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)

The activation of blood cells, including T cells, triggers intracellular signals that control the expression of critical molecules, including cytokines and cytokine receptors. We show that T-cell receptor (TCR) ligation increases the cellular level of the protein linker for activation of T cells (LAT), a molecule critical for T-cell development and function. T-cell activation increased LAT messenger RNA, as determined by reverse transcription-polymerase chain reaction and by Northern blotting. The TCR-induced increase in LAT expression involved the activation of the serine/threonine kinases PKC and MEK, because inhibitors of these kinases blocked the increase in LAT. Accordingly, the PKC activator phorbol myristate acetate up-regulated LAT expression. Strikingly, the calcineurin inhibitors cyclosporin A (CsA) and FK506 strongly potentiated TCR-induced LAT expression, suggesting that the activation of calcineurin following TCR ligation negatively regulates LAT expression. Accordingly, Ca(++ )ionophores, which can activate calcineurin by increasing intracellular Ca(++), blocked the TCR-induced increase in cellular LAT. CsA and FK506 blocked the Ca(++ )ionophores' inhibitory effect on LAT expression. Notably, CsA and FK506 preferentially up-regulated TCR-induced LAT expression; under the same conditions, these compounds did not increase the expression of 14 other molecules that previously had been implicated in T-cell activation. These data show that TCR-induced LAT expression involves the activation of the PKC-Erk pathway and is negatively regulated by the activation of calcineurin. Furthermore, the potentiation of TCR-induced LAT expression by CsA and FK506 suggests that the action of these agents involves up-regulating the cellular level of critical signaling molecules. These findings may have important therapeutic implications. (Blood. 2000;95:2733-2741)
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PMID:Potentiation of CD3-induced expression of the linker for activation of T cells (LAT) by the calcineurin inhibitors cyclosporin A and FK506. 1077 14

Integrin-mediated substrate adhesion of endothelial cells leads to intracellular signaling, including the activation of ERK 1/2 (extracellular regulated kinases 1 and 2), members of the mitogen-activated protein kinase (MAPK) family. MKP-1 is a dual-specificity protein phosphatase that may play an important role in regulating MAPK activity through dephosphorylation of threonine and tyrosine. Adhesion of human umbilical vein endothelial cells to fibronectin increased MKP-1 protein and mRNA levels, which reached a maximum at 60 min, while MAPK activity was maximal at 30 min. The MEK inhibitor PD98059 blocked activation of MAPK as well as the induction of MKP-1 during adhesion. The transcription inhibitor actinomycin D blocked MKP-1 induction and produced prolonged MAPK activation during adhesion. In contrast, endothelial adhesion to poly-L-lysine did not alter MAPK activity or MKP-1 levels. These findings demonstrate that integrin-mediated adhesion of endothelial cells to fibronectin results in transcriptional activation of MKP-1 through a MAPK-dependent mechanism. Regulation of MKP-1 by MAPK likely represents an important negative-feedback mechanism.
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PMID:Adhesion to fibronectin enhances MKP-1 activation in human endothelial cells. 1087 41

Vav is expressed exclusively in hematopoietic cells and becomes phosphorylated on tyrosine in response to antigen receptor ligation. Although Vav can act as a Rac-specific guanine nucleotide exchange factor in vitro and as a c-Jun N-terminal kinase (JNK) activator in ectopic expression systems, its physiological functions in lymphocytes remain unclear. Indirect evidence suggests that Vav interacts with the Ras/ERK pathway in T cells. Here, we analyzed the effects of Vav on three known downstream targets of Ras, i. e. activation of ERK and NFAT, and up-regulation of the activation antigen CD69. The MEK inhibitor PD90859 inhibited Vav-induced activation of ERK, and Vav- or anti-CD3-induced activation of NFAT, suggesting that MEK and ERK are involved in Vav-mediated NFAT activation. Similarly to Ras, Vav cooperated with constitutively active calcineurin and with ERK to activate NFAT, and was capable of up-regulating CD69 expression in T cells. Moreover, these Vav-mediated functions were all inhibited by a dominant negative Ras mutant. Conversely, however, dominant negative Vav did not inhibit NFAT and ERK activation or CD69 expression induced by an active Ras mutant. These findings indicate that Ras functions as an important downstream target of Vav in signaling pathways that lead to NFAT and ERK activation, and to CD69 expression. Moreover, the finding that Vav- (or Ras-) induced CD69 expression was not inhibited by a dominant negative Rac mutant indicates that Vav mediates some Ras-dependent, but Rac-independent, functions in T cells.
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PMID:Vav modulation of the Ras/MEK/ERK signaling pathway plays a role in NFAT activation and CD69 up-regulation. 1089 94

Chick pineal mitogen-activated protein kinase (MAPK) exhibits circadian activation and light-dependent deactivation at nighttime. Here we report that, in the chick pineal gland, levels of active forms of MAPK, MEK, Raf-1 and Ras exhibited synchronous circadian rhythms with peaks during the subjective night, suggesting a sequential activation of components in the classical Ras-MAPK pathway in a circadian manner. In contrast, the light-dependent deactivation of MAPK was not accompanied by any change of MEK activity, but it was attributed to the light-dependent activation of protein phosphatase dephosphorylating MAPK. These results indicate that the photic and clock signals regulate MAPK activity via independent pathways, and suggest a pivotal role of MAPK in photic entrainment and maintenance of the circadian oscillation.
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PMID:Circadian and photic regulation of MAP kinase by Ras- and protein phosphatase-dependent pathways in the chick pineal gland. 1122 22

The immunosuppressive effects of cyclosporin A (CsA) and FK506 are mediated through binding to immunophilins. Here we show that FK506-FKBP complex suppresses the activation of JNK and p38 pathways at a level upstream of mitogen-activated protein kinase (MAPK) kinase kinase (MAPKK-K) besides the calcineurin-NFAT pathway. A238L, a viral gene product that binds to immunophilin, also blocks activation of both pathways. In contrast, direct inhibitors of calcineurin, Cabin 1 and FR901725, suppress the activation of NFAT but not the JNK or p38 pathway. We further demonstrate that co-expression of a constitutively active NFAT and a constitutively active MEKK1 renders the interleukin-2 promoter in Jurkat T lymphocytes resistant to CsA and FK506, whereas Jurkat cells expressing a constitutively active NFAT alone are still sensitive to CsA or FK506. Therefore, CsA and FK506 exert their immunosuppressive effects through targeting both the calcineurin-dependent NFAT pathway and calcineurin-independent activation pathway for JNK and p38.
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PMID:Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation. 1125 83

The human (hPRL) PRL gene proximal promoter (-164/+15) is the target for numerous signal transduction pathways involving protein kinases. The inhibitor of Ser/Thr-protein phosphatases okadaic acid (OA) was shown to induce this promoter in rat pituitary GH3B6 through a synergism between increased amounts of the ubiquitous factor AP-1 and the pituitary-specific factor Pit-1. Here we show that this activation results mainly from transcriptional stimulation of the c-fos promoter leading to increased AP-1 activity. We report the surprising absence of the hPRL and c-fos promoter stimulation by OA in GH3 cells, closely related to GH3B6 cells, and we use this discrepancy to dissect the precise mechanism of action. c-fos gene activation involves the mitogen-activated kinase (MAPK)-ternary complex factor (TCF) pathway and can be obtained by expressing active V12ras in both cell lines. We show that OA acts by inhibiting protein phosphatase PP1, thereby protecting MAPK kinase (MEK)1/2 and/or a MEK1/2-kinase from dephosphorylation. PP1 inhibition of MEK activation by V12ras does not occur in GH3 cells, indicating that a distinct, PP1-sensitive phosphorylation site is used in GH3B6 cells to activate the TCF pathway in GH3B6 cells. Finally, we show that the synergistic OA activation of the hPRL promoter by Pit-1 and AP-1 is independent of the Pit-1 transactivation domain and is mediated by the general coactivator (CRE-binding protein)-binding protein (CBP)/p300.
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PMID:Inhibition of protein phosphatase PP1 in GH3B6, but not in GH3 cells, activates the MEK/ERK/c-fos pathway and the human prolactin promoter, involving the coactivator CPB/p300. 1126 13

Interleukin (IL)-3-induced Bcl2 phosphorylation at Ser(70) may be required for its full and potent antiapoptotic activity. However, in the absence of IL-3, increased expression of Bcl2 can also prolong cell survival. To determine how Bcl2 may be functionally phosphorylated following IL-3 withdrawal, a stress-activated Bcl2 kinase (SAK) was sought. Results indicate that anisomycin, a potent activator of the stress kinase JNK/SAPK, can induce Bcl2 phosphorylation at Ser(70) and that JNK1 can be latently activated following IL-3 withdrawal to mediate Bcl2 phosphorylation. JNK1 directly phosphorylates Bcl2 in vitro, co-localizes with Bcl2, and collaborates with Bcl-2 to mediate prolonged cell survival in the absence of IL-3 or following various stress applications. Dominant-negative (DN)-JNK1 can block both anisomycin and latent IL-3 withdrawal-induced Bcl2 phosphorylation (>90%) and potently enhances cell death. Furthermore, low dose okadaic acid (OA), a potent protein phosphatase 1 and 2A inhibitor, can activate the mitogen-activated protein kinases JNK1 and ERK1/2, but not p38 kinase, to induce Bcl2 phosphorylation and prolong cell survival in factor-deprived cells. Since PD98059, a specific MEK inhibitor, can only partially inhibit OA-induced Bcl2 phosphorylation but completely blocks OA-induced Bcl2 phosphorylation in cells expressing DN-JNK1, this supports the conclusion that OA may stimulate Bcl2 phosphorylation via a mechanism involving both JNK1 and ERK1/2. Collectively, these findings indicate a novel role for JNK1 as a SAK and may explain, at least in part, how functional phosphorylation of Bc12 can occur in the absence of growth factor.
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PMID:Novel role for JNK as a stress-activated Bcl2 kinase. 1132 15

Retinoic acid induces cell differentiation and suppresses cell growth in a wide spectrum of cell lines, and down-regulation of activator protein-1 activity by retinoic acid contributes to these effects. In embryonic stem cell-like F9 teratocarcinoma cells, which are widely used to study retinoic acid actions on gene regulation and early embryonic differentiation, retinoic acid treatment for 4 days resulted in suppression of cell growth and differentiation into primitive and then visceral endoderm-like cells, accompanied by a suppression of serum-induced c-Fos expression. The MAPK (ERK) pathway was involved in mitogenic signaling in F9 cells stimulated with serum. Surprisingly, although c-Fos expression was reduced, the MAPK activity was not decreased by retinoic acid treatment. We found that retinoic acid treatment inhibited the phosphorylation of Elk-1, a target of activated MAPK required for c-Fos transcription. In F9 cells, the MAPK/MEK inhibitor PD98059 suppressed Elk-1 phosphorylation and c-Fos expression, indicating that MAPK activity is required for Elk-1 phosphorylation/activation. Phosphoprotein phosphatase 2B (calcineurin), the major phosphatase for activated Elk-1, is not the target in the disassociation of MAPK activation and c-Fos expression since its inhibition by cyclosporin A or activation by ionomycin had no significant effects on serum-stimulated c-Fos expression and Elk-1 phosphorylation. Thus, we conclude that retinoic acid treatment to induce F9 cell differentiation uncouples Ras/MAPK activation from c-Fos expression by reduction of Elk-1 phosphorylation through a mechanism not involving the activation of phosphoprotein phosphatase 2B.
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PMID:Disassociation of MAPK activation and c-Fos expression in F9 embryonic carcinoma cells following retinoic acid-induced endoderm differentiation. 1140 55

The current studies were designed to examine the mechanisms of acute effects of ethanol on cerebellar granule neurons (CGNs) during neurodevelopment, with specific reference to activator protein-1 (AP-1). CGNs, isolated from 3-day-old Sprague-Dawley rats and cultured for 3 days, were exposed to 0, 22.5, and 100 mM ethanol for 1 h. Gel shift assays performed on the nuclear protein extracts showed increased AP-1 and heat shock factor-1 (HSF-1) transcriptional activation in response to ethanol. Western blots and RT-PCR showed increased c-JUN and phosphorylated c-JUN (serine 73) protein, as well as c-jun mRNA. Ethanol paradoxically decreased the activity of stress-activated protein kinase-1 (SAPK-1) while increasing p44 and p42 mitogen-activated protein kinase (MAPK) activity. The protein synthesis-inhibiting and SAPK-1 activity-inducing antibiotic, anisomycin (30 and 500 microM) decreased AP-1 transcriptional activation to 47 and 23% of control values, respectively. The anisomycin effect was enhanced in the presence of 100 mM ethanol. Similarly, cycloheximide decreased ethanol-induced AP-1 transcriptional activation. Pretreatment with the MAPK kinase (MEK) pathway inhibitor PD98059 resulted in decreases in both ethanol-induced and control AP-1 DNA binding. Thus this acute ethanol-induced increased AP-1 transcriptional activation requires protein synthesis and involves MEK-independent increased MAPK phosphorylation, on the one hand, and decreased SAPK-1 activity on the other. The ethanol effect is thus ascribed to the activities of alternate kinase pathways and/or the inhibition of (a) protein phosphatase(s). Exposure of CGNs to ethanol for 24 h resulted in decreased AP-1 DNA binding, an observation that could have consequences for overall neuronal function under chronic exposure conditions.
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PMID:Acute exposure of cerebellar granule neurons to ethanol suppresses stress-activated protein kinase-1 and concomitantly induces AP-1. 1150 22

The present study examined the role of calcineurin in insulin-like growth factor (IGF)-1-induced hypertrophy in primary cultures of adult rat ventricular myocytes (ARVM), prepared from the ventricles of 14-16-week-old male Sprague-Dawley rats. The effects of several humoral factors, including phenylephrine, angiotensin II, endothelin-1, IGF-1 and interleukin-6, on the morphology of ARVM were studied. Myocyte surface area was significantly increased by IGF-1 (2,268 +/- 571 to 3,018 +/- 836 microm2, p < 0.01), but not by other humoral factors. This hypertrophic effect of IGF-1 was blocked by genistein (tyrosine kinase inhibitor), PD98059 (MEK inhibitor). These findings suggest that IGF-1 produces ARVM hypertrophy by a tyrosine kinase-MEK mediated pathway as has been reported in neonatal cardiomyocytes. IGF-1-mediated ARVM hypertrophy was also attenuated by cyclosporine A (calcineurin inhibitor), and staurosporine and chelerythrine (protein kinase C inhibitors). IGF-1 markedly increased calcineurin activity (8.7 +/- 1.2 to 98.0 +/- 54.3 pmol x h(-1) mg(-1), p < 0.01), and this activation was completely blocked by pre-treatment with cyclosporine A (8.5 +/- 11.4pmol x h(-1) x mg(-1), p < 0.01) and chelerythrine (2.3 +/- 2.7 pmol x h(-1) mg(-1), p < 0.01). It appears that IGF-1 activates calcineurin by a protein kinase C-dependent pathway. Increased mRNA expression of atrial natriuretic factor by IGF-1 was inhibited by cyclosporine A (p < 0.01). The findings indicate that IGF-1 induces ARVM hypertrophy by protein kinase C and calcineurin-related mechanisms. The fact that elevated calcineurin activity and induced atrial natriuretic factor mRNA expression by IGF-1 were blocked by cyclosporine A further supports the hypothesis that calcineurin is critically involved in IGF-1-induced ARVM hypertrophy.
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PMID:Role of calcineurin in insulin-like growth factor-1-induced hypertrophy of cultured adult rat ventricular myocytes. 1154 82


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