Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The early events of signal transduction associated with interleukin-2 (IL-2) binding to its receptor were examined using a human IL-2 dependent T-cell line, Kit225. Cell cycle analysis showed that 90% of Kit225 cells were in the G0/G1 phase after a 72-hr incubation in the absence of exogenous IL-2. At this point, stimulation of the cells with IL-2 resulted in the rapid initiation of RNA and DNA synthesis by 9 and 20 hr, respectively. Within 5 min after addition of IL-2, rapid activation of tyrosine and ribosomal S6 kinases was detected. Addition of IL-2 also increased mRNA levels for c-fos, c-myc, IL-2 receptor alpha, and IL-2 receptor beta chain. These events increased in the absence of detectable changes in free cytosolic [Ca2+]i, inositol phosphate metabolism, or the activity of several kinases including cAMP-dependent protein kinase, Ca2+/calmodulin-dependent protein kinase, or protein kinase C. These findings demonstrate that the signals triggered by IL-2 binding to its receptors are quickly transduced into the nucleus with increased mRNA transcription of activation-associated genes. Furthermore, the data indicate that tyrosine and ribosomal S6 kinases may be important for IL-2-induced cell growth.
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PMID:Signal transduction by interleukin 2 in human T cells: activation of tyrosine and ribosomal S6 kinases and cell-cycle regulatory genes. 131 23

Cellular immediate early genes (IEGs) are a class of genes whose transcription is transiently activated within minutes of exposure of cells to a wide range of extracellular stimuli. In mature neurons IEG expression can be triggered by a variety of neutrotransmitters and neurotrophic factors. The IEGs, many of which encode transcription factors, are believed to control the physiological response of the cells to the initial stimulation event by activating secondary programs of gene expression. The mechanism by which membrane depolarization/Ca2+ influx trigger the activation of one IEG, c-fos, has been characterized in PC12 cells. In these cells, the cAMP response element-binding protein (CREB) functions as a Ca2+ regulated transcription factor. In addition, CREB is an in vitro substrate for several Ca2+ calmodulin-dependent protein kinases (CaM kinases). These results suggest a model whereby activation of voltage sensitive Ca2+ channels stimulates CaM kinase activation leading to CREB phosphorylation and c-fos transcriptional activation.
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PMID:Calcium regulation of immediate early gene transcription. 134

In a variety of nerve cells of the brain, action potentials activate gene expression by means of Ca2+ influx. To determine how Ca2+ influx alters gene expression, we have examined the pattern of phosphorylation of a protein that binds to the cAMP response element (CRE). We have found that purified bovine brain CRE-binding protein is a substrate for the Ca2+/calmodulin-dependent kinase II (Cam kinase) as it is for the cAMP-dependent protein kinase (kinase A). Tryptic peptide maps show that the same peptide is phosphorylated in vitro both by kinase A and by Cam kinase. Moreover, in vitro transcription assays using a CRE-containing c-fos promoter indicate that phosphorylation of CRE-binding protein by Cam kinase increases gene transcription. Thus, action potentials in nerve cells and the consequent influx of Ca2+ can activate CRE-binding proteins by means of Cam kinase. This kinase therefore provides a direct second-messenger pathway by which impulse activity at the membrane can influence gene transcription. This has been shown independently by Sheng et al. (Sheng, M., Thomson, M. A. & Greenberg, M. E. (1991) Science, in press), who found that depolarization and Ca2+ influx mediate induction of c-fos in PC12 rat pheochromocytoma cells through phosphorylation of CRE-binding protein. These several findings indicate that CRE-binding protein(s) is a convergence point for synaptic activity acting through kinase A and impulse activity acting through Cam kinase. Together the two kinases could activate transcription in a synergistic manner, which could allow CRE-binding protein to couple short-term to long-term associative forms of synaptic plasticity.
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PMID:cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase. 164 24

Exposing primary cultures of cerebellar granule neurons to 100 nM phorbol 12-myristate 13-acetate (PMA) for 24 hr decreases the Ca2+/phosphatidylserine/diolein-dependent protein kinase C (PKC; ATP:protein phosphotransferase, EC 2.7.1.37) by approximately 90% in the 100,000 x g supernatant and pellet fractions of neuronal culture homogenates. Immunoblot analysis of the homogenates with polyclonal antibodies raised against either the beta-type PKC peptide or total rat brain PKC reveals a virtual loss of 78-kDa PKC immunoreactivity in the supernatant and a marked decrease of PKC immunoreactivity in the pellet. Exposure of the cultures to 50 microM glutamate for 15 min (no Mg2+) induces the translocation of supernatant PKC immunoreactivity to the pellet. Such translocation persists after glutamate withdrawal and is followed by a progressive increase in neuronal death, which begins 2 hr later. Neuronal death approaches completion in about 24 hr. PMA-induced down-regulation of PKC decreases glutamate-elicited neurotoxicity. Yet, the culture exposure to 100 nM PMA fails to decrease the high-affinity binding of [3H]glutamate to neuronal membranes and does not reduce glutamate-induced activation of ionotropic or metabolotropic receptors (assayed as total membrane current measured in whole-cell voltage-clamped neurons, 45Ca2+ uptake in intact monolayers, inositolphospholipid hydrolysis, and transcriptional activation and translation of c-fos mRNA). Moreover, the immediate cell-body swelling and activation of spectrin proteolysis elicited by glutamate remain unchanged. On the other hand, PMA-induced PKC down-regulation reduces any increase in 45Ca2+ uptake or Ca2(+)-dependent proteolysis (measured as spectrin degradation) after glutamate withdrawal. These results support the view that PKC translocation is operative in glutamate-induced destabilization of cytosolic ionized Ca2+ homeostasis and neuronal death.
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PMID:Down-regulation of protein kinase C protects cerebellar granule neurons in primary culture from glutamate-induced neuronal death. 168 50

In Swiss 3T3 fibroblasts a peptide mitogen bombesin, which acts through the phospholipase C-protein kinase C signaling pathway, stimulates DNA synthesis in a manner strictly dependent on the medium calcium concentration: [3H]thymidine incorporation into DNA in the presence of a saturating concentration of bombesin (10(-8) M) is 4-fold greater at 3.0 mM extracellular calcium as compared with a value obtained at 0.03 mM calcium. In the present study we attempted to identify the site and the mechanism of action of Ca2+ influx along the bombesin-induced mitogenic signaling pathway, by comparing bombesin effects at 0.03 and 3.0 mM of medium calcium. Bombesin induces the same extent of increases in [3H]inositol phosphates after 1 min, and comparable sustained increases in the cellular content of 1,2-diacylglycerol for up to 4 h, at either 0.03 or 3.0 mM calcium. Bombesin induces the same extent of phosphorylation of MARCKS protein, the major cellular substrate for protein kinase C, irrespective of the medium calcium concentration for at least 4 h. Moreover, diverse cellular responses elicited by bombesin, including c-fos expression, activation of microtubule-associated protein 2 kinase and S6 kinase, glucose uptake, and protein synthesis but not the release of arachidonic acid and its metabolites, are induced similarly at either 0.03 or 3.0 mM calcium. Down-regulation of cellular protein kinase C nearly completely abolishes bombesin effects on c-fos expression, S6 kinase activation, glucose uptake, and DNA synthesis. These results suggest that the target of Ca2+ influx in bombesin-induced mitogenic signaling pathway is not located along the phospholipase C-protein kinase C signal transduction system including cellular events in early G1 phase that exist downstream to protein kinase C action.
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PMID:Role of Ca2+ influx in bombesin-induced mitogenesis in Swiss 3T3 fibroblasts. 184 53

Agents that activate cAMP-dependent protein kinase (PKA) as well as agents that increase intracellular calcium induce the expression of certain immediate early genes (IEGs). Recently, it has been demonstrated that the same cis-acting element in the 5' region of the c-fos gene has the ability to mediate both cAMP- and calcium-induced c-fos expression in PC12 cells (Sheng, M., McFadden, G., and Greenberg, M. (1990) Neuron 4, 571-582). Here we demonstrate that both cAMP- and calcium-mediated induction of c-fos and egr1 are dependent on PKA activity. Addition of either depolarizing concentrations of KCl or the calcium ionophore, ionomycin, to PC12 cells increased the expression of both c-fos and egr1, but these inductions were dramatically reduced in three PKA-deficient cell lines, 123.7, AB.11, and A126-1B2. Furthermore, pretreatment of PC12 cells with 20 microM H89, a specific inhibitor of PKA, inhibited forskolin, dibutyryl cAMP, and KCl-induced c-fos and egr1 induction, while having no effect on NGF induction. Likewise, in the PKA-deficient cells, NGF or an activator of protein kinase C induced c-fos and egr1 normally. To determine if PKA deficiency modifies the ability of Ca2+ to activate calcium-dependent kinases, autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) in response to Ca2+ influx was determined. In parental PC12 cells, PC12 cells pretreated with H89, and PKA-deficient cell lines, CaM kinase was activated equivalently in response to KCl depolarization. These results suggest that PKA is not required for Ca(2+)-induced increase in CaM kinase activity and that the induction of IEGs in response to Ca2+ influx is PKA-dependent. Thus, the requirement for PKA resides at a point distal to the activation of calmodulin-dependent processes.
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PMID:Induction of immediate early genes by Ca2+ influx requires cAMP-dependent protein kinase in PC12 cells. 191 45

Recent studies indicate multiple mechanisms are involved in Ca2+ stimulation of gene expression. We have used cell-permeable, specific inhibitors of calmodulin-dependent protein kinases (CaM kinases) and phosphatase (calcineurin) to investigate the involvement of these enzymes in transcriptional regulation of three immediate early genes in PC12 cells stimulated with A23187 or KCl. Preincubation of PC12 cells with the CaM kinase inhibitor KN-62 blocked autophosphorylation of CaM kinase II in response to stimulation by the Ca2+ ionophore A23187. KN-62 treatment also resulted in a 60-70% inhibition of Ca(2+)-dependent transcription of c-fos, NGFI-A (zif 268), and NGFI-B (nur 77) as assessed by either Northern or nuclear run-on analyses. Preincubation with the calcineurin inhibitors FK-506 or cyclosporin A strongly enhanced expression of NGFI-A and blocked transcription of NGFI-B, but it had no significant effect on Ca(2+)-stimulated transcription of c-fos. Both FK-506 and KN-62 were specific for Ca(2+)-stimulated transcription as neither effected transcription in response to forskolin or phorbol ester (12-O-tetradecanoylphorbol-13-acetate) treatment. This is the first report of CaM kinase and calcineurin involvement in transcriptional regulation of NGFI-A and NGFI-B. Activation of CaM kinases and calcineurin, in response to elevated intracellular Ca2+, would exert antagonistic effects on transcription of NGFI-A. Since inhibition of either the kinase or phosphatase decreased transcription of NGFI-B by 60-90%, this suggests that each enzyme is necessary but not sufficient for Ca2+ stimulation. These results indicate that CaM kinases and calcineurin can mediate broad and complex regulation of Ca(2+)-stimulated gene expression.
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PMID:Roles of calmodulin-dependent protein kinases and phosphatase in calcium-dependent transcription of immediate early genes. 752 Apr 33

The signal pathway for light-induced expression of c-fos and the neuropeptide somatostatin (SS) in rat retinal cells was investigated. Flashing light induced c-fos and SS mRNA in the inner nuclear layer and the ganglion cell layer. As both c-fos and SS genes have a cyclic AMP response element (CRE) in their promoters, CRE-binding protein (CREB) phosphorylation in retinal cells was examined with a phospho-CREB-specific antibody. Both flashing light and administration of the L-type Ca2+ channel activator Bay K 8644 induced phosphorylation of CREB in the nuclei of the amacrine cells and the ganglion cells where c-fos/SS mRNAs were expressed. These cells could be double-stained with anti-calmodulin kinase II (anti-CaM kinase II) monoclonal antibody and phospho-CREB-specific polyclonal antiserum after Bay K 8644 administration, indicating the colocalization of phosphorylated CREB at Ser133 and CaM kinase II in the neural retina.
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PMID:Light-induced CREB phosphorylation and gene expression in rat retinal cells. 756 43

In the presence of costimulation, Ca2+ influx in T cells leads to activation (transcription of interleukin-2; ref. 2) via calcineurin. In the absence of costimulation, Ca2+ influx results in anergy (interleukin-2 transcriptional block) through an unknown mechanism. Specific attenuation of interleukin-2 transcriptional induction occurs in Jurkat T cells following pretreatment with a Ca2+ ionophore. A > 90% block of inducible interleukin-2 reporter gene activity was initiated by transfection of a constitutively active mutant of multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase or CaM kinase II), but not by constitutive mutants of CaM kinase IV, calcineurin or protein kinase C. The block was complete six hours after kinase transfection and showed specificity for interleukin-2; there was no change in beta-actin transcription or in c-fos transcription induced by phorbol myristyl acetate, and a Rous sarcoma virus promoter was stimulated threefold. Multifunctional CaM kinase also attenuated interleukin-2 activation by calcineurin plus phorbol ester. T-cell receptor signalling activates multifunctional CaM kinase. These findings suggest that two Ca2+/calmodulin-responsive enzymes, multifunctional CaM kinase and calcineurin, could mediate the divergent effects of Ca2+ signals in T-lymphocyte regulation.
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PMID:Interleukin-2 transcriptional block by multifunctional Ca2+/calmodulin kinase. 809 Feb 6

Calcium ions (Ca2+) act as an intracellular second messenger and can enter neurons through various ion channels. Influx of Ca2+ through distinct types of Ca2+ channels may differentially activate biochemical processes. N-Methyl-D-aspartate (NMDA) receptors and L-type Ca2+ channels, two major sites of Ca2+ entry into hippocampal neurons, were found to transmit signals to the nucleus and regulated gene transcription through two distinct Ca2+ signaling pathways. Activation of the multifunctional Ca(2+)-calmodulin-dependent protein kinase (CaM kinase) was evoked by stimulation of either NMDA receptors or L-type Ca2+ channels; however, activation of CaM kinase appeared to be critical only for propagating the L-type Ca2+ channel signal to the nucleus. Also, the NMDA receptor and L-type Ca2+ channel pathways activated transcription by means of different cis-acting regulatory elements in the c-fos promoter. These results indicate that Ca2+, depending on its mode of entry into neurons, can activate two distinct signaling pathways. Differential signal processing may provide a mechanism by which Ca2+ controls diverse cellular functions.
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PMID:Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. 809 60


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