Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that the secreted form of the beta-amyloid precursor protein (beta-APP) activates mitogen-activated protein (MAP) kinases in PC-12 pheochromocytoma cells. beta-APP as well as other treatments that activate MAP kinase also enhance phosphorylation of the microtubule-associated protein tau in these cells. In this study, we extended this analysis to neurons. Using dissociated cultures of cortical neurons, we found that exposure to beta-APP activated MAP kinase 4 and 7 days but not 1 day after plating. Phosphorylation of tau in neurons was measured by immunoreactivity with the AT8 antibody, which recognizes a phosphorylated epitope present in tau from paired helical filaments. We found that activation of MAP kinase in neurons was associated with increased amounts of AT8-reactive tau. These results support a role for MAP kinase in transducing the biological effects of secreted beta-APP on neurons and suggest possible mechanisms by which beta-APP might be involved in the pathogenesis of Alzheimer's disease.
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PMID:Secreted beta-APP stimulates MAP kinase and phosphorylation of tau in neurons. 756 49

Biological effects related to cell growth, as well as a role in the pathogenesis of Alzheimer disease, have been ascribed to the beta-amyloid precursor protein (beta-APP). Little is known, however, about the intracellular cascades that mediate these effects. We report that the secreted form of beta-APP potently stimulates mitogen-activated protein kinases (MAPKs). Brief exposure of PC-12 pheochromocytoma cells to beta-APP secreted by transfected Chinese hamster ovary cells stimulated the 43-kDa form of MAPK by > 10-fold. Induction of a dominant inhibitory form of ras in a PC12-derived cell line prevented the stimulation of MAPK by secreted beta-APP, demonstrating the dependence of the effect upon p21ras. Because the microtubule-associated protein tau is hyperphosphorylated in Alzheimer disease, we sought and found a 2-fold enhancement in tau phosphorylation associated with the beta-APP-induced MAPK stimulation. In the ras dominant inhibitory cell line, beta-APP failed to enhance phosphorylation of tau. The data presented here provide a link between secreted beta-APP and the phosphorylation state of tau.
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PMID:Secreted beta-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation. 804 53

The secreted form of the beta-amyloid precursor protein (beta-APP) has previously been shown to stimulate mitogen-activated protein (MAP) kinases in PC-12 pheochromocytoma cells. The amino-terminal half of secreted beta-APP contains a region rich in cysteine residues reminiscent of cysteine-rich binding regions in other families of extracellular proteins. We found that reductive alkylation of disulfide linkages eliminated the ability of secreted beta-APP to activate MAP kinase. To confirm the role of the cysteine-rich amino-terminal region, fragments representing the amino- and carboxyl-terminal halves of secreted beta-APP were expressed in bacteria as fusion proteins and purified. Ten-minute treatment with the amino-terminal segment of beta-APP activated MAP kinase approximately 15-fold, while the carboxyl segment had no effect. The amino-terminal fragment, like intact secreted beta-APP, was substantially inactivated by reduction of sulfhydryl groups. These results suggest that the amino-terminal region of beta-APP is responsible for activation of MAP kinase and that it requires structural loops created by disulfide linkages for activity.
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PMID:Amino-terminal region of the beta-amyloid precursor protein activates mitogen-activated protein kinase. 857 96

We have investigated in rat pheochromacytoma PC12 cells the activation of the mitogen-activated protein kinases ERK1 and ERK2 by the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP). This treatment slowly decreases ATP levels to 30% of control, whereas the internal calcium level rises very rapidly to 250% of control, derived from internal stores. Tyrosine phosphorylation of ERK1 and ERK2 increases gradually, starting after 5 min of treatment, to reach a maximum at 30 min; the kinase activity reaches 250% when measured after 1 hr of treatment. The drop in ATP levels is slower still. Comparison of the time courses of the rapid rise in cytosolic calcium with the slower increase in ERK1 and ERK2 activation suggests one or more intermediate stages in this pathway. Chelation of cytosolic calcium with dimethyl bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid abolished the FCCP-stimulated rise in internal calcium, as well as the tyrosine phosphorylation and the activation of the ERKs. Surprisingly, caffeine, which releases calcium from different internal stores, did not increase the tyrosine phosphorylation and did not activate the ERKs. The FCCP effect on calcium storage may be related to mitochondrial dysfunction in Alzheimer disease, which might result in ineffective buffering of cytosolic calcium that leads to mitogen-activated protein kinase activation and subsequent protein phosphorylations.
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PMID:Compromised mitochondrial function leads to increased cytosolic calcium and to activation of MAP kinases. 927 88

Activation of protein kinase C (PKC) regulates the processing of Alzheimer amyloid precursor protein (APP) into its soluble form (sAPP) and amyloid beta-peptide (A beta). However, little is known about the intermediate steps between PKC activation and modulation of APP metabolism. Using a specific inhibitor of mitogen-activated protein (MAP) kinase kinase activation (PD 98059), as well as a dominant negative mutant of MAP kinase kinase, we show in various cell lines that stimulation of PKC by phorbol ester rapidly induces sAPP secretion through a mechanism involving activation of the MAP kinase cascade. In PC12-M1 cells, activation of MAP kinase by nerve growth factor was associated with stimulation of sAPP release. Conversely, M1 muscarinic receptor stimulation, which is known to act in part through a PKC-independent pathway, increased sAPP secretion mainly through a MAP kinase-independent pathway. A beta secretion and its regulation by PKC were not affected by PD 98059, supporting the concept of distinct secretory pathways for A beta and sAPP formation.
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PMID:Regulation of secretion of Alzheimer amyloid precursor protein by the mitogen-activated protein kinase cascade. 945 46

It has been reported that in differentiated PC12 cells and neurons from the superior cervical ganglion and hippocampus, that the activation of the stress-activated protein kinases jun-N-terminal kinase (JNK) and/or p38 mitogen-activated protein (p38MAP) kinase is central to the induction of apoptosis by serum or neurotrophic factor withdrawal. Here we demonstrate that in cerebellar granule cells, withdrawal of serum does not result in the activation of JNK or p38MAP kinase, under conditions where profound apoptosis was observed. In addition, these protein kinases were not activated during the induction of apoptosis caused by addition of excitotoxic levels of glutamate or of beta-amyloid (25-35) peptide. BDNF and insulin can prevent apoptosis induced by serum withdrawal or the addition of glutamate or beta-amyloid peptide. EGF on the other can prevent apoptosis induced by glutamate and beta-amyloid peptide, but not that caused by serum withdrawal. We conclude that the induction of apoptosis of cerebellar granule cells is independent of JNK or p38MAP kinase activation and that the mechanism by which serum withdrawal promotes apoptosis of these neurons may differ from that caused by glutamate and beta-amyloid peptide.
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PMID:Apoptosis of cerebellar granule cells induced by serum withdrawal, glutamate or beta-amyloid, is independent of Jun kinase or p38 mitogen activated protein kinase activation. 969 64

Angiogenesis, the formation of new capillary blood vessels, is essential not only for the growth and metastasis of solid tumors, but also for wound and ulcer healing, because without the restoration of blood flow, oxygen and nutrients cannot be delivered to the healing site. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used drugs for pain, arthritis, cardiovascular diseases and, more recently, the prevention of colon cancer and Alzheimer disease. However, NSAIDs produce gastroduodenal ulcers in about 25% of users (often with bleeding and/or perforations) and delay ulcer healing, presumably by blocking prostaglandin synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both selective and nonselective NSAIDs inhibit angiogenesis through direct effects on endothelial cells. We also show that this action involves inhibition of mitogen-activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear translocation, is independent of protein kinase C and has prostaglandin-dependent and prostaglandin-independent components. Finally, we show that both COX-1 and COX-2 are important for the regulation of angiogenesis. These findings challenge the premise that selective COX-2 inhibitors will not affect the gastrointestinal tract and ulcer/wound healing.
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PMID:Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. 1058 Oct 68

Glutamate is the principal excitatory neurotransmitter in the mammalian brain. Several lines of evidence suggest that glutamatergic hypoactivity exists in the Alzheimer's disease brain, where it may contribute to both brain amyloid burden and cognitive dysfunction. Although metabotropic glutamate receptors have been shown to alter cleavage of the amyloid precursor protein, little attention has been paid to the role of N-methyl-D-aspartate receptors in this process. We now report that activation of N-methyl-D-aspartate receptors in transiently transfected human embryonic kidney 293 cells increases production of the soluble amyloid precursor protein derivative. Moreover, using both pharmacological and gene transfer techniques, we show that this effect is largely due to activation of the mitogen-activated protein kinase cascade, specifically the pathway leading to activation of extracellular signal-regulated protein kinase but not other mitogen-activated protein kinases. These observations further our understanding of the pathways that regulate amyloid precursor protein cleavage, and buttress the notion that regulation of amyloid precursor protein cleavage is critically dependent upon the mitogen-activated protein kinase cascade.
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PMID:Mitogen-activated protein kinase is involved in N-methyl-D-aspartate receptor regulation of amyloid precursor protein cleavage. 1062 71

The effect of the beta-amyloid peptide (beta-AP) 25-35 and SB203580, the p38 mitogen-activated protein (MAP) kinase inhibitor, were investigated on long term potentiation (LTP) in the dentate gyrus of the rat hippocampal slice. In the presence of 1 microM beta-AP (25-35) basal synaptic transmission was reduced to 88.9+/-5.2% of control (n=4, P<0.5). Tetanic stimulation of control slices gave rise to a robust LTP (139+/-4%, n=5, P<0.05). 1 microM beta-AP (25-35) was found to inhibit this LTP (104.0+/-4.5% at 90 min; n=4, P<0.05). Perfusion of SB203580 alone (1 microM) had no significant effect on baseline synaptic transmission or LTP (n=4). However, in the presence of SB203580, beta-AP (25-35; 1 microM) did not give rise to a reduction in LTP (150+/-11.8%, n=4). These results suggest that high levels of beta-AP (25-35) may inhibit LTP through a pathway involving the p38 MAP kinase.
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PMID:SB203580, the p38 mitogen-activated protein kinase inhibitor blocks the inhibitory effect of beta-amyloid on long-term potentiation in the rat hippocampus. 1087 75

Alzheimer's Disease (AD) is characterized by cerebral accumulation of beta-amyloid peptides (Abeta), which are proteolytically derived from beta-amyloid precursor protein (betaAPP). betaAPP metabolism is highly regulated via various signal transduction systems, e.g., several serine/threonine kinases and phosphatases. Several growth factors known to act via receptor tyrosine kinases also have been demonstrated to regulate sbetaAPP secretion. Among these receptors, insulin and insulin-like growth factor-1 receptors are highly expressed in brain, especially in hippocampus and cortex. Emerging evidence indicates that insulin has important functions in brain regions involved in learning and memory. Here we present evidence that insulin significantly reduces intracellular accumulation of Abeta and that it does so by accelerating betaAPP/Abeta trafficking from the trans-Golgi network, a major cellular site for Abeta generation, to the plasma membrane. Furthermore, insulin increases the extracellular level of Abeta both by promoting its secretion and by inhibiting its degradation via insulin-degrading enzyme. The action of insulin on betaAPP metabolism is mediated via a receptor tyrosine kinase/mitogen-activated protein (MAP) kinase kinase pathway. The results suggest cell biological and signal transduction mechanisms by which insulin modulates betaAPP and Abeta trafficking in neuronal cultures.
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PMID:Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. 1130 9


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