Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Alzheimer's disease (AD), oxidative stress-induced lipid peroxidation leads to accumulation of unsaturated aldehydes including acrolein and 4-hydroxynonenal (4HNE) in brain. In this study, we examined the effects of these lipid peroxidation products on apoptotic pathways in cultured neurons. Acrolein and 4HNE increased the levels of active phosphorylated forms of c-jun and CREB, the transcription factors that promote apoptosis and cell survival, respectively. However, they decreased the activity of CREB-dependent BDNF promoter while they increased the activity of promoters responsive to c-jun. We hypothesized that this differential regulation could be due to competition between proapoptotic c-jun and cytoprotective CREB for CBP (CREB-binding protein), a coactivator shared by several transcription factors. In support of this hypothesis, we demonstrate that the decrease of BDNF promoter activity by acrolein and 4HNE could be restored (i) by cotransfection with CBP, (ii) by cotransfection with VP 16-CREB, a constitutively active form of CREB that does not depend on CBP for its activation, or (iii) by inhibiting JNK-mediated c-jun activation. Finally, adenoviral transduction of hippocampal neurons with VP 16-CREB resulted in significant reduction in caspase-3 activation by acrolein and 4HNE. These observations suggest that lipid peroxidation-induced differential regulation of CREB and c-jun might play a role in neurodegeneration in AD.
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PMID:Differential regulation of c-jun and CREB by acrolein and 4-hydroxynonenal. 1633 76

The transcriptional coactivator CREB-binding protein plays a key role in regulating gene expression in a number of different cell types. Recently, a report has suggested a link between CREB-binding protein and presenilins, which are mutated in many cases of early onset Alzheimer's disease. Thus, presenilin 1 and 2 double knockout mice showed reductions in CREB-binding protein levels and in cAMP response element-dependent gene expression in the cerebral cortex, which is likely to contribute to the subsequent neuronal degeneration. This suggests that the inactivation of CREB-binding protein caused by mutation in presenilin 1 may be involved in the disease process. We have shown that wild-type presenilin 1 stimulates the transcriptional activity ability of CREB-binding protein whereas presenilin 1 M146L mutant did not produce such an effect. The activation of CREB-binding protein by wild-type presenilin 1 involves the PI 3-kinase, p38 mitogen-activated protein kinase (MAPK) and p42/p44 MAPK pathways and targets primarily the C terminus of CREB-binding protein. To our knowledge, this is the first report that shows regulation of CREB-binding protein activity by wild-type presenilin 1 and not by its M146L mutant, and suggests a mechanism in which mutation of presenilin 1 may lead to neurodegeneration.
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PMID:CREB-binding protein activation by presenilin 1 but not by its M146L mutant. 1673 88

Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Cytokines such as transforming growth factor-beta (TGF-beta) play a fundamental role in the development of tissue fibrosis by stimulating matrix deposition and other profibrotic responses, but less is known about pathways that might inhibit fibrosis. Increased cAMP formation inhibits myofibroblast differentiation and collagen production by cardiac fibroblasts, but the mechanism of this inhibition is not known. We sought to characterize the signaling pathways by which cAMP-elevating agents alter collagen expression and myofibroblast differentiation. Treatment with 10 microM forskolin or isoproterenol increased cAMP production and cAMP response element binding protein (CREB) phosphorylation in cardiac fibroblasts and inhibited serum- or TGF-beta-stimulated collagen synthesis by 37% or more. These same cAMP-elevating agents blunted TGF-beta-stimulated expression of collagen I, collagen III, and alpha-smooth muscle actin. Forskolin or isoproterenol treatment blocked the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) induced by TGF-beta despite the fact that these cAMP-elevating agents stimulated ERK1/2 activation on their own. cAMP-elevating agents also attenuated the activation of c-Jun NH(2)-terminal kinase and reduced binding of the transcriptional coactivator CREB-binding protein 1 to transcriptional complexes containing Smad2, Smad3, and Smad4. Pharmacological inhibition of ERK completely blocked TGF-beta-stimulated collagen gene expression, but expression of an active mutant of MEK was additive with TGF-beta treatment. Thus, cAMP-elevating agents inhibit the profibrotic effects of TGF-beta in cardiac fibroblasts largely through inhibiting ERK1/2 phosphorylation but also by reducing Smad-mediated recruitment of transcriptional coactivators.
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PMID:cAMP inhibits transforming growth factor-beta-stimulated collagen synthesis via inhibition of extracellular signal-regulated kinase 1/2 and Smad signaling in cardiac fibroblasts. 1695 41

Nasopharyngeal carcinoma (NPC) is a particularly common malignant disease in areas of south China and Southeast Asia. To characterize the gene expression profiling of NPC, we detected the gene expression profiles in 22 NPC and 10 nontumor nasopharyngeal epithelial tissues by complementary DNA microarray. We identified 503 genes that were significantly (P < .001) differentially regulated between NPC and nontumor nasopharyngeal epithelial tissues. The differentially expressed genes are involved in many signaling pathways, such as the Wnt, transforming growth factor-beta, and mitogen-activated protein kinase signaling pathways. The aberrant expression of the Wnt signaling pathway components, such as wingless-type MMTV integration site family, member 5A, Frizzled homolog 7, casein kinase IIbeta, beta-catenin, CREB-binding protein, and Dishevelled-associated activator of morphogenesis 2 was validated on the NPC tissue microarrays. The data suggest that the Wnt signaling pathway may be abnormally regulated in NPC, which provides insight into the molecular mechanisms of NPC.
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PMID:Gene expression profiling of nasopharyngeal carcinoma reveals the abnormally regulated Wnt signaling pathway. 1699 64

In skeletal muscle, the transformation of fast into slow fiber type is accompanied by shifts in fiber type-specific gene expression that includes down-regulation of the adult fast fiber myosin heavy chain IId/x (MyHCIId/x) gene. Here, we report that the mitogen-activated protein kinases (MAPKs) p38alpha/beta regulate MyHCIId/x gene expression. Electrical stimulation of rabbit skeletal muscle cells with a slow fiber type activity pattern and treatment of C2C12 myotubes with Ca(2+)-ionophore inhibited p38alpha/beta MAPKs and reduced fast fiber type MyHC protein expression and promoter activity. Pharmacological inhibition of p38alpha/beta also down-regulated MyHCII gene expression. In controls, binding of the myocyte enhancer factor-2 (MEF-2) isoforms C and D as a heterodimer to a proximal consensus site within the MyHCIId/x promoter and recruitment of a transcriptional coactivator, the CREB-binding protein CBP, were observed. Overexpression of wild type MEF-2C but not of a MEF-2C mutant that cannot be phosphorylated by p38 induced promoter activity. Mutation of the MEF-2-binding site decreased the inducing effect of overexpressed CBP. Inhibition of p38alpha/beta MAPKs abolished CBP binding, whereas enforced induction of p38 by activated MAPK kinase 6 (MKK6EE) enhanced binding of CBP and increased promoter activity. Furthermore, knockdown of endogenous CBP by RNA interference eliminated promoter activation by MEF-2C or MKK6EE. In electrical stimulated and Ca(2+)-ionophore-treated myotubes, CBP was absent in complex formation at that site. Taken together, the data indicate that p38alpha/beta MAPKs-mediated coactivator recruitment at a proximal MEF-2 site is important for MyHCIId/x gene regulation in skeletal muscle.
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PMID:The p38alpha/beta mitogen-activated protein kinases mediate recruitment of CREB-binding protein to preserve fast myosin heavy chain IId/x gene activity in myotubes. 1721 May 68

Hypoxia-induced multidrug resistance 1 (MDR1) gene expression is known to be mediated by c-Jun NH(2)-terminal kinase (JNK) activation. However, the molecular mechanisms underlying this action of JNK remain elusive. On the contrary, there has been increasing evidence for a negative correlation of JNK activity with MDR1 expression under normoxic conditions. Here, we present evidence that the JNK pathway represses MDR1 expression in normoxia and activates MDR1 expression in hypoxia. Our data show that JNK pathway-induced MDR1 repression in normoxia is mediated by increased c-Jun binding to activator protein 1 site, located in the MDR1 promoter, and requires the activity of histone deacetylase 5. In contrast, JNK pathway-induced MDR1 activation in hypoxia is independent of the activator protein 1 site. Rather, this action is dependent on increased hypoxia-inducible factor 1 (HIF1) binding to the hypoxia response element in the MDR1 promoter, which is promoted by the interaction of HIF1alpha with c-Jun in the nucleus and requires the activity of the p300/CBP (CREB-binding protein) coactivator.
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PMID:PO(2)-dependent differential regulation of multidrug resistance 1 gene expression by the c-Jun NH2-terminal kinase pathway. 1745 36

Chromatin remodeling by posttranslational modification of histones plays an important role in brain plasticity, including memory, response to stress and depression. The importance of H3/4 histones acetylation by CREB-binding protein (CBP) or related histone acetyltransferase, including p300, was specifically demonstrated using knockout (KO) mouse models. The physiological role of a related protein that also acts as a transcriptional coactivator with intrinsic histone acetylase activity, the p300/CBP-associated factor (PCAF), is poorly documented. We analyzed the behavioral phenotype of homozygous male and female PCAF KO mice and report a marked impact of PCAF deletion on memory processes and stress response. PCAF KO animals showed short-term memory deficits at 2 months of age, measured using spontaneous alternation, object recognition, or acquisition of a daily changing platform position in the water maze. Acquisition of a fixed platform location was delayed, but preserved, and no passive avoidance deficit was noted. No gender-related difference was observed. These deficits were associated with hippocampal alterations in pyramidal cell layer organization, basal levels of Fos immunoreactivity, and MAP kinase activation. PCAF KO mice also showed an exaggerated response to acute stress, forced swimming, and conditioned fear, associated with increased plasma corticosterone levels. Moreover, learning and memory impairments worsened at 6 and 12 months of age, when animals failed to acquire the fixed platform location in the water maze and showed passive avoidance deficits. These observations demonstrate that PCAF histone acetylase is involved lifelong in the chromatin remodeling necessary for memory formation and response to stress.
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PMID:Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice. 1780 10

The activation of NF-kappaB by neutrophil lactoferrin (Lf) is regulated via the IkappaB kinase (IKK) signaling cascade, resulting in the sequential phosphorylation and degradation of IkappaB. In this study, we observed that Lf protein augmented p65 phosphorylation at the Ser(536), but not the Ser(276) residue, and stimulated the translocation of p65 into the nucleus. Lf was also shown to enhance the association between p65 and CREB-binding protein/p300 in vivo. To elucidate the mechanism by which Lf triggers these signaling pathways, we attempted to delineate the roles of the upstream components of the IKK complex, using their dominant-negative mutants and IKKalpha(-/-) and IKKbeta(-/-) mouse embryonic cells. We demonstrated that both IKKalpha and IKKbeta as well as NF-kappaB-inducing kinase are indispensable for Lf-induced p65 phosphorylation. However, MAPK kinase kinase 1 is not essentially required for this activation. We also observed that Lf-induced p65 phosphorylation was either partially or completely abrogated as the result of treatment with the mutant forms of TNFR-associated factor (TRAF) 2, TRAF5, or TRAF6. Moreover, we demonstrated that Lf directly interacted with TRAF5. Expression of the dominant-negative mutant of TRAF5 or its small interfering RNA almost completely abrogated the Lf-induced p65 phosphorylation. These results suggest that signaling pathways, including TRAFs/NF-kappaB-inducing kinase/IKKs, may be involved in the regulation of Lf-induced p65 activation, thereby resulting in the activation of members of the NF-kappaB family.
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PMID:A distinct role of neutrophil lactoferrin in RelA/p65 phosphorylation on Ser536 by recruiting TNF receptor-associated factors to IkappaB kinase signaling complex. 1794 40

Immunological activation of macrophages/microglia within the CNS leads to the production of cytokines and chemokines that ultimately impact on glial and neuronal function. Suppressor of cytokine signaling (SOCS) proteins are negative regulators of adaptive and innate immune responses. Our previous studies demonstrated that SOCS-3 attenuates macrophage/microglial activation in vitro, suggesting that SOCS-3 may exert beneficial effects for immune-mediated CNS diseases in vivo. In this study, we describe LPS as a potent inducer of SOCS-3 transcription and expression in macrophages/microglia. An analysis of the SOCS-3 promoter indicates that AP-1 and IFN-gamma activation sequence (GAS) elements are involved in LPS-induced SOCS-3 transcription. LPS-induced SOCS-3 expression was diminished in IL-10-deficient macrophages at later time points, indicating the involvement of endogenous IL-10 in this response. Blocking STAT-3 expression and activation using STAT-3 small interfering RNA reduced LPS-induced SOCS-3 gene expression. LPS activated the MAPK-ERK1/2, JNK, and p38 pathways that, in addition to STAT-3, were also involved in LPS-induced SOCS-3 expression. LPS treatment of cells led to the acetylation of histones H3 and H4 on the SOCS-3 promoter and the recruitment of STAT-3, c-Jun, c-Fos, CREB-binding protein, p300, and RNA polymerase II to the endogenous SOCS-3 promoter in a time-dependent manner. These results indicate that LPS-induced MAPK activation, the production of endogenous IL-10, and STAT-3 activation play critical roles in SOCS-3 expression, which provides for feedback attenuation of cytokine-induced immune and inflammatory responses in macrophages and microglia.
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PMID:Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia. 1794 70

Lysophosphatidic acid (LPA) is a lipid growth factor that exerts diverse biological effects through its cognate receptor-mediated signaling cascades. Recently, we reported that LPA stimulates cAMP response element-binding protein (CREB) through mitogen- and stress-activated protein kinase-1 (MSK1). Previously, LPA has been shown to stimulate c-fos mRNA expression in Rat-2 fibroblast cells via a serum response element binding protein (SRF). However, involvement of CREB in LPA-stimulated c-fos gene expression is not elucidated yet. To investigate the CREB-mediated c-fos activation by LPA, various c-fos promoter-reporter constructs containing wild-type and mutated SRE and CRE were tested for their inducibility by LPA in transient transfection assays. LPA-stimulated c-fos promoter activation was markedly decreased when SRE and CRE were mutated. A dominant negative CREB significantly down-regulated the LPA-stimulated c-fos promoter activation. Chromatin immunoprecipitation assay revealed that LPA induced an increased binding of phosphorylated CREB and CREB-binding protein (CBP) to the CRE region of the endogenous c-fos promoter. Immunoblot analyses with various pharmacological inhibitors further showed that LPA induces up-regulation of c-fos mRNA level by activation of ERK, p38 MAPK, and MSK1. Taken together, our results suggest that CREB plays an important role in up-regulation of c-fos mRNA level in LPA-stimulated Rat-2 fibroblast cells.
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PMID:Lysophosphatidic acid-induced c-fos up-regulation involves cyclic AMP response element-binding protein activated by mitogen- and stress-activated protein kinase-1. 1817 55


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