Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Misfolding of the prion protein yields amyloidogenic isoforms, and it shows exacerbating neuronal damage in neurodegenerative disorders including prion diseases. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) potently stimulate neuritogenesis and survival of neuronal cells in the central nervous system. Here, we tested these neuropeptides on neurotoxicity in PC12 cells induced by the prion protein fragment 106-126 [PrP (106-126)]. Concomitant application of neuropeptide with PrP(106-126) (5x10(-5) M) inhibited the delayed death of neuron-like PC12 cells. In particular, PACAP27 inhibited the neurotoxicity of PrP(106-126) at low concentrations (>10(-15) M), characterized by the deactivation of PrP(106-126)-stimulated caspase-3. The neuroprotective effect of PACAP27 was antagonized by the selective PKA inhibitor, H89, or the MAP kinase inhibitor, U0126. These results suggest that PACAP27 attenuates PrP(106-126)-induced delayed neurotoxicity in PC12 cells by activating both PKA and MAP kinases mediated by PAC1 receptor.
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PMID:PACAP protects neuronal PC12 cells from the cytotoxicity of human prion protein fragment 106-126. 1209 20

We examined the influence of cellular prion protein (PrP(c)) in the control of cell death in stably transfected TSM1 cells. PrP(c) expression enhanced staurosporine-stimulated neuronal toxicity and DNA fragmentation, caspase 3-like activity and immunoreactivity, and p53 immunoreactivity and transcriptional activities. Caspase activation was reduced by the chemical inhibitor of p53, pifithrin-alpha, as well as by PrP(c)- or p53-antisense approaches but remained insensitive to the Fyn kinase inhibitor PP2 (4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine). We establish that PrP(c) controls p53 at a post-transcriptional level and is reversed by Mdm2 transfection and p38 MAPK inhibitor. We propose that endogenous cellular prion protein sensitizes neurons to apoptotic stimuli through a p53-dependent caspase 3-mediated activation controlled by Mdm2 and p38 MAPK.
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PMID:Cellular prion protein sensitizes neurons to apoptotic stimuli through Mdm2-regulated and p53-dependent caspase 3-like activation. 1252 24

We assessed the contribution of the cellular prion protein (PrPc) in the control of neuronal apoptosis by examining cell death in both human cells and murine primary cultured neurons. We first confirmed our previous finding that staurosporine-induced caspase activation is increased by PrPc overexpression in HEK293 cells. We show here that this phenotype is fully dependent on p53 and that the control of p53 activity by PrPc occurs at both transcriptional and post-transcriptional levels in human cells. Of most interest, we demonstrate that neuronal endogenous PrPc also controls a p53-dependent pro-apoptotic phenotype. Thus, DNA fragmentation and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling)-positive cells were lower in primary cultured neurons derived from Zrch-1 mice embryos in which PrPc has been abrogated than in wild-type neurons. PrPc knock-out neurons also displayed drastically diminished caspase-3-like activity and immunoreactivity together with reduced p53 expression and transcriptional activity, a phenotype complemented in part by PrPc transfection. Interestingly, p53 expression was also reduced in the brain of adult Prnp-/- mice. Neuronal PrPc likely controls p53 at a post-transcriptional level because the deletion of cellular prion protein is accompanied by a higher Mdm2-like immunoreactivity and reduced phosphorylated p38 MAPK expression. We therefore propose that the physiological function of endogenous cellular prion could be to regulate p53-dependent caspase-3-mediated neuronal cell death. This phenotype likely occurs through up-regulation of p53 promoter transactivation as well as downstream by controlling p53 stability via Mdm2 expression.
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PMID:Primary cultured neurons devoid of cellular prion display lower responsiveness to staurosporine through the control of p53 at both transcriptional and post-transcriptional levels. 1457 Aug 92

Putative functions of the cellular prion protein, PrPC, include resistance to oxidative stress, copper uptake, cell adhesion, and cell signaling. Here, we report NADPH oxidase-dependent reactive oxygen species (ROS) production and extracellular regulated kinases 1/2 (ERK1/2) phosphorylation on PrPC stimulation in the 1C11 neuroectodermal precursor, in its neuronal differentiated progenies, and in GT1-7 neurohypothalamic and BW5147 lymphoid cells. In neuroprogenitor, hypothalamic, and lymphoid cells, ERK1/2 activation is fully controlled by the NADPH oxidase-dependent ROS production. In 1C11-derived bioaminergic cells, ROS signaling and ERK1/2 phosphorylation are both controlled by Fyn kinase activation, introducing some specificity in PrPC transduction associated with this neuronal context. These data argue for an ubiquitous function of PrPC in cell-redox homeostasis through ROS production.
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PMID:NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells. 1459 99

While long-term effects of temperature treatment in respect of, e.g., gene-expression and cellular function have already been studied in some detail, nothing is known on the physiological responses of lymphocytes during short-term hypothermal shifts. In this report, we characterized the effects of such a stimulation using the human lymphocyte cell line Jurkat E6.1 and present evidence that warming from 4 to 37 degrees C for only 2 min is sufficient to cause co-localization of CD3, prion protein and the lipid-raft ganglioside GM1 paralleling lymphocyte activation as observed by Ca(2+) mobilization and mitogen-activated protein kinase-phosphorylation.
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PMID:Co-localization of CD3 and prion protein in Jurkat lymphocytes after hypothermal stimulation. 1514 80

1. Cellular prion protein, PrP(C), is a ubiquitous glycoprotein strongly expressed in neurons with an as yet unknown biological function. In previous studies, we demonstrated that PrP(C) could be regulated by heat shock stress, implying that it might be a stress-responsive protein. Hyperbaric oxygen (HBO) administration is a well-defined model for the study of oxidative stress. 2. This study investigated the effect of HBO on PrP(C) and Hsp 70 expression in mouse neuroblastoma cell lines (N18), assessing the expression of PrP(C) and Hsp 70 using RT-PCR and Western blotting. HBO administration resulted in a time- and dose-dependent increase in PrP(C) and Hsp70 expression in N18 cells at both mRNA and protein levels, with a concomitant upregulation of c-Jun N-terminal kinase (JNK). 3. Under HBO treatment, luciferase reporter constructs of the rat PrP(C) promoter, containing the heat shock element (HSE) also present in Hsp70, expressed higher luciferase activity (3- to 10-fold) than those constructs without HSE. 4. In summary, these data suggest that PrP(C) and Hsp 70 may be regulated by HBO, through the activation of JNK. Thus, the activated heat shock transcriptional factor 1, phosphorylated by JNK interacted with HSE in the promoter of PrP(C) resulted in increased gene expression. These findings are vital for future therapeutic approaches in transmissible spongiform encephalopathies and the understanding of the function of the PrP(C).
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PMID:Hyperbaric oxygen enhances the expression of prion protein and heat shock protein 70 in a mouse neuroblastoma cell line. 1517 39

The cellular prion protein (PrPc) resides in lipid rafts, yet the type of raft and the physiological function of PrPc are unclear. We show here that cross-linking of PrPc with specific antibodies leads to 1) PrPc capping in Jurkat and human peripheral blood T cells; 2) to cocapping with the intracellular lipid raft proteins reggie-1 and reggie-2; 3) to signal transduction as seen by MAP kinase phosphorylation and an elevation of the intracellular Ca2+ concentration; 4) to the recruitment of Thy-1, TCR/CD3, fyn, lck and LAT into the cap along with local tyrosine phosphorylation and F-actin polymerization, and later, internalization of PrPc together with the reggies into limp-2 positive lysosomes. Thus, PrPc association with reggie rafts triggers distinct transmembrane signal transduction events in T cells that promote the focal concentration of PrPc itself by guiding activated PrPc into preformed reggie caps and then to the recruitment of important interacting signaling molecules.
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PMID:PrPc capping in T cells promotes its association with the lipid raft proteins reggie-1 and reggie-2 and leads to signal transduction. 1534 93

The physiological role of the prion protein is largely unknown. Here, clustering of prion at the surface of GT1-7 cells was observed upon anti-prion antibody treatments. This clustering was associated with a rapid and transient phosphorylation of the mitogen activated protein kinases (MAPKs) extracellular receptor kinases 1 and 2 (ERK1/2), and also of the microtubule-destabilizing protein stathmin at serine 16. The specificity of this antibody-mediated activation was ascertained by its inhibition by prion small interfering RNA. The phosphorylation of ERK1/2 but not that of stathmin was abolished by the MAPK/ERK kinase 1 inhibitor U0126, whereas both signaling pathways were blocked by the specific inhibitor of the epidermal growth factor receptor AG1478, suggesting the likely recruitment of this receptor upon prion clustering.
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PMID:Clustering of cellular prion protein induces ERK1/2 and stathmin phosphorylation in GT1-7 neuronal cells. 1547 21

Transmissible spongiform encephalopathies are accompanied by the recruitment of microglial cells in the vicinity of amyloid aggregates of the pathological prion protein (PrPres). We previously showed that PrPres itself triggered the recruitment of microglia by interacting with neurons leading to the up-regulation of the expression level of chemokines, mainly RANTES (regulated on activation normal T cell expressed and secreted). The intracellular mechanisms underlying the PrPres-inducible expression of chemokines in this setting are not clear. Here we demonstrate that the mitogen-activated protein kinase pathway is switched on shortly after PrPres exposure to neurons leading to the expression of early growth response factor-1 (Egr-1), a transcription factor initially linked to differentiation and growth and to up-regulation of RANTES mRNA expression. PD98059, a selective inhibitor of extracellular signal-regulated kinase1/2 activation, resulted in a decrease of RANTES mRNA expression and as a consequence to the lowering of microglial cell migration. Neuronal overexpression of Nab2, a corepressor of Egr-1, produced similar effects. PrPres-induced chemoattraction is independent of the presence of PrPc and the laminin receptor on the neuronal cell surface. Our report is the first demonstration that PrPres exposure on neurons results in the activation of the MAP kinase signaling pathway that acts as a master switch to trigger neuronal expression of regulators of chemoattraction.
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PMID:Pathological prion protein exposure switches on neuronal mitogen-activated protein kinase pathway resulting in microglia recruitment. 1552 2

Cellular prion protein (PrP(C)) expression can be regulated by heat-shock stress, and we designed the present study to determine whether hypoglycemia could affect PrP(C) expression. RT-PCR and Western blotting were used to measure the expression of PrP(C) and heat-shock protein (Hsp70) in mouse neuroblastoma (N18) cells cultured 3 hr to 3 days in media deprived of 97.5% (L) or 75% (M) of its glucose. Hypoglycemia caused a concomitant time-dependent and glucose dose-dependent increase in PrP(C) and Hsp70. In addition, hypoglycemia also increased phosphorylated c-Jun N-terminal kinase (JNK) protein levels in a time-dependent manner. The upregulation of PrP(C) and Hsp70 under hypoglycemic conditions was disrupted by the specific JNK inhibitor SP600125. It was also found from in vitro studies that hypoglycemic conditions induced higher levels of PrP(C) promoter activity in PrP(C) promoters containing a heat-shock element (HSE) than in PrP(C) promoters lacking HSE. We propose that hypoglycemia-increased PrP(C) expression might be due to JNK phosphorylation of a heat-shock transcriptional factor, which then interacts with HSE in the promoter of PrP(C).
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PMID:Hypoglycemia enhances the expression of prion protein and heat-shock protein 70 in a mouse neuroblastoma cell line. 1588 19


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