Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyloid beta peptide (A beta) is released into the media of a variety of cells in culture during normal metabolism. The discovery of several missense mutations within or flanking the A beta region of the beta amyloid precursor protein (beta APP) in familial Alzheimer's disease provides strong evidence for a role of altered processing of beta APP in the pathogenesis of this disorder. The cellular mechanisms that regulate the relative utilization of the secretory pathway, which causes beta APP to be cleaved within the A beta domain, and the alternative proteolytic pathway, which produces intact A beta, are unknown. It is hypothesized that a number of neurodegenerative diseases, including Alzheimer's disease, are characterized by abnormal calcium metabolism. We investigated the effect of disordered calcium homeostasis on A beta production in human kidney 293 cells transfected with beta APP cDNA. A beta immunoprecipitated from the conditioned media of cells was compared to immunoprecipitated full-length and secreted forms of beta APP in both metabolic labeling and pulse-chase labeling paradigms. The calcium ionophore A23187 consistently increased the production of A beta approximately 3-fold. This effect was dependent on the presence of extracellular calcium in intact cells. Caffeine also increased A beta production, possibly through release of calcium from intracellular stores. The increase in A beta was cAMP-independent, and it was not mediated by a protein kinase C-dependent pathway, as treatment with phorbol esters decreased A beta levels. The effects of the ionophore on beta APP maturation and phosphorylation were also established. We conclude that elevation of intracellular calcium levels has an important effect on beta APP maturation and proteolytic processing and substantially enhances the production and release of the amyloidogenic A beta peptide.
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PMID:Calcium ionophore increases amyloid beta peptide production by cultured cells. 816 10

Various first messengers linked to phospholipase C, including acetylcholine and interleukin 1, regulate the production both of the secreted form of the amyloid protein precursor (APP) and of amyloid beta-protein. We have now identified intracellular signals which are responsible for mediating these effects. We show that activation of phospholipase C may affect APP processing by either of two pathways, one involving an increase in protein kinase C and the other an increase in cytoplasmic calcium levels. The effects of calcium on APP processing appear to be independent of protein kinase C activation. The observed effects of calcium on APP processing may be of therapeutic utility.
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PMID:Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. 818 35

The 39-43-amino acid amyloid beta-protein (A beta), which is progressively deposited in cerebral plaques and blood vessels in Alzheimer's disease (AD), is released by cultured human cells during normal metabolism. Here we show that agents which activate protein kinase C or otherwise enhance protein phosphorylation caused a substantial decrease in A beta production in vitro. Protein kinase C activation also markedly decreased A beta release from cells that express mutant forms of the beta-amyloid precursor protein genetically linked to familial AD. Inhibition of A beta secretion could also be effected by direct stimulation of m1 muscarinic acetylcholine receptors with carbachol. These results demonstrate that activation of the protein kinase C signal transduction pathways down-regulates the generation of the amyloidogenic A beta peptide. Pharmacologic agents that activate this system, including a variety of first messengers, could potentially slow the development or growth of some A beta plaques during the early stages of AD.
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PMID:Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. 822 7

The Alzheimer amyloid precursor protein (APP) is a phosphoprotein, and the phosphorylation state of APP at Ser655 can be regulated by protein kinase C, calcium/calmodulin-dependent protein kinase II, and okadaic acid-sensitive protein phosphatases. Other enzymes may also play a role at Ser655 of APP and, perhaps, at other residues. Signal transduction via protein phosphorylation regulates APP metabolism. In particular, APP processing via the nonamyloidogenic secretory cleavage pathway is increased following the activation of protein kinase C or the inactivation of okadaic acid-sensitive protein phosphatases. The mechanism(s) by which protein phosphorylation regulates APP secretory cleavage include (among others): substrate activation, substrate redistribution, protease activation and/or protease redistribution. Current experimental evidence will be discussed, addressing the relative importance of each of these possibilities and the implications for these events in the modulation of beta/A4-amyloidogenesis.
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PMID:Protein phosphorylation regulates relative utilization of processing pathways for Alzheimer beta/A4 amyloid precursor protein. 823 68

The family of beta-amyloid protein precursors (APP) can be processed via several alternative proteolytic pathways. Some generate potentially amyloidogenic APP derivatives, whereas others preclude the formation of such fragments. The cellular mechanisms regulating the relative activities of these pathways are thus important in determining the factors contributing to the formation of amyloidogenic APP derivatives. In order to investigate whether cell-surface receptor activity can regulate APP processing, HEK 293 cell lines stably expressing human muscarinic acetylcholine receptors (mAChR; subtypes m1, m2, m3, m4) were stimulated with the muscarinic agonist carbachol, and the release of APP derivatives was measured. Carbachol increased the release of large amino-terminal APP-fragments 4- to 6-fold in cell lines expressing the m1 or m3 receptors but not in those expressing m2 or m4 subtypes. This increase was blocked by various protein kinase inhibitors and mimicked by phorbol esters, indicating that it is mediated by protein kinase activation, presumably by protein kinase C (PKC). To determine whether additional cell-surface receptor types linked to this signal transduction pathway could also regulate APP processing, we stimulated differentiated PC-12 cells with bradykinin and found that this neuropeptide also increased the secretion of amino-terminal APP derivatives. We next investigated the possibility that neuronal depolarization might affect APP processing in mammalian brain. Electrically stimulated rat hippocampal slices released two times more amino-terminal APP derivatives than unstimulated control slices. This release increased with increasing stimulation frequencies in the physiological firing range of hippocampal pyramidal cells, and was blocked by tetrodotoxin. These results suggest that, in brain, APP processing is regulated by neuronal activity.
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PMID:Receptor-coupled amyloid precursor protein processing. 823 69

Release of the amyloid precursor protein (APP) of Alzheimer's disease from Swiss 3T3 fibroblasts was stimulated in a concentration-dependent manner by phorbol 12-myristate 13-acetate. In fibroblasts overexpressing protein kinase C alpha (PKC alpha), the EC50 for this response was 7 nM, while in control cells the EC50 was 63 nM. The effect of PMA was inhibited by the PKC antagonist H-7 in control cells, but not in cells that overexpressed PKC alpha. Basal release of APP was higher in cells that overexpressed PKC alpha, and was not affected by the phosphatase inhibitor okadaic acid, although this compound doubled APP release from control cells. The results suggest that PKC alpha regulates APP processing in mammalian cells. Alterations in the activity of PKC have been reported to occur in Alzheimer's disease and might potentially contribute to abnormalities of APP metabolism characteristic of this disorder.
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PMID:Regulation of amyloid precursor protein release by protein kinase C in Swiss 3T3 fibroblasts. 823 70

The cellular factors regulating the generation of beta-amyloid from the amyloid precursor protein (APP) are unknown. Activation of protein kinase C (PKC) by phorbol ester treatment inhibited the generation of the 4-kDa beta-amyloid peptide in transfected COS cells, a human glioma cell line, and human cortical astrocytes. An analogue of diacylglycerol, the endogenous cellular activator of PKC, also inhibited the generation of beta-amyloid. Activation of PKC increased the level of secreted APP in transfected COS cells but did not significantly affect the level of secreted APP in primary human astrocytes or in the glioma cell line. Cell-associated APP and the secreted APP derivative, but not beta-amyloid, were phosphorylated on serine residues. Activation of PKC did not increase the level of APP phosphorylation, suggesting that PKC modulates the proteolytic cleavage of APP indirectly by phosphorylation of other substrates. These results indicate that PKC activation inhibits beta-amyloid production by altering APP processing and suggest that beta-amyloid production can be regulated by the phospholipase C-diacylglycerol signal transduction pathway.
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PMID:Inhibition of beta-amyloid production by activation of protein kinase C. 824 86

We attempted to determine whether changes in protein kinase C (PKC) activity in Alzheimer's disease (AD) brains are also present in cultured skin fibroblasts from living patients. Biopsies collected from shoulder skin were transferred to culture plates with an appropriate growth medium, and histone-directed PKC activity as well as phorbol ester binding were individually determined in soluble and particulate fractions prepared from AD and non-AD fibroblast cell lines. Binding experiments indicated that PKC was unevenly distributed between cytosol (78%) and particulate (22%). The Bmax values for phorbol ester binding in soluble and particulate fractions were similar in AD and non-AD patients. Kd values in the cytosol were 94% higher in AD patients, indicating lower affinity of the enzyme for the ligand. Accordingly, the soluble PKC activity was 30% lower in AD patients. The data suggest that the changes in PKC phosphorylating activity represent a diffuse cellular defect in AD and are not confined to the brain. The alterations of the enzyme may participate in the disregulation in processing of beta-amyloid precursor protein in AD.
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PMID:Cytosol protein kinase C downregulation in fibroblasts from Alzheimer's disease patients. 825 61

In order to explore the effect of aberrant sprouting in the CNS, phorbol 12-myristate 13-acetate (PMA) was administered into the neocortex of adult rats. PMA is a growth-promoting agent that activates and eventually downregulates protein kinase C (PKC), and induces in the rat the expression of several genes, including amyloid precursor protein (APP). We found that multiple injections of 100 nM PMA into the rat neocortex promote, in the first week postinjection, a widespread vacuolization of the neuropil with a subsequent disruption of the synapses in the injection site, followed, at d 15, by the formation of abnormally distended clusters of neurites that resembled aberrant, sprouting axons. At d 30, fewer aberrant sprouts were observed, and many degenerating neurites were found. At the ultrastructural level, the PMA-induced abnormal neurites at d 7-15 resembled growth cones, whereas the dystrophic neurites at d 30 contained abundant dense and laminated bodies. Immunohistochemical analysis indicated that the abnormal neurites in the areas of denervation and PMA administration were positive with antisynaptophysin and antigrowth-associated protein 43 (GAP-43), with an increased APP immunoreactivity surrounding them. APP immunoreactivity around the injection site was mostly associated with pyramidal neurons and glial cells. Control experiments, where saline alone or 4 alpha-phorbol 12, 13-didecanoate (PDD, an inactive phorbol derivative) was injected, failed to show aberrant sprouting neurites. Further immunohistochemical analysis showed that the PMA-treated animals presented increased amyloid beta immunoreactivity in the pyramidal cells at the site of injection, when compared with control injections. These findings suggest that aberrant sprouting induced by overstimulation could be followed by neurodegeneration. Alternatively, PKC downregulation could directly induce the neurodegeneration, with a secondary sprouting response.
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PMID:Phorbol ester-induced neuritic alterations in the rat neocortex. Structural and immunocytochemical studies. 829 18

Alzheimer beta-amyloid precursor protein can be phosphorylated on residues Thr654, Ser655 and Thr668 on its cytoplasmic domain. Proteolytic cleavage of the amyloid precursor protein and release of the amyloid precursor protein ectodomain into the medium of cultured cells can be activated by phorbol esters which stimulate protein kinase C. In the present study, using mutated amyloid precursor protein, we show that phosphorylation of cytoplasmic residues is not required for the phorbol ester-activated cleavage and release of the amyloid precursor protein ectodomain. Remarkably, deletion of the entire amyloid precursor protein cytoplasmic tail had no effect on the phorbol ester-activated cleavage/release. The results indicate that activation of amyloid precursor protein cleavage/release by protein kinase C involves phosphorylation of some component of the processing pathway, instead of or in addition to the cytoplasmic tail of the amyloid precursor protein.
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PMID:Regulated cleavage of Alzheimer beta-amyloid precursor protein in the absence of the cytoplasmic tail. 830 47


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