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)

alpha-Secretase cleaves the full-length Alzheimer's amyloid precursor protein (APP) within the amyloid beta peptide sequence, thus precluding amyloid formation. The resultant soluble truncated APP is constitutively secreted. This nonamyloidogenic processing of APP is increased on stimulation of the phospholipase C/protein kinase C pathway by phorbol esters. Here we used C6 cells transfected with APP751 to examine whether the alpha-secretase cleavage is regulated by the adenylate cyclase signal transduction pathway. Forskolin, an activator of adenylate cyclase, inhibited both the constitutive and phorbol ester-stimulated secretion of nexin II (NXII), the secreted product of the alpha-secretase cleavage of APP751. At 1 microM, forskolin inhibited secretion of NXII by approximately 50% without affecting either the intracellular levels of total APP or the secretion of secretory alkaline phosphatase. In contrast, 1,9-dideoxyforskolin, an inactive analogue of forskolin, did not affect secretion of NXII. These results indicated that forskolin specifically inhibited the alpha-secretase cleavage of APP751. Forskolin treatment increased the intracellular concentration of cyclic AMP (cAMP), suggesting that the forskolin effects on APP cleavage may be mediated by cAMP. In support of this suggestion, both dibutyryl cAMP, a cAMP analogue, and isoproterenol, an activator of adenylate cyclase, also inhibited secretion of NXII. These data indicate that forskolin inhibition of the nonamyloidogenic cleavage of APP is mediated by the second messenger cAMP, which together with the protein kinase C signal transduction pathway modulates the secretory cleavage of APP.
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PMID:Intracellular cyclic AMP inhibits constitutive and phorbol ester-stimulated secretory cleavage of amyloid precursor protein. 876 18

The present study shows that cultured fibroblasts from sporadic Alzheimer's disease patients are deficient in protein kinase C-regulated secretion of amyloid precursor protein. In particular, Alzheimer fibroblasts show a reduced basal secretion and a reduced response at low concentrations of phorbol-12,13-dibutyrate, with an EC50 twofold higher than control fibroblasts. Furthermore, we observed that such defective regulation of the amyloid precursor secretion can possibly be correlated to a specific defect in protein kinase C alpha in fibroblasts from Alzheimer patients.
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PMID:Defective phorbol ester-stimulated secretion of beta-amyloid precursor protein from Alzheimer's disease fibroblasts. 883 Mar

We characterized the secretion of amyloid precursor protein (APP) in rat primary neurons and conditionally immortalized central nervous system (CNS) derived progenitor cell lines, to evaluate their suitability as models for studies on APP metabolism. We observed that primary cells dissociated from different regions of the embryonic brain secreted progressively more APP during in vitro maturation. The increase in basal secretion resulted in an offset of the response to protein kinase C (PKC) activated secretion and was correlated with an increased PKC alpha expression. The same type of analysis was performed on CNS derived conditionally immortalized cells whose growth potential becomes restricted upon shifting of the culture conditions to a non-permissive temperature (39 degrees C), an event that coincides with their progression toward differentiation. With a pattern consistent with that observed in primary neurons, conditionally immortalized cells exposed to 39 degrees C showed an offset of the secretory response to activation by PdBu and also an increased expression of PKC alpha. These data suggest that APP secretion and its regulation in CNS derived cells is influenced by the proliferative status of the cells.
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PMID:Changes in beta amyloid precursor protein secretion associated with the proliferative status of CNS derived progenitor cells. 884 7

The present study investigates the ability of the pharmacologic activation of protein kinase C (PKC) to modulate amyloid precursor protein (APP) secretion in human skin fibroblasts from patients affected by Down's syndrome (DS). We assessed DS subjects at the Hospital Institute of Sospiro, Cremona, and at the Alzheimer's Disease Unit of the Sacred Heart Hospital in Brescia, and we subdivided them into nondemented (NDS) and demented (DDS) patients. All DS patients were trisomy 21 karyotype. DS fibroblasts had an increased content of APP immunoreactive material as revealed by immunocytochemistry analysis. The basal secretion of soluble APP was higher (+94.6%) in Down's cells with respect to controls. The observation on the fibroblasts prepared from DS is consistent with these patients' possessing an extra copy of the APP gene (mapped on chromosome 21) leading to increased APP expression. Phorbol-12,13-dibutyrate (PdBu, 9 to 150 nM) treatment promoted a dose-dependent increase of secreted APP in the conditioned medium of control fibroblasts. The peak response (+102.2%) was attained using 150 nM PdBu. In Down's fibroblasts, PdBu stimulated APP secretion already maximally at low concentrations (9 nM), but the peak response, due to the higher basal release, was lower on a percentage basis (+16.4%) than in control fibroblasts. The results indicate that in Down's fibroblasts the mechanisms controlling APP release are at least quantitatively altered. In addition, these results suggest caution when using information obtained from Down's patients to model Alzheimer's disease biochemical defects.
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PMID:Fibroblasts of patients affected by Down's syndrome oversecrete amyloid precursor protein and are hyporesponsive to protein kinase C stimulation. 885 47

Conventional secretory processing of the amyloid precursor protein is nonamyloidogenic, releasing carboxyl-terminus-truncated amyloid precursor protein derivatives while cleaving the amyloid beta-peptide within its sequence. Alternative processing routes are potentially amyloidogenic, yielding the amyloid beta-peptide segment intact. In continuous cell lines, secretory processing of the amyloid precursor protein is regulated by both protein kinase C and muscarinic receptor stimulation. However, the first and second messenger systems that regulate amyloid precursor protein release in central neurons are still under investigation. In the present investigation, we examined whether or not first and second messengers of cholinergic neurotransmission increase production of soluble derivatives of the amyloid precursor protein in primary cultures of rat cortical neurons. Activation of protein kinase C by the phorbol esters phorbol 12,13-dibutyrate and phorbol 12-myristate 13-acetate increased production of the soluble form of the amyloid precursor protein dramatically. In contrast, activation of muscarinic receptors by oxotremorine-M or carbachol did not result in a significant increase in amyloid precursor protein release. Similarly, chemically induced depolarization using 35 mM KCl did not alter production of soluble amyloid precursor protein derivatives. Our data suggest that although protein kinase C stimulation plays an important role in regulating release of the amyloid precursor protein, cholinergic neurotransmission does not regulate its release in cultured rat cortical neurons.
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PMID:Phorbol esters but not the cholinergic agonists oxotremorine-M and carbachol increase release of the amyloid precursor protein in cultured rat cortical neurons. 885 34

Deposition of beta-amyloid protein (beta A4) in extracellular senile plaques is a pathologic hallmark of Alzheimer's disease (AD). The neurotoxic effect of beta A4 has been ascribed to a discrete 11-amino acid internal sequence (beta A(4)25-35). Substance P (SP) has been found to be depleted in the brain of AD patients while its presence was found to protect against the neurodegenerative effect of beta A(4)25-35. Our previous studies, in vivo, in aged rats showed that beta A(4)25-35 exhibits a potent vasoconstrictor (VC) effect in rat skin microvasculature and can prevent SP but not calcitonin gene-related peptide (CGRP) from inducing a vasodilator (VD) response. It was postulated that beta A(4)25-35 might be interacting with SP at the level of the second messenger system via the phosphoinositide pathway. Using a blister model of inflammation in the rat hind footpad, we examined the ability of beta A(4)25-35 to modulate the vascular activity of bradykinin (BK) and serotonin (5-HT) which also activate the phosphoinositide pathway. In addition, the role of nitric oxide (NO), endothelin (ET, an endothelium-derived constrictor factor) and protein kinase C (PKC) in the vascular effects of beta A(4)25-35 were examined using the NO synthase inhibitor, NG-nitro-L-arginine (L-NOARG), the ET-receptor antagonist, BQ-123, and the PKC inhibitor, bisindolylmaleimide (BIM) respectively. Changes in microvascular blood flow were monitored using laser Doppler flowmetry and the area within the response curve measured. The results showed that beta A(4)25-35 (10 microM) induced a VC effect and inhibited the subsequent VD response to BK (10 microM) and 5-HT (1 microM) in a similar fashion to its effect on SP (1 microM). In the presence of L-NOARG (100 microM), the VD effect of SP was reduced and further attenuated after perfusion of beta A(4)25-35. Superfusion of the blister base with BQ-123 (10 microM) or BIM (1 microM) prior to and during perfusion with beta A(4)25-35 abolished its VC effect and allowed SP to induce a normal VD response in both young and old rats. Based on these results, we suggest that the vascular activity of the active fragment, beta A(4)25-35, is mediated by ET via activation of PKC. This study provides new findings which may help to elucidate the signal transduction mechanisms involved in the vascular activity of beta A(4)25-35. The relevance of these mechanisms to those underlying the pathological effects of beta A4 and their significance in AD remains to be determined.
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PMID:Mechanisms underlying the vascular activity of beta-amyloid protein fragment (beta A(4)25-35) at the level of skin microvasculature. 893 Mar 26

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

Secretory cleavage of the amyloid precursor protein (APP), a process that releases soluble APP derivatives (APPs) into the extracellular space, is stimulated by the activation of muscarinic receptors coupled to phosphoinositide hydrolysis. The signalling pathways involved in the release process exhibit both protein kinase C- and protein tyrosine phosphorylation-dependent components [Slack, Breu, Petryniak, Srivastava and Wurtman (1995) J. Biol. Chem. 270, 8337-8344]. The possibility that elevations in intracellular Ca2+ concentration initiate the tyrosine phosphorylation-dependent release of APPs was examined in human embryonic kidney cells expressing muscarinic m3 receptors. Inhibition of protein kinase C with the bisindolylmaleimide GF 109203X decreased the carbachol-evoked release of APPs by approx. 30%, as shown previously. The residual response was further decreased, in an additive manner, by the Ca2+ chelator EGTA, or by the tyrosine kinase inhibitor tyrphostin A25. The Ca2+ ionophore, ionomycin, like carbachol, stimulated both the release of APPs and the tyrosine phosphorylation of several proteins, one of which was identified as paxillin, a component of focal adhesions. The effects of ionomycin on APPs release and on protein tyrosine phosphorylation were concentration-dependent, and occurred over similar concentration ranges; both effects were inhibited only partly by GF 109203X, but were abolished by EGTA or by tyrosine kinase inhibitors. The results demonstrate for the first time that ionophore-induced elevations in intracellular Ca2+ levels elicit APPs release via increased tyrosine phosphorylation. Part of the increase in APPs release evoked by muscarinic receptor activation might be attributable to a similar mechanism.
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PMID:Elevated intracellular calcium concentration increases secretory processing of the amyloid precursor protein by a tyrosine phosphorylation-dependent mechanism. 900 86

Immunological mechanisms, including stimulation of brain microglia and elevation of various inflammatory cytokines, have been implicated in the pathogenesis of Alzheimer's disease, where accumulation of beta-amyloid peptide (A beta) is one of its main pathological features. In this study we investigated the interaction of human monocyte-like cells with synthetic beta-amyloid peptide A beta (1-40) and its subfragment A beta (25-35). THP-1 cells (a transformed human monocyte cell line) were used with or without prior differentiation by phorbol myristate acetate (PMA), and cell activation was assessed by the secretion of tumor necrosis factor-alpha (TNF-alpha). First, it was shown that THP-1 cells could be induced to secrete significant amounts of TNF-alpha by interleukin-1, lipopolysaccharide, interferon-gamma (IFN-gamma) and PMA alone or in combination with each other. Next it was shown that A beta (1-40) could also induce secretion of TNF-alpha by THP-1 cells, but the effect was diminished when this peptide was applied in combination with IFN-gamma. The A beta subfragment A beta (25-35) was ineffective in inducing TNF-alpha production. The cellular action of A beta (1-40) appears to involve protein kinase C since pretreatment of THP-1 cells by PMA or the protein kinase C inhibitor H-7 diminished the cellular response to A beta (1-40). Identification of the pathway by which extracellular A beta activates the intracellular PKC-dependent secretion of TNF-alpha may help in developing new therapeutic strategies for Alzheimer's disease.
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PMID:Interaction of Alzheimer beta-amyloid peptide with the human monocytic cell line THP-1 results in a protein kinase C-dependent secretion of tumor necrosis factor-alpha. 904 34

This study investigated the immunostaining of protein kinase C (PKC) isoforms and amyloid precursor protein (APP) in rat brain cortex and determined alterations following an excitotoxic challenge in vivo. Cellular alterations in APP and PKC isoforms (alpha, beta, gamma, delta, epsilon, and zeta) following glutamate perfusion in the rat parietal cortex were compared with NaCl perfusion. In all animals, two histological zones could be defined consistently, a necrotic core and a boundary zone immediately adjacent to the core. Following glutamate and NaCl perfusion, cellular immunoreactivity to PKC isoforms and amino-terminal APP was significantly reduced within the necrotic core. Striking carboxy-terminal APP immunoreactivity was observed in some neurons remaining within the necrotic core. In the boundary of the glutamate lesion, the perikarya of most neurons were intensely immunoreactive to PKC alpha and beta. Furthermore, within the boundary zone, enhanced immunoreactivity within neuronal perikarya was observed to amino-terminal APP and, to a lesser extent, carboxy-terminal APP. Increased immunostaining of PKC alpha and beta and APP at the boundary zone was a consistent feature of intracortical glutamate perfusion and was not observed following NaCl perfusion. There were minimal alterations in PKC isoforms gamma, delta, epsilon, and zeta, in the boundary region following intracortical glutamate or NaCl perfusion. There was no astrocytic response, as detected by GFAP immunoreactivity, at the boundary zone. These findings indicate that there is a topographical relationship between cellular alterations of specific PKC isoforms and APP following an excitotoxic challenge in vivo.
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PMID:Intracortical glutamate perfusion in vivo induces cellular alterations in specific protein kinase C isoforms and amyloid precursor protein. 905 84


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