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)

The turnover and processing of the Alzheimer beta/A4 amyloid precursor protein (beta APP) has been studied in PC12 cells after treatment with agents that regulate protein phosphorylation. Phorbol 12,13-dibutyrate, an agent that stimulates protein kinase C, decreased the levels of mature beta APP and increased the levels of 15- and 19-kDa peptides. These peptides appeared to be COOH-terminal fragments of beta APP, which arose when phorbol 12,13-dibutyrate increased the rate of proteolytic processing of mature forms of beta APP. Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, also led to decreased levels of mature beta APP and increased levels of the 15- and 19-kDa peptides. H-7, an inhibitor of protein kinase C and of several other protein kinases, apparently decreased the rate of proteolytic processing of mature beta APP. The sizes of the putative COOH-terminal fragments observed after treatment with either phorbol 12,13-dibutyrate or okadaic acid suggest that one or both may contain the entire beta/A4 region of beta APP and thus be amyloidogenic. Our results support the hypothesis that abnormal protein phosphorylation may play a role in the development of the cerebral amyloidosis that accompanies Alzheimer disease.
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PMID:Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. 211 15

Protein phosphorylation mediated by phorbol ester stimulates secretion of the beta-amyloid precursor protein (beta-APP) in the cell culture. This increase in secretion is produced by a transient increase in cleavage to produce non-amyloidogenic protease nexin II products mediated by the alpha-secretase activity, and a concomitant decrease in beta-protein production. Cells expressing the Swedish familial Alzheimer's disease (FAD) variant of beta-APP produce more beta-protein and potentially amyloidogenic fragments than cells expressing wild-type protein; furthermore, cleavage shifts from the alpha- to the beta-secretase cleavage site of the precursor. We show that treatment with phorbol 12,13-dibutyrate (PDBu) of cells expressing the Swedish FAD reverses the mutant phenotype to wild-type. The alpha-secretase cleavage increases with a concomitant loss of beta-protein and other beta-secretase cleaved products. These results show that modulating beta-secretase cleavage directly affects beta-protein production. It suggests that activating protein kinase C through, for example, muscarinic receptor agonists could reduce amyloidosis by modulating the level of beta-protein produced.
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PMID:Reversal of the Swedish familial Alzheimer's disease mutant phenotype in cultured cells treated with phorbol 12,13-dibutyrate. 797 Jan 75

The major component of amyloid plaque cores and cerebrovascular amyloid deposits found in Alzheimer disease is the beta/A4 peptide, which is derived from the Alzheimer amyloid protein precursor (APP). Recent evidence suggests that abnormalities in beta/A4 peptide production or beta/A4 peptide aggregation may underlie cerebral amyloidosis. In the present study, treatment of cells with phorbol dibutyrate, which activates protein kinase C, and/or okadaic acid, which inhibits protein phosphatases 1 and 2A, reduced beta/A4 peptide production by 50-80%. These effects were observed with APP695 and APP751 expressed in stably transfected CHO cells, as well as with endogenous APP in human glioma (Hs 683) cells. Phorbol dibutyrate also decreased beta/A4 peptide production in cells expressing various mutant forms of APP associated with familial Alzheimer disease, one of which was reported to manifest greatly increased beta/A4 peptide production in cultured cells. Mastoparan and mastoparan X, compounds which can activate phospholipase C and hence protein kinase C, also decreased beta/A4 peptide production in CHO cells stably transfected with APP695. A model is presented in which decreases in beta/A4 peptide production can be achieved by accelerating the metabolism of APP through a nonamyloidgenic secretory pathway.
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PMID:Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide. 841 76

Alzheimer's disease (AD) is the most prevalent form of dementia, and its effective disease modifying therapies are desperately needed. Promotion of non-amyloidogenic alpha-secretase cleavage of amyloid precursor protein (APP) to release soluble sAPPalpha, based on the most widely accepted "amyloid model" as a plausible mechanism for AD treatment, is the focus of this review. Modulation of alpha-secretase or "a disintegrin and metalloprotease (ADAM)"s activity via protein kinase C (PKC), calcium ion (Ca(2+)), tyrosine kinase (TK), MAP kinase (MAPK), and hormonal signaling, which regulate catabolic processing of APP, are discussed. The inhibition of amyloidogenic processing of APP by the beta- and gamma-secretase has been considered till now a promising strategy to treat AD. But beta- and gamma-secretase inhibitors, along with the available therapeutic tools for AD, have side effects. These challenges can be circumvented to certain extent; but activation of sAPPalpha release appears to be a potential alternative strategy to reduce cerebral amyloidosis. Drug screens have been performed to identify therapeutics for AD, but an effective screening strategy to isolate activators of alpha-secretase has been rarely reported. Novel reporter-based screens targeted toward APP mRNA 5' untranslated region (UTR), followed by counter-screens to detect alpha-secretase stimulators, could be important in detecting compounds to promote sAPPalpha release and reduce amyloid beta (Abeta) buildup. The primary inflammatory cytokine interleukin-1, which stimulates APP 5'UTR-directed translation of cell-associated APP, enhances processing to sAPPalpha in astrocytes and co-activates ADAM-10/ADAM-17 through MAPK signaling; thus illustrating a novel pathway that could serve as therapeutic model for AD.
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PMID:Role of the APP non-amyloidogenic signaling pathway and targeting alpha-secretase as an alternative drug target for treatment of Alzheimer's disease. 1804 31