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)

Efficient transcription and replication of the bovine leukemia virus (BLV) genome require both the viral long terminal repeat (LTR) and the virus-coded transcriptional activator Tax, which functions through a 21-bp sequence (Tax-responsive element [TxRE]) which is repeated three times within the LTR. Since Tax does not bind directly to DNA, host cell transcription factors play a central role in BLV expression. Electrophoretic mobility shift assays with nuclear extracts prepared with infected bovine B lymphocytes revealed five TxRE-specific complexes (C1, C2, C3, C4, and C5). Here, by using a UV-induced indirect labeling technique (UV cross-linking) in conjunction with mobility shift assays, eight major polypeptides of 31, 33, 42, 46, 51, 57, 87, and 119 kDa were identified within these five complexes. Immunoprecipitation experiments identified the 57- and 119-kDa proteins as cyclic AMP response element-binding (CREB) proteins, the 46- and 51-kDa proteins as activating transcription factor-1 (ATF-1), and the 87-kDa as protein ATF-2. All of these proteins (except the ATF-1 protein of 51 kDa) belong to the complex C1, which is the major complex identified in freshly isolated BLV-infected lymphocytes from cattle with persistent lymphocytosis. In transient-cotransfection experiments, these three transcription factors were able to activate LTR-directed gene expression in the presence of protein kinase A or Ca2+/calmodulin-dependent protein kinase IV. CREB protein, ATF-1, and ATF-2 thus appear to be the major transcription factors involved in the early stages of viral expression.
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PMID:The CREB, ATF-1, and ATF-2 transcription factors from bovine leukemia virus-infected B lymphocytes activate viral expression. 862 25

We have generated transgenic mice that express a catalytically inactive form of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) specifically in thymic T cells. The presence of this protein results in a markedly reduced thymic cellularity, although the distribution of the remaining cells is normal based on evaluation of the CD4 and CD8 cell surface antigens that are used to gauge T cell development. Isolated thymic T cells from the transgenic mice also show a dramatically decreased survival rate when evaluated in culture under conditions that do not favor activation. When challenged with an activating stimulus such as alpha-CD3 or a combination of phorbol ester plus ionophore, the cells are severely compromised in their ability to produce the cytokine interleukin-2 (IL-2). Reduction of IL-2 production is secondary to the inability to phosphorylate the cAMP response element binding protein, CREB, and induce expression of the immediate early genes such as Fos B that are required to transactivate the IL-2 promoter. Because transgene expression was regulated by the proximal promoter of the murine lck gene and this promoter is inactivated in T cells that exit the thymus, the mutant hCaMKIV is not present in peripheral T cells. Consequently, T lymphocytes present in the spleen can be activated normally in response to either stimulus mentioned above, demonstrating that the effects of the inactive CaMKIV on activation are reversible. Our results suggest that CaMKIV may represent a physiologically relevant CREB kinase in T cells and that the enzyme is also required to ensure normal expansion of T cells in the thymus. Whereas the pathway responsible for this latter role is yet to be elucidated, it is unlikely to include CREB phosphorylation.
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PMID:Defective survival and activation of thymocytes in transgenic mice expressing a catalytically inactive form of Ca2+/calmodulin-dependent protein kinase IV. 917 Dec 36

Four NPY receptor subtypes have been cloned, and shown to be coupled to both Ca2+ and cAMP. However, very little is known about the downstream elements mediating NPY actions. It has recently been demonstrated in our laboratory that intrahypothalamic (i.h.t.) administration of NPY induces hypothalamic CaM kinase activity, cyclic AMP response element binding protein (CREB) phosphorylation and cyclic AMP response element (CRE) binding activity in rat hypothalamic nuclear proteins. In the present study, we have investigated whether these changes in CRE binding transcriptional factors activated by NPY results in gene regulation using a human neuroblastoma cell line (SK-N-BE2). This cell line which expresses the Y2 subtype of NPY receptors was transfected with a fusion gene containing 1.305 kb of human CRF 5' flanking region with a perfect palindromic CRE site linked to firefly luciferase gene. NPY treatment increased CaM kinase II activity, CREB phosphorylation and CRE binding in these cells. In transfected cells, luciferase activity was also increased by NPY (1.8-4-fold) within 4 h of treatment. Moreover, forskolin (7-30-fold), which stimulates cAMP production, and thapsigargin (6-8-fold), which mobilizes intracellular calcium, also increased luciferase activity within 4 h of treatment. PMA (phorbol-12-myristate-13-acetate), an activator of protein kinase-C, induced luciferase activity by 1.8-fold. NPY augmented forskolin-stimulated luciferase activity from 11- to 15-fold, but had no significant effect on thapsigargin-induced luciferase activity. These findings suggest that activation of protein kinase A (PKA) or CaM kinase leads to the induction of fusion gene. NPY treatment upregulated fusion gene expression through Ca2+ pathway in SK-N-BE2 cell line. Pretreatment with CREB antisense, but not the sense oligodeoxynucleotides, inhibited forskolin-, thapsigargin- and NPY-stimulated luciferase activity. However, CREB sense or antisense oligodeoxynucleotide treatment had no effect on PMA-stimulated luciferase activity. Furthermore, NPY induced CRE binding activity and the expression of CRE containing Y1 receptor gene in SK-N-MC cell line. These findings suggest that NPY can upregulate CRE containing reporter gene including Y1 receptor gene and NPY-induced reporter gene regulation in SK-N-BE2 cells is mediated by intracellular Ca2+ and CREB protein.
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PMID:NPY upregulates genes containing cyclic AMP response element in human neuroblastoma cell lines bearing Y1 and Y2 receptors: involvement of CREB. 980 24

This investigation examined the effects of chronic ethanol treatment (15 days) and its withdrawal (24 h) on the expression and phosphorylation of cyclic AMP-response element-binding (CREB) protein in the rat cortex. The effects of chronic ethanol treatment and withdrawal on protein kinase A (PKA) activity and on the expression of the regulatory RII-beta- and the alpha-subtype catalytic subunits of PKA, and on the protein expression of Ca(2+)/calmodulin-dependent protein kinase IV (CaM kinase IV) and calcineurin in the rat cortex were also investigated. It was found that ethanol withdrawal but not ethanol treatment produced a significant decrease in the phosphorylated CREB (p-CREB) and CaM kinase IV protein levels in the frontal, parietal, and piriform cortex. Ethanol treatment and its withdrawal had no effect on the protein levels of total CREB in the frontal, parietal, and piriform cortex. On the other hand, ethanol treatment produced a significant reduction in the protein levels of CREB, p-CREB, and CaM kinase IV in the cingulate gyrus, and these changes reverted to normal levels during ethanol withdrawal. Total CREB protein levels were significantly higher in the cingulate gyrus during ethanol withdrawal. It was also observed that mRNA levels of CREB were significantly higher in the rat cortex during ethanol withdrawal but not during ethanol treatment. The protein levels of RII-beta- and alpha-subtype catalytic subunits of PKA and PKA activity were not modified in the rat cortex by chronic ethanol treatment and its withdrawal. Furthermore, the expression of calcineurin in the rat cortex was not altered during ethanol treatment and withdrawal. Taken together, these results suggest the possibility that decreased CREB-dependent events in the neurocircuitry of the frontal, parietal, and piriform cortex may play an important role in the phenomenon of alcohol dependence and also that decreased CREB-dependent events in the neurocircuitry of the cingulate gyrus may play a role in alcohol tolerance.
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PMID:Effects of chronic ethanol intake and its withdrawal on the expression and phosphorylation of the creb gene transcription factor in rat cortex. 1118 17

We have investigated mechanisms of nicotine-induced phosphorylation of extracellular signal-regulated protein kinase (p42/44 MAP kinase, ERK) and cAMP response element binding protein (CREB) in PC12h cells. Nicotine transiently induced ERK phosphorylation at more than 1 microM. The maximal level of nicotine-induced ERK phosphorylation was lower than that of the membrane depolarization induced and, to a great extent, the nerve growth factor (NGF)-induced ERK phosphorylation. Nicotinic acetylcholine receptor (nAChR) alpha7 subunit-selective inhibitors had no significant effect on nicotine-induced ERK phosphorylation. L-Type voltage-sensitive calcium channel antagonists inhibited nicotine-induced ERK phosphorylation. Calcium imaging experiments showed that alpha7-containing nAChR subtypes were functional at 1 microM of nicotine in the nicotine-induced calcium influx, and non-alpha7 nAChRs were prominent in the Ca(2+) influx at 50 microM of nicotine. An expression of dominant inhibitory Ras inhibited nicotine-induced ERK phosphorylation. A calmodulin antagonist, a CaM kinase inhibitor, a MAP kinase kinase inhibitor inhibited nicotine-induced ERK and CREB phosphorylation. The time course of the phosphorylation of CREB induced by nicotine was similar to that of ERK induced by nicotine. These results suggest that non-alpha7 nAChRs are involved in nicotine-induced ERK phosphorylation through CaM kinase and the Ras-MAP kinase cascade and most of the nicotine-induced CREB phosphorylation is mediated by the ERK phosphorylation in PC12h cells.
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PMID:Nicotine-induced phosphorylation of extracellular signal-regulated protein kinase and CREB in PC12h cells. 1170 52

To define the molecular basis of alcohol drinking behaviors, the effects of voluntary ethanol intake on the expression of Ca(2+)/calmodulin-dependent protein kinase IV (CaM kinase IV) and on the expression and phosphorylation of cAMP responsive element binding protein (CREB) [corrected] in the nucleus accumbens (NAc), central amygdala, and frontal cortex of rats were investigated. Voluntary ethanol intake significantly decreased the expression of CaM kinase IV and CREB phosphorylation but not of CREB protein levels [corrected], specifically in the shell of NAc. These changes were not observed in the core of NAc, central amygdala and frontal cortex. Mianserin treatment significantly attenuated ethanol intake and antagonized the voluntary ethanol-induced reduction in expression of CaM kinase IV and CREB phosphorylation in the shell of NAc. This is the first evidence to suggest that decreased CaM kinase IV-dependent CREB phosphorylation in the shell region of NAc may play a role in the reward mechanisms of alcohol drinking.
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PMID:Effects of voluntary ethanol intake on the expression of Ca(2+) /calmodulin-dependent protein kinase IV and on CREB expression and phosphorylation in the rat nucleus accumbens. 1174 52

The barrel cortex has yielded a wealth of information about cortical plasticity in recent years. Barrel cortex is one of the few cortical areas studied so far where plasticity can be examined from birth through to adulthood. This review looks at plasticity mechanisms in three periods of life: early post-natal development, adolescence and adulthood. Separate consideration is given to depression and potentiation mechanisms. Plasticity can be induced in barrel cortex by whisker deprivation. Single whisker experience leads to expansion of the area of cortex responding to the spared whisker. In early post-natal life, plasticity occurs in thalamocortical pathways, while later in adolescence, intracortical pathways become more important. Ablation of the spared whisker's barrel prevents expression of plasticity in the cortex. A row of lesions between the spared and an adjacent barrel prevents expression of plasticity in the adjacent barrel. This evidence, together with latency of response data and an analysis of pathways capable of inducing long-term potentiation (LTP) within barrel cortex, leads to the view that horizontal and/or diagonal pathways between barrels are responsible for plasticity expression. The mouse has become the most commonly mutated mammalian species and has a well-developed barrel cortex. Therefore, mutations can be used to study the role of particular molecules in experience-dependent plasticity of barrel cortex. Through this work, it has become clear that the major post-synaptic density protein, alpha-CaMKII, and its T286 autophosphorylation site are essential for experience-dependent plasticity. This points to a major role for excitatory transmission in cortical plasticity and raises the possibility that LTP like mechanisms are involved. Furthermore, transgenic mice carrying a reporter gene for CRE have provided evidence that CRE-mediated gene expression is also involved in barrel cortex plasticity. This view is supported by studies on alpha/delta CREB knockouts, and provides a starting point for studying the role of gene expression in experience-dependent cortical plasticity.
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PMID:Anatomical pathways and molecular mechanisms for plasticity in the barrel cortex. 1203 5

We studied the early pathophysiological response of lenticulostriate arterioles in rats in three models of human conditions associated with stroke: (a) chronic angiotensin II-hypertension; (b) chronic nicotine administration; (c) oxidative endothelial injury. In all three models, quantitative patch clamp analysis of freshly isolated vascular smooth muscle cells from lenticulostriate arterioles and posterior cerebral arteries showed significant increases in activity of functional L-type calcium channels that were due to an increase in open channel probability, with no change in other biophysical properties or in channel expression. In addition, all three models showed evidence of endothelial dysfunction, but of a different nature in the three. With chronic angiotensin II-hypertension, but not in the other two models, endothelial nitric oxide synthase (eNOS) was dysfunctional, was mislocalized away from its normal abluminal location, and was accumulated in peri-nuclear Golgi. By contrast, the other two models showed no mislocalization of eNOS, but instead showed evidence of oxidative stress in endothelium, with up-regulation of superoxide dismutase and hexose kinase. All three models showed significant up-regulation of expression of proliferative cell nuclear antigen (PCNA) (PCNA index, 70-80%) in arterioles in situ, which is associated with increased activation of the nuclear transcription factor, phospho-cAMP response element binding protein (phospho-CREB). In addition, calmodulin-dependent protein (CaM) kinase II was activated, in concert with the activation of L-type calcium channels. Furthermore, blockers of either L-type calcium channels (amlodipine) or of CaM kinase II (KN-93) completely prevented the activation of CREB and the up-regulation of PCNA in arterioles. Our findings demonstrate that abnormal regulation of L-type calcium channels is directly responsible for abnormal proliferative responses in vascular smooth muscle in various forms of cerebral arteriolar injury associated with endothelial dysfunction.
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PMID:Early pathophysiological changes in cerebral vessels predisposing to stroke. 1472 53

The transcription factor cAMP response element-binding protein (CREB) plays an important role in opioids dependence. To better understand the role of CREB in opioids dependence and underlying signal pathways, we compared the effects of three ohmfentanyl stereoisomers ((-)-cis-(3R,4S,2'R) OMF (F9202), (+)-cis-(3R,4S,2'S) OMF (F9204), (-)-cis-(3S,4S,2'R) OMF (F9203)) and morphine on CREB phosphorylation and the expression of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) in hippocampus derived from mice which displayed conditioned place preference (CPP) behavior by Western blot, and immunohistochemistry analyses. Moreover, we studied the effects of OMF and morphine on CREB phosphorylation and colocalization of phosphorylated CREB (P-CREB) with CaMKIV in cultured rat hippocampal neurons by Western blot, and confocal fluorescence microscopy analyses. The results showed that F9202, F9204 or morphine, which could induce CPP, enhanced CREB phosphorylation and the expression of CaMKIV in hippocampus from CPP mice without affecting total CREB protein level. The CREB phosphorylation of cultured hippocampal neurons was also enhanced and reached its peak level at 30 min upon exposure to F9202 (100 nM), F9204 (100 nM) or morphine (1 microM), while the total CREB protein level was not altered. KN-62 (10 microM), an inhibitor of CaM kinases, prevented CREB phosphorylation induced by morphine, F9202, and F9204 without change of total CREB level. The results of confocal fluorescence microscopy further demonstrated that the activated CREB (P-CREB) was colocalized with CaMKIV in nucleus. F9203, which could not induce CPP, failed to increase the CREB phosphorylation and the colocalization of P-CREB with CaMKIV both in hippocampus from CPP mice and in cultured hippocampal neurons. This is the first evidence to suggest that the increased CREB phosphorylation via CaMKIV signal pathway in hippocampus is relevant to opioids psychological dependence.
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PMID:Colocalization of phosphorylated CREB with calcium/calmodulin-dependent protein kinase IV in hippocampal neurons induced by ohmfentanyl stereoisomers. 1545 64

Significant body of evidence indicates an important role for brain-derived neurotrophic factor (BDNF) in the hippocampal synaptic plasticity; however, the exact mechanisms how the BDNF signal is converted to plastic changes during memory processes are under an intense investigation. To specifically address the role of the trkB receptor, we have previously generated transgenic mice overexpressing the full-length trkB receptor and observed a continuous activation of the trkB.TK+ receptor, improved learning and memory but an attenuated LTP in these mice. In this study, we describe the trkB.TK+ mRNA and protein distribution in the transgenic mice, showing the most prominent increase in the full-length trkB expression in the cortical layer V pyramidal neurons and dentate gyrus of the hippocampus. In addition, we have analyzed the mRNA expression patterns of a group of genes associated with both plastic changes in the nervous system and BDNF signaling. Regulated expression of immediate early genes c-fos, fra-2 and junB was observed in the transgenic mice. Furthermore, the mRNA expression of alpha-Ca2+/calmodulin-dependent kinase II (alpha-CaMKII) was reduced in both the hippocampus and parietal cortex, whereas growth-associated protein 43 (GAP-43) mRNA expressions were induced in the corresponding regions. Conversely, the mRNA expression of the transcription factor cAMP response element binding protein (CREB) was not altered in the trkB.TK+mice. Finally, the density of neuropeptide Y (NPY)-expressing cells was increased in the trkB.TK+ mice dentate hilus. Altogether, these results demonstrate in vivo that the increased trkB.TK+ signaling regulates several important plasticity-related genes.
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PMID:Overexpression of the full-length neurotrophin receptor trkB regulates the expression of plasticity-related genes in mouse brain. 1551 79


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