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

The present study shows that cultured fibroblasts from sporadic AD patients present: a) reduced (-30%) cytosolic protein kinase C (PKC) activity; b) increased KD of phorbol ester binding (+94%) in cytosolic fractions; c) reduced (-30%) soluble protein kinase C alpha immunoreactivity; d) lower (-27.5%) basal soluble APP secretion and e) reduced soluble APP secretion in response to low phorbol ester concentrations (over threefold difference using 9 nM phorbol-12,13-dibutyrate-PdBu). Since the PKC-stimulated secretion of APP leads to the cleavage of the precursor within the amyloidogenic beta-A4 fragment, the reduced PKC activity in AD patients may lead to accumulation of potentially amyloidogenic or toxic APP fragments. A defect in the secretion of soluble amyloid beta-protein precursor is indeed suggested by literature data on familial AD fibroblasts as well as by the reported results.
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PMID:Defective protein kinase C alpha leads to impaired secretion of soluble beta-amyloid precursor protein from Alzheimer's disease fibroblasts. 862 9

The beta-amyloid precursor protein undergoes a physiological cleavage by alpha-secretase that leads to the release of a secreted C-terminally truncated fragment called APP alpha and likely concomitantly reduces the formation of the amyloidogenic A beta peptide. Here we demonstrate that APP alpha secretion is increased by the protein kinase A (PKA) effectors 8-bromo cyclic AMP and forskolin in human embryonic kidney cells (HK293), and that this can be prevented by a proteasome inhibitor. Furthermore, we establish that PKA effectors but not protein kinase C agonists increase the chymotrypsin-like activity and phosphorylation state of the proteasome in vitro and in vivo in HK293 cells. Altogether, this report demonstrates that the alpha-secretase pathway is under the control of PKA in human cells and that the proteasome likely contributes, either directly or through yet unknown intermediates, to the PKA-stimulated APP alpha secretion in human cells.
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PMID:Protein kinase A phosphorylation of the proteasome: a contribution to the alpha-secretase pathway in human cells. 893 98

Expression of the beta-amyloid precursor protein (beta-APP), a proteoglycan whose proteolytically derived fragments have been implicated in the neuropathology observed in Alzheimer's disease, is regulated by a variety of stimuli including cytokines, phorbol esters, and growth factors. In this study we report the effects of basic fibroblast growth factor (bFGF) and the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), on beta-APP expression and secretion in SKNMC human neuroblastoma cells. Treatment of the cells with bFGF for 24 h increased APP promoter activity 200%, cell-associated full-length protein 189%, and secreted amino-terminal fragments 192% compared to basal levels. Treatment of the cells with PMA for 24 h also up-regulated APP expression and secretion with increases of 170, 112, and 161% being observed for promoter activity, cell-associated full-length protein, and secreted amino-terminal fragments, respectively. The effects of bFGF and PMA on the expression and secretion of beta-APP were additive and distinct in that: (a) co-treatment of the cells with maximally stimulating doses of bFGF and PMA had an additive effect on both induced full-length protein expression (242%) and secretion of amino-terminal fragments (311%) compared to basal levels; (b) net levels of full-length protein expression and secretion induced by bFGF and PMA differed significantly from each other; and (c) down-regulation of phorbol ester-stimulated protein kinase C by pre-treatment of the cells for 24 h with 1 microM PMA failed to attenuate bFGF-induced transcription or induced secretion of beta-APP.
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PMID:Additive effects of basic fibroblast growth factor and phorbol ester on beta-amyloid precursor protein expression and secretion. 910 63

Neurotransmitter receptors that increase phosphatidylinositol hydrolysis generate second messengers that activate protein kinase C. Here, we used metabotropic glutamate receptor agonists to increase both phosphatidylinositol hydrolysis and secretion of the soluble extracellular fragment of amyloid precursor protein (APPs) from cortical astrocyte cultures. The increase in APPs secretion was mimicked by direct activation of protein kinase C with phorbol ester and was suppressed by the metabotropic glutamate receptor antagonist L-(+)-2-amino-3-phosphonopropionic acid or by the protein kinase C inhibitor GF109203X. Ionotropic glutamate agonists did not increase APPs secretion. Forskolin or dibutyryl cyclic AMP inhibited the increase in APPs secretion caused by metabotropic glutamate receptor agonists or by phorbol ester treatment but did not affect basal APPs levels. Therefore, glutamatergic agonists that increase protein kinase C activation or decrease cyclic AMP formation may enhance the conversion of full-length APP to nonamyloidogenic APPs in Alzheimer's disease.
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PMID:Metabotropic glutamate receptors increase amyloid precursor protein processing in astrocytes: inhibition by cyclic AMP. 910 7

Although regulated ectodomain shedding is a well known process that affects a large group of transmembrane molecules, it is not clear how the shedding system selects its substrates. Here we investigate the structural requirements for the regulated shedding of two substrates of the general shedding system, the transforming growth factor-alpha precursor, pro-TGF-alpha, and the beta-amyloid precursor protein, beta-APP. The ability of different regions of pro-TGF-alpha or beta-APP to confer susceptibility to the shedding system was tested using as a reporter a transmembrane molecule that is not a substrate of this shedding system. For this purpose we chose the TGF-beta accessory receptor, betaglycan, since genetic and biochemical evidence showed that betaglycan is not a substrate of the shedding system. We determined that replacement of the 14 extracellular amino acids adjacent to the transmembrane region of betaglycan with the corresponding regions of TGF-alpha or beta-APP rendered betaglycan susceptible to ectodomain shedding. These domain swap constructs were cleaved in response to protein kinase C stimulation, and cleavage was prevented by the metalloprotease inhibitor TAPI, both effects being characteristic of the general shedding system. Domain swap constructs containing the transmembrane and/or the cytoplasmic domains of pro-TGF-alpha did not undergo regulated ectodomain cleavage. We conclude that despite a lack of sequence similarity, the extracellular regions of pro-TGF-alpha and beta-APP immediately preceding their transmembrane domains are key determinants of ectodomain shedding.
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PMID:Role of the juxtamembrane domains of the transforming growth factor-alpha precursor and the beta-amyloid precursor protein in regulated ectodomain shedding. 920 36

The physiological processing of the beta-amyloid precursor protein (betaAPP) by a protease called alpha-secretase gives rise to APP alpha, a C-terminally truncated fragment of betaAPP with known neurotrophic and cytoprotective properties. Several lines of evidence indicate that protein kinase C (PKC)-mediated events regulate this physiological pathway. We show here that the proteasome multicatalytic complex modulates the phorbol 12,13-dibutyrate-stimulated APP alpha secretion at several levels in human kidney 293 (HK293) cells. Two blocking agents of the proteasome, namely, Z-IE(Ot-Bu)A-leucinal and lactacystin, elicit a dual effect on PKC-regulated APP alpha secretion by metabolically labeled HK293 cells. Thus, short periods of preincubation (2-5 h) of the cells with the inhibitors trigger a drastic potentiation of APP alpha recovery, whereas long-term treatment of the cells (15-20 h) with the blocking agents leads to an overall decrease in the secretion of APP alpha. Such a dual effect was not observed on constitutive APP alpha secretion and intracellular formation generated by HK293 cells, which both only increase upon inhibitor treatments. Similar effects on the constitutive and PKC-regulated APP alpha secretion were observed with PC12 cells. Altogether, these data suggest distinct mechanisms underlying basal and PKC-regulated APP alpha production, indicating that this multicatalytic complex appears as a key contributor of the alpha-secretase pathway.
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PMID:Constitutive and protein kinase C-regulated secretory cleavage of Alzheimer's beta-amyloid precursor protein: different control of early and late events by the proteasome. 937 83

Amyloid beta protein is the major protein component of neuritic plaques found in the brain of Alzheimer's disease. The activation of phospholipase D by amyloid beta protein (25-35), quisqualate and phorbol 12, 13-dibutyrate was investigated in LA-N-2 cells by measuring phosphatidylethanol formation. The activation of phospholipase D by quisqualate and APP (25-35) was calcium-independent. The AbetaP (25-35) and quisqualate activation of phospholipase D appeared to be mediated through a pertussis toxin-sensitive GTP-binding protein. Phospholipase D activation by AbetaP (25-35), quisqualate and phorbol dibutyrate was not blunted by the protein kinase C inhibitors, staurosporine, H-7 and RO-31-8220. However, it was abolished by overnight exposure to phorbol dibutyrate. This activation of phospholipase D was prevented by the tyrosine kinase inhibitor, genistein but not by tyrophostin A. Several excitatory amino acid antagonists were tested for their ability to prevent the phospholipase D activation by quisqualate and AbetaP (25-35). Only NBQX was effective with an IC50 of 75 microM for AbetaP (25-35) and quisqualate. Activation of phospholipase D by AbetaP or quisqualate was absent in LA-N-2 cells previously desensitized by quisqualate or AbetaP (25-35), but the activation by phorbol dibutyrate was unaltered. The responsiveness to AbetaP and quisqualate in previously desensitized cells reappeared subsequent to a period of resensitization. The observations with the antagonist NBQX, and the desensitization and resensitization experiments, are consistent with a receptor occupancy mediated activation of phospholipase D by quisqualate and by AbetaP (25-35).
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PMID:Activation of LA-N-2 cell phospholipase D by amyloid beta protein (25-35). 980 77

Muscarinic agonists alter the metabolism of amyloid precursor protein, leading to an increase in alpha-secretase cleavage and a decreased production of amyloidogenic peptides; suggesting that these compounds might modify the Alzheimer's disease process. A second therapeutic target in AD is the accumulation of stably phosphorylated tau into neurofibrillary tangles; an early event correlating with cognitive impairment. Glycogen synthase kinase-3 (GSK-3beta) phosphorylates tau and is inhibited via protein kinase C (PKC). As certain muscarinic receptors are linked to PKC, we examined the effect of a range of agonists on GSK-3beta phosphorylation of tau. In neurons a nonspecific muscarinic agonist, carbachol, reduced tau phosphorylation. In nonneuronal cells expressing the ml receptor a range of ml agonists reduced transiently-expressed tau phosphorylation and altered its microtubulebinding properties. These findings link the two pathological process of AD-APP metabolism and tau phosphorylation - and suggest that muscarinic and other cholinergic compounds might have disease-modifying properties.
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PMID:Muscarinic agonists reduce tau phosphorylation in non-neuronal cells via GSK-3beta inhibition and in neurons. 1112 10

We investigated the effects of different apolipoprotein E (apoE) isoforms, Abeta (1-42), and apoE/Abeta complexes on PKC-alpha translocation and APP processing in human SH-SY5Y neuroblastoma cells and fibroblasts. Treatment of cells with either 10 nM apoE3 or apoE4, 10 microM Abeta (1-42), or apoE/Abeta complexes induced significant translocation of PKC-alpha in both cell types. Effects were seen using both human recombinant apoE and apoE loaded into beta-very low density lipoprotein (beta-VLDL) particles. Time course (5-24 h) studies of APP processing revealed that some conditions induced transient or moderate increases in the secretion of proteins detected by 22C11. In contrast, the secretion of alpha-secretase cleaved APP was either not modified or transiently decreased, as determined by immunoblotting with the antibody 6E10. These results suggest that apoE, Abeta (1-42) and apoE/Abeta complexes can modulate PKC activity but do not have major consequences for APP processing. These effects could contribute to the reported PKC alterations seen in AD. However, it is unlikely that the contribution of different apoE isoforms to AD pathology occurs via effects on APP processing.
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PMID:Effects of apolipoprotein E (apoE) isoforms, beta-amyloid (Abeta) and apoE/Abeta complexes on protein kinase C-alpha (PKC-alpha) translocation and amyloid precursor protein (APP) processing in human SH-SY5Y neuroblastoma cells and fibroblasts. 1129 Mar 87

Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and anti-apoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [(N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S-enantiomer TV3279 [(N-Propargyl-(3S)Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The anti-apoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glyceraldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PKI 1195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by rasagiline and TV3326 is closely linked to the anti-apoptotic action of these drugs and their ability to process APP by activation of alpha-secretase.
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PMID:Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. 1204 33


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