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)

Mice engineered to overexpress disease-causing mutant amyloid precursor proteins (APP) display plaque deposition, but lack the hyperphosphorylated tau and massive neuronal loss characteristic of Alzheimer's disease (AD). Global gene expression profiles of brain regions from AD patients show upregulation of proapoptotic and inflammatory genes and down-regulation of neurotrophic, MAPK, phosphatase, and synaptic genes, while a profile of mice overexpressing a mutant APP shows the opposite trends in apoptotic and neurotrophic genes. The proteolytic fragments of the amyloid precursor protein have distinct biological actions. Both the gamma-secretase cleaved COOH-terminal fragment (CTFgamma) and the alpha-secretase cleaved NH2-terminal of APP (sAPPalpha) can regulate gene expression. While Abeta and CTFgamma can lead to toxicity and cell death, sAPPalpha promotes neurite outgrowth, enhances memory, and protects against a variety of insults, including Abeta toxicity. In AD, Abeta levels increase while sAPPalpha levels decrease. These subtleties in the levels of APP cleavage products are not reproduced in mice overexpressing mutant APP. In fact, the gene expression changes driven by sAPPalpha, such as increases in transthyretin and insulin-like growth factor 2, may protect these mice from high levels of Abeta.
 ...
PMID:Genetic programming by the proteolytic fragments of the amyloid precursor protein: somewhere between confusion and clarity. 1464 Mar 19

We have previously shown that the cognition enhancer (1R)-1-benzo[b]thiophen-5-yl-2-[2-(diethylamino)ethoxy]ethan-1-ol hydrochloride (T-588) protects astrocytes against hydrogen peroxide (H2O2) injury via activation of extracellular signal-regulated kinase (ERK) pathway. The present study examines whether the effect of T-588 on astrocytes contributes to neuroprotection in neuronal injury models. Astrocyte-conditioned medium (ACM) protected against neuronal injury induced by amyloid-beta protein (A beta) in cultured cortical neurons. The effect of ACM on A beta-induced injury was blocked by the ERK kinase inhibitor 2'-amino-3'-methoxyflavone. ACM stimulated ERK phosphorylation in cultured neurons. ACM derived from astrocytes exposed to H2O2 lost the activities to stimulate ERK phosphorylation and protect against neuronal injury. T-588 blocked the H2O2-induced loss of the activities of ACM. These results suggest that ACM protects against neuronal injury by an ERK-dependent mechanism, and the effect of T-588 on astrocytic injury results in neuroprotection.
 ...
PMID:Possible involvement of astrocytes in neuroprotection by the cognitive enhancer T-588. 1464 17

Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and betaA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH-SY5Y cell line, agonists for A1R led to a dose-dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK-dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD.
 ...
PMID:A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation. 1465 50

In this study we have used the transgenic mouse model Tg2576 to analyze the involvement of anomalous loss of regulation of cdk5 and the stress kinases JNK and p38 in brain neuronal death as related to neurodegenerative disorders such as Alzheimer's disease. Previous studies on hippocampal cells led us to the discovery that the cdk5/p35 complex is activated in neurodegeneration, a finding that was confirmed later in the transgenic mouse model. Here we show a link between the cdk5 system and JNK and p38 phosphoproteins, as an alternative pathway to neuronal death. Brains of the Tg2576 transgenic mice overexpressing amyloid precursor protein exhibited immunoreactivity with the phosphoproteins p-JNK, p-p38 and the GTPase protein Rac1 surrounding neuritic plaques. A significant increase in the immunodetection of JNK and p38 phosphoproteins in the Tg2576 mouse compared with wild type controls confirmed these findings. The significant increase in co-immunoprecipitation of p-JNK, p-p38 and Rac1 proteins with cdk5 in the transgenic mouse provided evidence for these interactions. At the cellular level, p-JNK and cdk5 colocalized in the cytoplasm of the cell bodies and neurites of brain cortical areas of the transgenic mouse. The present evidence suggests a cellular link between the cdk5 system and the stress kinase JNK and p38 pathways in an in vivo model. This study sheds new light on the pathogenesis of neuronal degeneration processes such as those occurring in Alzheimer's disease.
 ...
PMID:Modulation of the JNK and p38 pathways by cdk5 protein kinase in a transgenic mouse model of Alzheimer's disease. 1466

Lipid rafts and their component, cholesterol, modulate the processing of beta-amyloid precursor protein (APP). However, the role of sphingolipids, another major component of lipid rafts, in APP processing remains undetermined. Here we report the effect of sphingolipid deficiency on APP processing in Chinese hamster ovary cells treated with a specific inhibitor of serine palmitoyltransferase, which catalyzes the first step of sphingolipid biosynthesis, and in a mutant LY-B strain defective in the LCB1 subunit of serine palmitoyltransferase. We found that in sphingolipid-deficient cells, the secretion of soluble APPalpha (sAPPalpha) and the generation of C-terminal fragment cleaved at alpha-site dramatically increased, whereas beta-cleavage activity remained unchanged, and the epsilon-cleavage activity decreased without alteration of the total APP level. The secretion of amyloid beta-protein 42 increased in sphingolipid-deficient cells, whereas that of amyloid beta-protein 40 did not. All of these alterations were restored in sphingolipid-deficient cells by adding exogenous sphingosine and in LY-B cells by transfection with cLCB1. Sphingolipid deficiency increased MAPK/ERK activity and a specific inhibitor of MAPK kinase, PD98059, restored sAPPalpha level, indicating that sphingolipid deficiency enhances sAPPalpha secretion via activation of MAPK/ERK pathway. These results suggest that not only the cellular level of cholesterol but also that of sphingolipids may be involved in the pathological process of Alzheimer's disease by modulating APP cleavage.
 ...
PMID:Modulation of amyloid precursor protein cleavage by cellular sphingolipids. 1471 66

Brain-derived neurotrophic factor (BDNF) stimulates beta-amyloid precursor protein (APP) promoter activity by a Ras-dependent mechanism in TrkB-expressing SH-SY5Y cells. To determine the signalling pathways involved in the BDNF-induced response, we have analysed the ability of TrkB mutated forms to mediate promoter stimulation. Brain-derived neurotrophic factor causes a significant induction of promoter activity and mutation K540R in the active site of TrkB completely abolishes the neurotrophin-induced response. A substitution of the Y484 residue by phenylalanine, which blocks binding of Shc, reduces the activation of APP promoter by BDNF by approximately 50% whereas mutation Y785P, which blocks binding of phospholipase C gamma, does not affect the response. In addition, the phosphatidylinositide 3-kinase (PI3K)-specific inhibitors wortmannin and LY294002 reduced BDNF-induced activation. In agreement with a participation of both Ras/MAPK- and PI3K/Akt-mediated mechanisms, transient expression of constitutive active forms of Ras, PI3K and other components of both signalling pathways led to a significant increase of APP promoter activity. Furthermore, the stimulation of the APP promoter by BDNF was completely precluded by expression of dominant-negative forms of Ras and PI3K effectors. Taken together, our results suggest that simultaneous activation of at least two signalling pathways, Ras/MAPK and PI3K/Akt, is necessary to mediate a full activation of the APP promoter by BDNF.
 ...
PMID:Regulation of beta-amyloid precursor protein expression by brain-derived neurotrophic factor involves activation of both the Ras and phosphatidylinositide 3-kinase signalling pathways. 1475 23

Beta-amyloid precursor protein (APP) is the precursor of beta-amyloid (Abeta), which is implicated in Alzheimer's disease pathogenesis. APP complements amyloid precursor-like protein 2 (APLP2), and together they play essential physiological roles. Phosphorylation at the Thr(668) residue of APP (with respect to the numbering conversion for the APP 695 isoform) and the Thr(736) residue of APLP2 (with respect to the numbering conversion for the APLP2 763 isoform) in their cytoplasmic domains acts as a molecular switch for their protein-protein interaction and is implicated in neural function(s) and/or Alzheimer's disease pathogenesis. Here we demonstrate that both APP and APLP2 can be phosphorylated by JNK at the Thr(668) and Thr(736) residues, respectively, in response to cellular stress. X11-like (X11L, also referred to as X11beta and Mint2), which is a member of the mammalian LIN-10 protein family and a possible regulator of Abeta production, elevated APP and APLP2 phosphorylation probably by facilitating JNK-mediated phosphorylation, whereas other members of the family, X11 and X11L2, did not. These observations revealed an involvement of X11L in the phosphorylation of APP family proteins in cellular stress and suggest that X11L protein may be important in the physiology of APP family proteins as well as in the regulation of Abeta production.
 ...
PMID:Facilitation of stress-induced phosphorylation of beta-amyloid precursor protein family members by X11-like/Mint2 protein. 1497 Feb 11

Interferon-inducible, double-stranded RNA-dependent protein kinase PKR is well known as an early cellular responder to viral infection. Activation of PKR has been associated with a number of downstream cell stress and cell death events, including a generalized shutdown of protein translation, activation of caspase-8, participation in JNK and p38 MAPK pathways, activation of NF-kappaB, etc. Recently, the activation of PKR has also been described in several neurodegenerative diseases, including Huntington disease, Alzheimer disease, and amyotrophic lateral sclerosis. Although the relationship between PKR and these diseases is still unclear, the overlap between known functions of PKR and biochemical events that occur in these neuropathologies are discussed here.
 ...
PMID:PKR activation in neurodegenerative disease. 1498 95

The effects of the beta-amyloid peptide (Abeta) fragment 25-35 were investigated on hippocampal synaptic transmission and long-term potentiation (LTP) in vitro. Abeta([25-35]) was found to impair both post-tetanic potentiation (PTP) and LTP in the hippocampal CA1. The anthra[1,9-cd]pyrazol-6(2H)-one, SP600125, was used to inhibit c-Jun N-terminal kinase (JNK) activity, which is believed to mediate cell death. Prior application of SP600125 attenuated the Abeta([25-35])-mediated impairment of PTP and LTP, when measured from the pre-drug baseline. In the presence of SP600125 alone, we observed an increase in baseline synaptic transmission and reduction in paired-pulse facilitation, consistent with an increase in synaptic transmission. There was no alteration in the level of PTP and LTP obtained, when measured from the pre-drug baseline. In the presence of both SP600125 and Abeta, however, PTP was greatly enhanced compared with controls. We therefore suggest that the activation of the JNK signalling pathway mediates the effects of Abeta on synaptic plasticity. Our data also indicate that endogenous JNK activity may regulate neurotransmitter release in the hippocampal CA1 in vitro.
 ...
PMID:The role of c-Jun N-terminal kinase in the A beta-mediated impairment of LTP and regulation of synaptic transmission in the hippocampus. 1499 43

Primary cultures of rat cortical neurons exposed to toxic concentrations of beta-amyloid peptide (betaAP) begin an unscheduled mitotic cell cycle that does not progress beyond the S phase. To analyze possible signal transduction pathways involved in this effect, the action of betaAP has been studied in SH-SY5Y neuroblastoma cells differentiated by a 7-d exposure to 10 microM retinoic acid. Treatment with the betaAP fragment, betaAP(25-35), (25 microM) for 24, 48, or 72 h caused apoptotic cell death, detected by flow cytometry as a prediploid cell population. Cell cycle analysis showed that betaAP(25-35) modified cell cycle profiles by markedly increasing the number of cells in the S phase and reducing the population of the G2/M area. These effects seem to involve activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK1/2). Inhibition of this pathway by the specific inhibitor PD98059 (2 microM) completely prevented changes of cell cycle distribution induced by betaAP and significantly reduced neuronal death. The data suggest that MAPK cascade can mediate the induction of cell cycle induced by betaAP, thus contributing to the toxicity of the peptide.
 ...
PMID:Beta-amyloid-activated cell cycle in SH-SY5Y neuroblastoma cells: correlation with the MAP kinase pathway. 1499 17


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>