-ceramide-induced suppression of calpain phosphorylation results in decreased secretion of mu- and m-calpains from lung cancer cells into culture medium, which may have potential clinic relevance in controlling metastasis of lung cancer. These findings reveal a novel role for PP2A as a physiological calpain phosphatase that not only directly dephosphorylates but also inactivates mu- and m-calpains, leading to suppression of migration and invasion of human lung cancer cells.
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PMID:Suppression of cancer cell migration and invasion by protein phosphatase 2A through dephosphorylation of mu- and m-calpains. 1698 26

The calpain proteinases and their specific inhibitor calpastatin have been proposed to influence both the rates of myofibrillar protein turnover in vivo and meat tenderization postmortem. Elevated calpastatin concentrations in particular are associated with certain forms of hypertrophic growth and meat toughness. In the 5'region of the porcine calpastatin gene, there are 3 calpastatin promoters upstream of exons 1xa, 1xb, and 1u, respectively, each of which contain transcription factor-binding motifs, suggesting sensitivity to a variety of growth-promoting stimuli. This study examined the effect of the beta-adrenergic agonist clenbuterol and porcine ST (pST) treatment on calpastatin promoter usage in porcine LM in vivo using real-time PCR and also the responsiveness of transfected calpastatin promoter sequences to cyclic adenosine monophosphate (cAMP) and calcium (Ca2+)-related stimuli in reporter gene systems in cell studies. The effect of clenbuterol and pST on potential signaling pathways in vivo was also assessed by monitoring protein phosphatase 2B (calcineurin), NFATc3, calpain 3, IkappaB alpha, and NFkappaB by quantitative immunoblotting. Total calpastatin mRNA was increased by 52% (P < 0.05) after treatment with clenbuterol for 1 d and reduced by 35% (P < 0.01) after pST treatment for 7 d. Whereas clenbuterol had no significant differential effects on individual mRNA transcripts (types 1 to 3) derived from the 3 upstream promoters, pST significantly reduced all of these by 51, 39, and 40% (P < 0.001, 0.05, and 0.05), respectively. Promoter activity was increased in rat L6G8 cells transfected with a construct derived from exon 1u after treatment with dibutyryl cAMP (68%, P < 0.05) or forskolin (43%, P < 0.05), whereas 1xa activity was reduced by both of these agents (47 and 33%, respectively, P < 0.05). Treatment of cells with the calcium ionophore calcimycin reduced the activity of the 1u promoter by 40% (P < 0.01), with no effect on the other promoter constructs. Cyclosporin A had no effect on any promoter construct. The only signaling pathway component to be significantly altered by the in vivo treatments was calcineurin, which was decreased by 24% (P < 0.05) in clenbuterol-treated animals. In conclusion, 2 types of growth promoter in pigs had contrasting effects on calpastatin expression in LM. Transfected calpastatin promoters were differentially sensitive to cAMP- and Ca2+-related stimuli, in agreement with the proposed mode of action of the 2 growth promoters.
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PMID:Effect of anabolic agents on calpastatin promoters in porcine skeletal muscle and their responsiveness to cyclic adenosine monophosphate- and calcium-related stimuli. 1703 91

We previously reported that acetylcholinesterase plays a critical role in apoptosis and its expression is regulated by Ca(2+) mobilization. In the present study, we show that activated calpain, a cytosolic calcium-activated cysteine protease, and calcineurin, a calcium-dependent protein phosphatase, regulate acetylcholinesterase expression during A23187-induced apoptosis. The calpain inhibitor, calpeptin, and the calcineurin inhibitors, FK506 and cyclosporine A, inhibited acetylcholinesterase expression at both mRNA and protein levels and suppressed the activity of the human acetylcholinesterase promoter. In contrast, overexpression of constitutively active calcineurin significantly activated the acetylcholinesterase promoter. Furthermore, we identify a role for the transcription factor NFAT (nuclear factor of activated T cells), a calcineurin target, in regulating the acetylcholinesterase promoter during ionophore-induced apoptosis. Overexpression of human NFATc3 and NFATc4 greatly increased the acetylcholinesterase promoter activity in HeLa cells treated with A23187. Overexpression of constitutive nuclear NFATc4 activated the acetylcholinesterase promoter independent of A23187, whereas overexpression of dominant-negative NFAT blocked A23187-induced acetylcholinesterase promoter activation. These results indicate that calcineurin mediates acetylcholinesterase expression during apoptosis.
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PMID:Calcineurin mediates acetylcholinesterase expression during calcium ionophore A23187-induced HeLa cell apoptosis. 1732 Feb 3

The alpha-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) is an ionotropic glutamate receptor that governs most of excitatory synaptic transmission in neurons. In vitro biochemical assay has shown that calpain, a Ca2+-activated protease, can cleave AMPAR GluR1 subunits. Our physiological study found that calpain, which was activated by prolonged stimulation of the N-methyl-D-aspartate receptor (100 microM, 10 min), caused a substantial suppression of AMPAR currents in cortical neurons. Since the phosphorylation sites of GluR1 by several protein kinases are located in close proximity to the calpain cleavage sites, we investigated the effect of phosphorylation on the susceptibility of GluR1 to calpain cleavage. Interestingly, we found that the calpain regulation of AMPAR currents was diminished by inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) but was augmented by inhibition of protein phosphatase 1/2A (PP1/2A). In agreement with this, in vitro assay showed that the calpain-induced proteolytic cleavage of GluR1 C-terminal fusion protein was strongly potentiated by adding the purified active CaMKII, and GluR1 phosphorylated at Ser831 by CaMKII is much more sensitive to calpain cleavage. Taken together, our data suggest that calpain activation suppresses AMPA receptor currents via proteolytic cleavage of GluR1 subunits, and the susceptibility of AMPARs to calpain cleavage is determined by the phosphorylation state of GluR1 subunits, which is mediated by CaMKII-PP1/2A activity.
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PMID:The phosphorylation state of GluR1 subunits determines the susceptibility of AMPA receptors to calpain cleavage. 1742 97

Intracellular calcium is a powerful secondary messenger that affects a number of calcium sensors, including calpain, a Ca2+-dependent cysteine protease, and calcineurin, a Ca2+/calmodulin-dependent protein phosphatase. Maintenance of low basal levels of intracellular calcium allows for the tightly regulated physiological activation of these proteins, which is crucial to a wide variety of cellular processes, such as fertilization, proliferation, development, learning, and memory. Deregulation of calpain and calcineurin has been implicated in the pathogenesis of several disorders, including hypertension, heart disease, diabetes, cerebral ischemia, and Alzheimer's disease. Recent studies have demonstrated an interplay between calpain and calcineurin, in which calpain can directly regulate calcineurin activity through proteolysis in glutamate-stimulated neurons in culture and in vivo. The calpain-mediated proteolytic cleavage of calcineurin increases phosphatase activity, which promotes caspase-mediated neuronal cell death. Thus, the activation of the calpain-calcineurin pathway could contribute to calcium-dependent disorders, especially those associated with Alzheimer's disease and myocardial hypertrophy. Here, we focus briefly on recent advances in revealing the structural and functional properties of these 2 calcium-activated proteins, as well as on the interplay between the 2, in an effort to understand how calpain-calcineurin signaling may relate to the pathogenesis of calcium- dependent disorders.
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PMID:Calpain-calcineurin signaling in the pathogenesis of calcium-dependent disorder. 1759 48

We recently demonstrated that a constitutively active form of calcineurin (CaN) is generated by calpain-mediated limited proteolysis following brain ischemia. The calpain-induced CaN activation mediated delayed neuronal death through translocation of nuclear factor of activated T-cells (NFAT) into nuclei after brain ischemia. We also previously demonstrated that activation of forkhead in rhabdomyosarcoma (FKHR), a forkhead transcription factor and substrate of protein kinase-B (Akt), mediated ischemia-induced neuronal death through Fas-ligand expression in gerbil hippocampus. FKHR activation occurred through decreased Akt activity and concomitant dephosphorylation mediated by undefined phosphatases. In this study, we show that phosphorylated Ser-256 of FKHR is dephosphorylated by constitutively active CaN and that in turn FKHR forms a complex with CaN that is translocated into nuclei after brain ischemia. After nuclear translocation of NFAT and FKHR, both NFAT and FKHR stimulated expression of Fas-ligand by binding to its promoter region. Consistent with activation of the Fas-ligand promoter by FKHR dephosphorylation, Fas-ligand expression increased 2 days after ischemia/reperfusion, and treatment with the CaN inhibitor FK506 inhibited that expression. These results suggest that FKHR is a downstream target of CaN and that constitutively active CaN mediates delayed neuronal death through Fas-ligand expression via up-regulation of both NFAT and FKHR transcriptional activity in brain ischemia.
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PMID:Constitutively active calcineurin mediates delayed neuronal death through Fas-ligand expression via activation of NFAT and FKHR transcriptional activities in mouse brain ischemia. 1766 23

Glioblastoma is the deadliest and most prevalent brain tumor, which is not yet amenable to any treatments. Therefore, new and innovative therapeutic strategies need to be developed for treating this deadly disease. We found that all-trans retinoic acid (ATRA) or 13-cis retinoic acid (13-CRA) induced astrocytic differentiation with down regulation of telomerase activity in rat glioblastoma C6 cells and enhanced sensitivity of the cells to interferon-gamma (IFN-gamma) or taxol (TXL) for apoptosis. Sensitivity of differentiated cells to IFN-gamma or TXL was greatly increased for apoptosis with increases in calcineurin expression, Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and expression and activity of calpain and caspases. Treatment with IFN-gamma activated caspase-8 indicating induction of apoptosis via the receptor-mediated pathway. Notably, IFN-gamma activated the signal transducer and activator of transcription-1 (STAT-1) for signaling via binding to gamma activator sequence (GAS), whereas TXL activated Raf-1 kinase for inactivation of Bcl-2 by its phosphorylation. We confirmed involvement of different proteolytic mechanisms in cell death by pretreating the cells with caspase-8 inhibitor II, calpeptin (calpain inhibitor), and caspase-9 inhibitor I, and caspase-3 inhibitor IV. Results demonstrated that retinoids induced astrocytic differentiation with down regulation of telomerase activity and worked synergistically to enhance sensitivity of cells to the cytotoxic agent IFN-gamma and the cytostatic agent TXL for apoptosis. This combination therapy for differentiation and apoptosis could be highly effective for controlling the malignant growth of glioblastoma.
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PMID:Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-gamma and taxol for apoptosis. 1769 33


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