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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The myocyte enhancer factor-2 (MEF2) family of transcription factors regulates transcription of muscle-dependent genes in cardiac, skeletal and smooth muscle. They are activated by calcium/calmodulin (CaM)-dependent protein kinases I and IV and silenced by CaM KIIdeltaC. MEF2 is held in an inactive form by the class II histone deacetylases (HDAC) until phosphorylated by either CaM kinase I or IV. Upon phosphorylation, HDAC is transported out of the nucleus via a 14-3-3 dependent mechanism freeing MEF2 to drive transcription. The 14-3-3 chaperone protein exists as a homodimer. In the region of homodimerization, there are two canonical CaM kinase II phosphorylation sites (ser60 and ser65). In vitro phosphorylation assay results indicate that 14-3-3beta is indeed a substrate for CaM kinase II. We hypothesize that CaM kinase IIdeltaC phosphorylation of 14-3-3beta will disrupt homodimer formation resulting in the return of HDAC to the nucleus and their reassociation with MEF2. To test this, we mutated serines 60 and 65 of 14-3-3beta to aspartates to mimic the phosphorylated state. In MEF2 enhancer-reporter assays in smooth muscle cells, expression of the 14-3-3beta double mutant attenuated MEF2-enhancer activity driven by CaM kinase I or IV. The intracellular fate of HDAC4 was followed by transfection of smooth muscle cells with an HDAC4-Green Fluorescent Protein fusion hybrid. The 14-3-3beta double mutant prevented HDAC4 cytoplasmic localization in the presence of active CaM kinase I or IV. These data suggest that the mechanism of CaM kinase IIdeltaC silencing of MEF-2-dependent genes is by phosphorylation of 14-3-3beta, which allows HDAC to return to the nucleus to reform a complex with MEF2, thereby silencing MADS box-dependent gene induction in smooth muscle.
Mol Cell Biochem 2003 Jan
PMID:CaM kinase IIdeltaC phosphorylation of 14-3-3beta in vascular smooth muscle cells: activation of class II HDAC repression. 1261 78

The Ca(2+)/calmodulin-dependent protein kinase kinases alpha and beta (CaMKKs alpha and beta) are novel members of the CaM kinase family. The CaMKKbeta was cloned from mouse brain. The deduced amino acid sequence shared 96.43% homology with the rat CaMKKbeta. Both the alpha and beta isoforms were widely distributed throughout the adult mouse brain. Additionally, all peripheral tissues examined displayed CaMKK alpha and beta expression.
Brain Res Mol Brain Res 2003 Mar 17
PMID:Cloning of mouse Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) and characterization of CaMKKbeta and CaMKKalpha distribution in the adult mouse brain. 1265 22

An inducible fluorescent system based on GFP is presented that allows for the uncoupling of dendritic mRNA transport from subsequent protein synthesis at the single cell level. The iron-responsive element (IRE) derived from ferritin mRNA in the 5'-UTR of the GFP reporter mRNA renders translation of its mRNA dependent on iron. The addition of the full-length 3'-UTR of the Ca(2+)/calmodulin-dependent protein kinase II alpha (CaMKIIalpha) after the stop codon of the GFP reading frame targets the reporter mRNA to dendrites of transfected fully polarized hippocampal neurons. As we show by time-lapse videomicroscopy, iron specifically turns on GFP reporter protein synthesis in a single transfected hippocampal neuron. We investigate whether GFP expression is affected--in addition to iron--by synaptic activity. Interestingly, synaptic activity has a clear stimulatory effect. Most importantly, however, this activity-dependent protein synthesis is critically dependent on the presence of the full-length 3'-UTR of CaMKIIalpha confirming that this sequence contains translational activation signals. The IRE-based system represents a new convenient tool to study local protein synthesis in mammalian cells where mRNA localization to a specific intracellular compartment occurs.
Mol Biol Cell 2003 Apr
PMID:A GFP-based system to uncouple mRNA transport from translation in a single living neuron. 1268 10

We report the crystal structure of the 143 residue association domain of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). The association domain forms a hub-like assembly, composed of two rings of seven protomers each, which are stacked head to head and held together by extensive interfaces. The tetradecameric organization of the assembly was confirmed by analytical ultracentrifugation and multiangle light scattering. Individual protomers form wedge-shaped structures from which N-terminal helical segments that connect to the kinase domain extend toward the equatorial plane of the assembly, consistent with the arrangement of the kinase domains in a second outer ring. A deep and highly conserved pocket present within the association domain may serve as a docking site for proteins that interact with CaMKII.
Mol Cell 2003 May
PMID:Crystal structure of a tetradecameric assembly of the association domain of Ca2+/calmodulin-dependent kinase II. 1276 48

The Ets1 proto-oncoprotein is a member of the Ets family of transcription factors that share a unique DNA binding domain, the Ets domain. The DNA binding activity of Ets1 is controlled by kinases and transcription factors. Some transcription factors, such as AML-1, regulate Ets1 by targeting its autoinhibitory module. Others, such as Pax-5, alter Ets1 DNA binding properties. Ets1 harbors two phosphorylation sites, threonine-38 and an array of serines within the exon VII domain. Phosphorylation of threonine-38 by ERK1/2 activates Ets1, whereas phosphorylation of the exon VII domain by CaMKII or MLCK inhibits Ets1 DNA binding activity. Ets1 is expressed by numerous cell types. In haemotopoietic cells, it contributes to the regulation of cellular differentiation. In a variety of other cells, including endothelial cells, vascular smooth muscle cells and epithelial cancer cells, Ets1 promotes invasive behavior. Regulation of MMP1, MMP3, MMP9 and uPA as well as of VEGF and VEGF receptor gene expression has been ascribed to Ets1. In tumors, Ets1 expression is indicative of poorer prognosis.
Mol Cancer 2003 Aug 20
PMID:The biology of the Ets1 proto-oncogene. 1297 29

2-Pyrrolidinone, a metabolite of aniracetam, potentiated currents through alpha7 receptors expressed in Xenopus oocytes, in a bell-shaped dose-dependent manner at concentrations ranged from 1 nM to 10 microM, with a maximum at 100 nM (189% of original levels 60 min after 20-min treatment). The potentiation was inhibited by GF109203X, a selective inhibitor of protein kinase C (PKC), but not by KN-93, a selective inhibitor of CaMKII, or H-89, a selective inhibitor of protein kinase A (PKA). In the PKC assay using reversed-phase high-performance liquid chromatography, 2-pyrrolidinone enhanced activity of PKC-epsilon activated by linoleic acid to about 1.8-times greater than that in the absence of 2-pyrrolidinone, although it did not directly activate PKC-epsilon. In the Western immunoblot analysis, rat hippocampal slices treated with 2-pyrrolidinone (100 nM) was more reactive to an antibody against phosphorylated myristoylated alanine-rich C kinase substrate (MARCKS) than untreated slices. 2-Pyrrolidinone (100 nM) induced a long-lasting facilitation of hippocampal synaptic transmission in the CA1 region of rat hippocampal slices, and the facilitation was inhibited by GF109203X or alpha-bungarotoxin, an inhibitor of alpha7 receptors. The results of the present study suggest that 2-pyrrolidinone enhances activity of activated PKC, thereby potentiating alpha7 receptor responses, and then leading to a facilitation of hippocampal synaptic transmission.
Brain Res Mol Brain Res 2003 Sep 10
PMID:2-pyrrolidinone induces a long-lasting facilitation of hippocampal synaptic transmission by enhancing alpha7 ACh receptor responses via a PKC pathway. 1449 85

The status of phospholamban (PLB) phosphorylation in the ischemia-reperfused hearts remains controversial. Although a decrease in the phosphorylation of both PLB residues (Ser16, PKA site, and Thr17, CaMKII site) was previously reported, experiments from our laboratory failed to detect this decrease. In an attempt to elucidate the cause for this discrepancy, experiments were performed in Langendorff-perfused rat hearts with two main goals: (1) To determine whether keeping pacing during ischemia, a protocol followed in other ischemia-reperfusion models, decreases the phosphorylation of PLB residues, below pre-ischemic values; (2) To investigate whether a maximal beta-adrenergic challenge allows to detect a decrease in the ability of PLB to be phosphorylated in ischemia-reperfused hearts. Hearts were submitted to a global ischemia/reperfusion protocol (20/30 min) with (P) or without (NP) pacing during ischemia, and phosphorylation of PLB residues was assessed by immunodetection. The recovery of contractility upon reperfusion was lower in P vs. NP hearts. Ser16 of PLB, was phosphorylated at the end of ischemia in NP hearts. This increase appeared earlier in P hearts and was significantly diminished by catecholamine depletion and beta-blockade. Thr17 site was phosphorylated at the beginning of ischemia and the onset of reperfusion. The ischemia-induced phosphorylation of Thr17 was higher and more sustained in P vs. NP hearts, and inhibited by the calcium channel blocker, nifedipine, whereas the reperfusion-induced increase in Thr17 phosphorylation was similar in P and NP hearts and was significantly diminished by the Na+/Ca2+ exchanger inhibitor KB-R7943. Phosphorylation of PLB residues did not decrease below basal levels at any time during ischemia and reperfusion. However, the phosphorylation, inotropic and lusitropic response to beta-adrenergic stimulation was significantly decreased both in P and NP hearts.
Mol Cell Biochem 2003 Oct
PMID:Phospholamban phosphorylation in ischemia-reperfused heart. Effect of pacing during ischemia and response to a beta-adrenergic challenge. 1457 98

Transcriptional activation is a key link between neuronal activity and long-term synaptic plasticity. Little is known about genes responding to this activation whose products directly effect functional and structural changes at the synapse. cpg15 is an activity-regulated gene encoding a membrane-bound ligand that regulates dendritic and axonal arbor growth and synaptic maturation. We report that cpg15 is an immediate-early gene induced by Ca(2+) influx through NMDA receptors and L-type voltage-sensitive calcium channels. Activity-dependent cpg15 expression requires convergent activation of the CaM kinase and MAP kinase pathways. Although activation of PKA is not required for activity-dependent expression, cpg15 is induced by cAMP in active neurons. CREB binds the cpg15 promoter in vivo and partially regulates its activity-dependent expression. cpg15 is an effector gene that is a target for signal transduction pathways that mediate synaptic plasticity and thus may take part in an activity-regulated transcriptional program that directs long-term changes in synaptic connections.
Mol Cell Neurosci 2003 Nov
PMID:Regulation of cpg15 by signaling pathways that mediate synaptic plasticity. 1466 6

Initially during acidosis, Ca transient amplitude (Delta[Ca]i) and the rate constant of [Ca]i decline (k(Ca)) are decreased, but later during acidosis Delta[Ca]i and k(Ca) partially recover. This recovery in rat myocytes could be inhibited by KN-93 suggesting that CaMKII-dependent protein phosphorylation (and enhanced SR Ca uptake) may be responsible. To test whether phospholamban (PLB) is required for the Delta[Ca]i and k(Ca) recovery during acidosis, we used isolated myocytes from PLB knockout (PLB-KO) vs. wild-type (WT) mice. [Ca]i was measured using fluo-3. During the initial phase of acidosis (1-4 min), Delta[Ca]i decreased in WT myocytes (n = 8) from 1.75 +/- 0.19 to 1.10 +/- 0.13 DeltaF/F0 (P < 0.05) and k(Ca) decreased from 3.20 +/- 0.22 to 2.38 +/- 0.18 s(-1) (P < 0.05). Later during acidosis (6-12 min), Delta[Ca]i partially recovered to 1.41 +/- 0.18 DeltaF/F0 and k(Ca) to 2.78 +/- 0.22 s(-1) (i.e. both recovered by approximately 50%). CaMKII inhibition using KN-93 completely prevented this recovery of Delta[Ca]i and k(Ca) during late acidosis in WT myocytes. In PLB-KO myocytes (n = 11) Delta[Ca]i decreased during early acidosis from 2.92 +/- 0.31 to 1.33 +/- 0.17 DeltaF/F0 (P < 0.05) and k(Ca) decreased from 10.45 +/- 0.56 to 7.58 +/- 0.68 s(-1) (P < 0.05). However, Delta[Ca]i did not recover during late acidosis and k(Ca) decreased even more (6.59 +/- 0.65 s(-1)). Parallel results were seen for contractile parameters. We conclude that PLB is crucial to the recovery of Delta[Ca]i and k(Ca) during acidosis. Moreover, PLB phosphorylation by CaMKII plays an important role in limiting the decline in Ca transients (and contraction) during acidosis.
J Mol Cell Cardiol 2004 Jan
PMID:Phospholamban is required for CaMKII-dependent recovery of Ca transients and SR Ca reuptake during acidosis in cardiac myocytes. 1473 43

beta-adrenergic stimulation helps to synchronize Ca release in myocytes from failing hearts. Transverse (t-) tubules, which synchronize Ca release in normal cells and contain many of the elements of the beta-adrenergic pathway, may be depleted in such cells. The objective of the present study was to determine whether beta-adrenergic stimulation could reverse the desynchronization of Ca release observed in detubulated ventricular myocytes. The effect of isoprenaline (0.5 microM) on control and detubulated rat ventricular myocytes was investigated. Ca transients were monitored using whole-cell fluorescence and confocal microscopy, and Ca current recorded using the patch-clamp technique. Immunocytochemistry was used to investigate phospholamban (PLB) phosphorylation. Detubulation reduces and slows the Ca transient; these effects were reversed by isoprenaline. This restoration was associated with partial reversal of the desynchronization of Ca release that occurs in detubulated cells. Sarcoplasmic reticulum Ca load increased by the same amount in normal and detubulated cells, but Ca current increased less in detubulated cells (64%) than in control cells (124%) in response to isoprenaline. The pattern and extent of cAMP-dependent protein kinase and CaMKII-induced phosphorylation of PLB in response to isoprenaline was the same in both cell types. Thus, the beta-adrenergic pathway is functional in the absence of t-tubules; such stimulation appears to increase the speed of propagation of Ca via Ca-induced Ca release between adjacent clusters of ryanodine receptors, which may be relevant in pathological conditions, such as heart failure, in which t-tubules are depleted. The data also suggest that the Ca current responds to local signaling pathways, which are better coupled to the channel in the t-tubules than at the surface membrane, whereas PLB responds to whole-cell signaling.
J Mol Cell Cardiol 2004 Feb
PMID:beta-adrenergic stimulation restores the Ca transient of ventricular myocytes lacking t-tubules. 1487 54


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