Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tripeptide thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH2) has been shown to possess neuroprotective activity in in vitro and in vivo models. Since its potential utility is limited by relatively rapid metabolism, metabolically stabilized analogues have been constructed. In the present study we investigated the influence of TRH and its three stable analogues: Montirelin (MON, CG-3703), RGH-2202 (L-6-keto-piperidine-2carbonyl-l-leucyl-l-prolinamide) and Z-TRH (N-carbobenzyloxy-pGlutamyl-Histydyl-Proline) in various models of mouse cortical neuronal cell injury. Twenty four hour pre-treatment with TRH and its analogues in low micromolar concentrations attenuated the neuronal cell death evoked by excitatory amino acids (EAAs: glutamate, NMDA, kainate, quisqualate) and hydrogen peroxide. All the peptides showed neuroprotective action on staurosporine (St)-evoked apoptotic neuronal cell death, but this effect was caspase-3 independent. Interestingly, in mixed neuronal-glial cell preparations only MON decreased St- and glutamate-evoked neurotoxicity. None of the peptides inhibited the doxorubicin- and lactacystin-induced neuronal cortical cell death, agents acting via activation of death receptor (FAS) or inhibition of proteasome function, respectively. Furthermore, we found that neither inhibitors of PI3-K (wortmannin, LY 294002) nor MAPK/ERK1/2 (PD 098059, U 0126) were able to inhibit neuroprotective properties of TRH and MON in St model of apoptosis. The protection mediated by TRH and MON it that model was also not connected with influence of peptides on the pro-apoptotic GSK-3beta and JNK protein kinase expression and activity. Further studies showed that calpains, calcium-activated proteases were induced by Glu, but not by St in cortical neurons. Moreover, the Glu-evoked increase in spectrin alpha II cleavage product induced by calpains was blocked by TRH. The obtained data showed that the potency of TRH and its analogues in inhibiting EAAs- and H(2)O(2)-induced neuronal cell death from the highest to lowest activity was: MON>TRH>Z-TRH>RHG. Interestingly, all peptides were active against St-induced apoptosis, however, on concentration basis MON was far more potent than the other peptides. None of the peptides inhibited Dox- and LC-evoked apoptotic cell death. Additionally, the data exclude potential role of pro-survival (PI3-K/Akt and MAPK/ERK1/2) and pro-apoptotic (GSK-3beta and JNK) pathways in neuroprotective effects of TRH and its analogues on St-induced neuronal apoptosis. Moreover, the results point to involvement of the inhibition of calpains in the TRH neuroprotective effect in Glu model of neuronal cell death.
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PMID:Effects of TRH and its analogues on primary cortical neuronal cell damage induced by various excitotoxic, necrotic and apoptotic agents. 1966 92

12/15-Lipoxygenase (12/15-LOX) is an important mediator of brain injury following experimental stroke in rodents. It contributes to neuronal death, but the underlying mechanism remains unclear. We demonstrate here that in neuronal HT22 cells subjected to glutamate-induced oxidative stress, 12/15-LOX damages mitochondria, and this represents the committed step that condemns the cell to die. Importantly these events, including breakdown of the mitochondrial membrane potential, the production of reactive oxygen species, and cytochrome c release, can all be replicated by incubation of 12/15-LOX with mitochondria in vitro, without the need to add other cytosolic factors. Proteasome activity is required downstream of mitochondrial damage to complete the cell death cascade, but proteasome inhibition is only partially protective. These findings position 12/15-LOX as the central executioner in an oxidative stress-related neuronal death program.
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PMID:12/15-Lipoxygenase targets neuronal mitochondria under oxidative stress. 1973 46

Long-term depression (LTD) in CA1 pyramidal neurons can be induced by activation of either N-methyl-D-aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs), both of which elicit changes in synaptic efficacy through alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) endocytosis. To address the role of the ubiquitin-proteasome system in regulating AMPAR endocytosis during these forms of LTD, we examined the effects of pharmacological inhibitors of proteasomal degradation and protein ubiquitination on endocytosis of glutamate receptor 1 (GluR1) -containing AMPARs in dissociated rat hippocampal cultures as well as LTD of excitatory synaptic responses in acute rat hippocampal slices. Our findings suggest that the contribution of the ubiquitin-proteasome system to NMDAR-induced vs. mGluR-induced AMPAR endocytosis and the consequent LTD differs significantly. NMDAR-induced AMPAR endocytosis and LTD occur independently of proteasome function but appear to depend, at least in part, on ubiquitination. In contrast, mGluR-induced AMPAR endocytosis and LTD are enhanced by inhibition of proteasomal degradation, as well as by the inhibitor of protein ubiquitination. Furthermore, the decay of mGluR-induced membrane depolarization and Erk activation is delayed following inhibition of either ubiquitination or proteasomal degradation. These results suggest that, although NMDAR-dependent LTD may utilize ubiquitin as a signal for AMPAR endocytosis, mGluR-induced signaling and LTD are limited by a feedback mechanism that involves the ubiquitin-proteasome system.
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PMID:N-methyl-D-aspartate receptor- and metabotropic glutamate receptor-dependent long-term depression are differentially regulated by the ubiquitin-proteasome system. 1982 36

The regulation of synaptic glutamate receptor and GABA(A)R (gamma-aminobutyric acid subtype A receptor) levels is a key component of synaptic plasticity. Most forms of neuronal plasticity are associated with the induction of the transcription factor zif268 (egr1). Hence, it is predicted that zif268 may regulate transcription of genes associated with glutamate receptors and/or GABA(A)Rs. It turns out that receptor regulation by zif268 tends to be indirect. Induction of zif268 in neurons leads to altered expression of proteasome subunit and proteasome-regulatory genes, thereby changing the capacity of the neuron to degrade synaptic proteins, including receptors and receptor subunits. In addition, zif268 alters the transcription of genes associated with GABA(A)R expression and trafficking, such as ubiquilin and gephyrin. This indirect regulation of receptor turnover is likely to contribute to the delayed, but long-lasting, phases of synaptic plasticity and also to the synaptic dysfunction associated with diseases such as schizophrenia and Alzheimer's disease, where zif268 expression is reduced.
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PMID:Activity-dependent gene transcription as a long-term influence on receptor signalling. 1990 79

It is assumed that much more functional importance for protein activity than expected may be granted by methylation that occurs at the side-chain of aspartate or glutamate residue. In vitro methylation mainly comes from the use of methanol in sample preparation prior to MS analysis. In this study, we first performed the methylation site-directed proteomic screening of bovine serum albumin, ovalbumin and 20S proteasome for gel staining using a meaningfully indicative MS-pattern of peak tag (termed as 4P tag) and manual inspection for mass spectral data. As a result, there were 17 proteolytic peptides with 20 modified sites confirmed to be in vitro methylated. Subsequently, the prevalence investigation was performed, focusing on the reaction kinetic behavior of in vitro methylation. This study provided a simple and robust approach for confirmation of in vitro methylation by methanol, as well as the precautious guide for the use of methanol in proteomic study.
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PMID:In vitro methylation by methanol: proteomic screening and prevalence investigation. 2011 17

Chronic changes in electrical excitability profoundly affect synaptic transmission throughout the lifetime of a neuron. We have previously explored persistent presynaptic silencing, a form of synaptic depression at glutamate synapses produced by ongoing neuronal activity and by strong depolarization. Here we investigate the involvement of the ubiquitin-proteasome system (UPS) in the modulation of presynaptic function. We found that proteasome inhibition prevented the induction of persistent presynaptic silencing. Specifically, application of the proteasome inhibitor MG-132 (carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) prevented decreases in the size of the readily releasable pool of vesicles and in the percentage of active synapses. Presynaptic silencing was accompanied by decreases in levels of the priming proteins Munc13-1 and Rim1. Importantly, overexpression of Rim1alpha prevented the induction of persistent presynaptic silencing. Furthermore, strong depolarization itself increased proteasome enzymatic activity measured in cell lysates. These results suggest that modulation of the UPS by electrical activity contributes to persistent presynaptic silencing by promoting the degradation of key presynaptic proteins.
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PMID:A role for the ubiquitin-proteasome system in activity-dependent presynaptic silencing. 2013 Jan 89

A prokaryotic protein tagging system called pupylation that is analogous to ubiquitylation in eukaryotes has recently been described. In this process, prokaryotic ubiquitin-like protein (Pup) is coupled to substrate proteins via an isopeptide bond in order to target them for degradation by the proteasome. The ligation occurs via a condensation reaction involving a carboxylate of the C-terminal glutamate of Pup (located in a conserved terminal Gly-Gly-Glu motif) and the side-chain amino group of a substrate lysine. Here we have used a combination of NMR and biochemical experiments with free lysine and a physiological protein substrate (PanB) to show that the coupling occurs through the side-chain carboxylate of the glutamate in the GGE motif rather than the carboxy terminus but that the glutamate must be located at the C-terminal position to be coupled.
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PMID:Prokaryotic ubiquitin-like protein (Pup) is coupled to substrates via the side chain of its C-terminal glutamate. 2035 27

Ascent to high altitude is associated with tissue hypoxia resulting from the decrease in partial pressure of atmospheric oxygen. The hippocampus, in particular, is highly vulnerable to hypoxic insult, which at least in part can be attributed to the occurrence of glutamate excitotoxicity. Although this excitotoxic damage is often related to increased NMDA receptor activation and subsequent calcium-mediated free radical generation, the mechanisms involving the transcriptional regulation of NMDA receptor subunit expression by hypoxic stress remains to be explored. Our study reveals a novel mechanism for the regulation of expression of the NR1 subunit of NMDA receptors by the Sp family of transcription factors through an oxidative-stress-mediated mechanism that also involves the molecular chaperone Hsp90. The findings not only show the occurrence of lipid peroxidation and DNA damage in hippocampal cells exposed to hypoxia but also reveal a calcium-independent mechanism of selective oxidation and degradation of Sp3 by the 20S proteasome. This along with increased DNA binding activity of Sp1 leads to NR1 upregulation in the hippocampus during hypoxic stress. The study therefore provides evidence for free radical-mediated regulation of gene expression in hypoxia and the scope of the use of antioxidants in preventing excitotoxic neuronal damage during hypoxia.
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PMID:Oxidative-stress-induced alterations in Sp factors mediate transcriptional regulation of the NR1 subunit in hippocampus during hypoxia. 2038 4

Glutamic acid decarboxylase is responsible for synthesizing GABA, the major inhibitory neurotransmitter, and exists in two isoforms--GAD65 and GAD67. The enzyme is cleaved under excitotoxic conditions, but the mechanisms involved and the functional consequences are not fully elucidated. We found that excitotoxic stimulation of cultured hippocampal neurons with glutamate leads to a time-dependent cleavage of GAD65 and GAD67 in the N-terminal region of the proteins, and decrease the corresponding mRNAs. The cleavage of GAD67 was sensitive to the proteasome inhibitors MG132, YU102 and lactacystin, and was also abrogated by the E1 ubiquitin ligase inhibitor UBEI-41. In contrast, MG132 and UBEI-41 were the only inhibitors tested that showed an effect on GAD65 cleavage. Excitotoxic stimulation with glutamate also increased the amount of GAD captured in experiments where ubiquitinated proteins and their binding partners were isolated. However, no evidences were found for direct GADs ubiquitination in cultured hippocampal neurons, and recombinant GAD65 was not cleaved by purified 20S or 26S proteasome preparations. Since calpains, a group of calcium activated proteases, play a key role in GAD65/67 cleavage under excitotoxic conditions the results suggest that GADs are cleaved after ubiquitination and degradation of an unknown binding partner by the proteasome. The characteristic punctate distribution of GAD65 along neurites of differentiated cultured hippocampal neurons was significantly reduced after excitotoxic injury, and the total GAD activity measured in extracts from the cerebellum or cerebral cortex at 24h postmortem (when there is a partial cleavage of GADs) was also decreased. The results show a role of the UPS in the cleavage of GAD65/67 and point out the deregulation of GADs under excitotoxic conditions, which is likely to affect GABAergic neurotransmission. This is the first time that the UPS has been implicated in the events triggered during excitotoxicity and the first molecular target of the UPS affected in this cell death process.
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PMID:Role of the proteasome in excitotoxicity-induced cleavage of glutamic acid decarboxylase in cultured hippocampal neurons. 2040 34

Amyloid beta (Abeta) is involved in the etiology of Alzheimer's disease (AD) and may contribute to cognitive deficits by increasing internalization of ionotropic glutamate receptors. Striatal-enriched protein tyrosine phosphatase 61 (STEP(61)), which is targeted in part to the postsynaptic terminal, has been implicated in this process. Here we show that STEP(61) levels are progressively increased in the cortex of Tg2576 mice over the first year, as well as in prefrontal cortex of human AD brains. The increased STEP(61) was associated with greater STEP activity, dephosphorylation of phospho-tyr(1472) of the NR2B subunit, and decreased NR1 and NR2B subunits on neuronal membranes. Treatment with Abeta-enriched medium also increased STEP(61) levels and decreased NR1/NR2B abundance in mouse cortical cultures as determined by biotinylation experiments. In STEP knock-out cultures, Abeta treatment failed to induce NMDA receptor internalization. The mechanism for the increase in STEP(61) levels appears to involve the ubiquitin proteasome system. Blocking the proteasome resulted in elevated levels of STEP(61). Moreover, STEP(61)-ubiquitin conjugates were increased in wild-type cortical slices upon Abeta treatment as well as in 12 month Tg2576 cortex. These findings reveal a novel mechanism by which Abeta-mediated accumulation of STEP(61) results in increased internalization of NR1/NR2B receptor that may contribute to the cognitive deficits in AD.
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PMID:Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61. 2042 54


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