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)

Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. alpha-Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death has not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed, and caspase-3 is activated in the affected midbrain. Here we report that a combination of 1-methyl-4-phenylpyridinium ion (MPP(+)) or rotenone and proteasome inhibition causes the appearance of alpha-synuclein-positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP(+)- or rotenone-induced dopaminergic neuronal death. MPP(+) elevated proteasome activity, dephosphorylated mitogen-activating protein kinase (MAPK), and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p42 and p44 MAPK kinase inhibitor. Thus, the proteasome plays an important role in both inclusion body formation and dopaminergic neuronal death but these processes form opposite sides on the proteasome regulation in this model.
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PMID:Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes alpha-synuclein inclusions. 1467 49

Human neutrophils normally have a very short half-life and die by apoptosis. Cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) can delay this apoptosis via increases in the cellular levels of Mcl-1, an anti-apoptotic protein of the Bcl-2 family with a rapid turnover rate. Here we have shown that inhibition of the proteasome (a) decreases the rate of Mcl-1 turnover within neutrophils and (b) significantly delays apoptosis. This led us to determine whether GM-CSF could enhance neutrophil survival by altering the rate of Mcl-1 turnover. Addition of GM-CSF to neutrophils enhanced Mcl-1 stability and delayed apoptosis by signaling pathways requiring PI3K/Akt and p44/42 Erk/Mek, because inhibitors of these pathways completely abrogated the GM-CSF-mediated effect on both Mcl-1 stability and apoptosis delay. Conversely, induction of Mcl-1 hyperphosphorylation by the phosphatase inhibitor, okadaic acid, significantly accelerated both Mcl-1 turnover and apoptosis. Neither the calpain inhibitor, carbobenzoxy-valinyl-phenylalaninal, nor the pan caspase inhibitor, benzyloxycarbonyl-VAD-fluoromethylketone, had any effect on Mcl-1 stability under these conditions. These observations indicate that profound changes in the rate of neutrophil apoptosis following cytokine signaling occur via dynamic changes in the rate of Mcl-1 turnover via the proteasome.
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PMID:Granulocyte macrophage colony-stimulating factor signaling and proteasome inhibition delay neutrophil apoptosis by increasing the stability of Mcl-1. 1507 92

During inflammation, microglial cells go through phenotypic and functional changes that include the production and release of large amounts of oxygen and nitrogen radicals. As such, activated microglia are subject to heightened oxidative stress. The multicatalytic proteasome clears oxidized and damaged proteins from cells, and has been shown to be an important aspect of the microglial compensatory response to activation. The female sex steroid estrogen is both cytoprotective and anti-inflammatory, and has been shown to affect microglial signaling in particular. To determine if estrogen might affect the proteasome in microglial cells, we examined the effects of 17 beta-estradiol treatment on proteasome activity in N9 microglial cells. Specifically, we measured ATP-dependent and ATP-independent chymotrypsin-like, trypsin-like, and peptidyl glutamyl peptide hydrolase (PGPH)-like activities in response to both 17 beta-estradiol and interferon gamma. Data indicate that estrogen, but not interferon gamma, significantly increases ATP-dependent chymotrypsin-like and PGPH-like activity. Furthermore, this effect was blocked by the p44/42 MAPK inhibitor PD98059. Hence, these data demonstrate that through the MAPK pathway, estrogen can upregulate proteasome activity, suggesting a possible mechanism for estrogen's cytoprotective effects.
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PMID:Estrogen increases proteasome activity in murine microglial cells. 1530 98

Breast cancers often have increased mitogen-activated protein kinase (MAPK) activity; this pathway influences breast cancer cell growth in part by targeting steroid hormone receptors. Activation of p42 and p44 MAPKs increases progesterone receptor (PR) transcriptional activity in the presence of progestins, and triggers their rapid down-regulation by the ubiquitin-proteasome pathway. In turn, progestins increase the expression of type I growth factor receptor tyrosine kinases that feed into MAPK activation. Most recently, progestins have been shown to activate the p42/p44 MAPK module in a progesterone receptor (PR) dependent manner, but independently of their function as transcription factors. Indeed, mechanisms of bi-directional cross-talk between these two pathways are becoming well-documented. In this reveiw we provide an overview of the primary ways in which steroid hormone receptor and growth factor cross-talk occurs, using examples from our work and others with human PR as a model receptor. We highlight the regulation of PR by phosphorylation and the role of intracellular protein kinases as key mediators of PR action. Cross-talk between growth factor and PR-mediated signaling events is an important means by which growth regulatory genes may be coordinately regulated, and may contribute to the growth and development of hormonally responsive normal breast tissue and to breast cancer progression.
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PMID:Cross-talk between growth factor and progesterone receptor signaling pathways: implications for breast cancer cell growth. 1568 86

Type II 5' deiodinase (D2) activity produces triiodothyronine (T3) from thyroxine (T4) and is induced by cold and norepinephrine (NE) in brown adipose tissue. T3 is required for and amplifies the adrenergic stimulation of D2 activity and mRNA in cultured brown adipocytes. D2 is upregulated by insulin and decrease in fasting. We now study the regulation by insulin of the adrenergically induced D2 activity and mRNA in primary cultures of rat brown adipocytes. Insulin alone does not increase D2 activity or mRNA. Insulin-depleted cells show a reduction in the adrenergically induced D2 activity, which is proportional to the length of insulin depletion and is restored after insulin addition. IGFs mimic this effect at higher doses. ERK 1/2 MAPK activity (p44/p42), stimulated by insulin, serum and NE, is an absolute requirement for the adrenergic stimulation of D2 activity and mRNA. PI3K is stimulated by insulin and serum, and NE increases the effect of insulin. The action of insulin on D2 is not due to changes in D2 half-life or in the proteasome-mediated degradation of D2, but it seems to modulate the transcriptional induction mediated by NE. D2 mRNA expression, induced by NE plus T3, is reduced when insulin is withdrawn at early differentiation stages. Insulin or IGF-I promotes increases in D2 mRNA. Insulin is required for the induction of D2 mRNA by T3. In conclusion, MAPK signaling is required for the adrenergic stimulation of D2 activity and mRNA, and insulin stimulates D2 activity via MAPK and PI3K and enhances the adrenergic pathways.
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PMID:Insulin increases the adrenergic stimulation of 5' deiodinase activity and mRNA expression in rat brown adipocytes; role of MAPK and PI3K. 1569 84

Binding of tumor necrosis factor-alpha (TNF-alpha) to its transmembrane receptors (TNFRs) mediates proinflammatory, apoptotic and survival responses in several cell types including vascular endothelial cells. Because ectodomain shedding of cell surface molecules can be modified by proteasome activity, we studied in human endothelial cells whether the TNF-alpha-TNFRs axis can be regulated by the cleavage of their transmembrane forms in a proteasome-dependent manner. We show that proteasome inhibition increases the release of TNF-alpha and TNFRs from human endothelial cells and decreases their cellular and cell surface expression. This phenomenon involves the transient activation of mitogen-activated protein kinase p42/p44 that triggers the dispersion of TNF-alpha and TNFRs from their intracellular Golgi-complex-associated pool towards the plasma membrane. This results in their enhanced cleavage by TNF-alpha converting enzyme (TACE) because it is reduced by synthetic metalloprotease inhibitors, recombinant TIMP-3 and by a dominant negative form of TACE. In the presence of TACE inhibitor, proteasome inhibition increases the cell surface expression of TNFRs and enhances the sensitivity of these cells to the proapoptotic effect of recombinant TNF-alpha. In conclusion, our data provide evidence that proteasome inhibitors increase TACE-dependent TNFR-shedding in endothelial cells, supporting the use of these molecules in inflammatory disorders. In association with TACE inhibitor, proteasome inhibitors increase the amount of TNFRs at the cell surface and enhance the sensitivity to the proapoptotic effect of TNF-alpha, which might be of interest in the antitumor therapy.
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PMID:Proteasome inhibition activates the transport and the ectodomain shedding of TNF-alpha receptors in human endothelial cells. 1573 Oct 11

A previous exposure to a non-harmful ischemic insult (preconditioning) protects the brain against subsequent harmful ischemia (ischemic tolerance). In contrast to delayed gene-mediated ischemic tolerance, little is known about the molecular mechanisms that regulate rapid ischemic tolerance, which occurs within 1 h following preconditioning. Here we have investigated the degradation of the pro-apoptotic Bcl-2 family member Bim as a mechanism of rapid ischemic tolerance. Bim protein levels were reduced 1 h following preconditioning and occurred concurrent with an increase in Bim ubiquitination. Ubiquitinated proteins are degraded by the proteasome, and inhibition of the proteasome with MG132 (a proteasome inhibitor) prevented Bim degradation and blocked rapid ischemic tolerance. Inhibition of p42/p44 mitogen-activated protein kinase activation by U0126 reduced Bim ubiquitination and Bim degradation and blocked rapid ischemic tolerance. Finally, inhibition of Bim expression using antisense oligonucleotides also reduced cell death following ischemic challenge. Our results suggest that following preconditioning ischemia, Bim is rapidly degraded by the ubiquitin-proteasome system, resulting in rapid ischemic tolerance. This suggests that the rapid degradation of cell death-promoting proteins by the ubiquitin-proteasome pathway may represent a novel therapeutic strategy to reduce cell damage following neuropathological insults, e.g. stroke.
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PMID:Rapid degradation of Bim by the ubiquitin-proteasome pathway mediates short-term ischemic tolerance in cultured neurons. 1643 16

D-type cyclins are direct targets of extracellular signals and critical regulators of G(1) progression. Our previous data demonstrated that IGF-I and FGF-2 synergize to enhance cyclin D1 expression, cyclin E/cdk2 complex activation, and S-phase entry in OP cells. Here, we provide a mechanistic explanation for how two growth factor signaling pathways converge on a major cell cycle regulator. IGF-I and FGF-2 differentially activate signaling pathways to coordinately promote cyclin D1 expression. We show that the p44/p42 MAPK signaling pathway is essential for FGF-2 induction of cyclin D1 mRNA. In contrast, blocking the PI3-Kinase pathway results in loss of IGF-I/FGF-2 synergistic induction of cyclin D1 protein levels. Moreover, the presence of IGF-I significantly enhances nuclear localization of cyclin D1, which also requires PI3K signaling. GSK-3beta, a downstream target of the PI3K/Akt pathway, is phosphorylated in the presence of IGF-I in OPs. Consistent with a known role for GSK-3beta in cyclin D1 degradation, we show that proteasome inhibition in OPs exposed to FGF-2 increased cyclin D1 levels, equivalent to levels seen in IGF-I/FGF-2 treated cells. Thus, we provide a model for cyclin D1 coordinate regulation where FGF-2 stimulation of the MAPK pathway promotes cyclin D1 mRNA expression while IGF-I activation of the PI3K pathway inhibits proteasome degradation of cyclin D1 and enhances nuclear localization of cyclin D1.
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PMID:Synergistic induction of cyclin D1 in oligodendrocyte progenitor cells by IGF-I and FGF-2 requires differential stimulation of multiple signaling pathways. 1750 24

The transcription factor STAT1 has roles in development, homeostasis, cellular differentiation, and apoptosis and has been postulated to function as a tumor suppressor. STAT1 is activated by tyrosine or serine phosphorylation in response to specific cytokines or following a variety of stress-induced stimuli. STAT1 activity is carefully regulated to prevent sustained STAT1-mediated transcription, although the molecular mechanisms involved in the modulation of STAT1 stability are poorly understood. Here we show that activated STAT1 is degraded at the proteasome by a mechanism involving the F-box E3 ligase, SCF(betaTRCP). Active p42/p44 MAPK-ERK phosphorylates STAT1 on serine 727 and targets it for proteasomal degradation. SCF(betaTRCP) binds wild-type STAT1 but not the nonphosphorylatable mutant STAT1(S727A). Moreover, silencing betaTRCP expression or pharmacological inhibition of ERK activity stabilized STAT1 expression. These data suggest that constitutively active ERK may inappropriately degrade STAT1, with loss of its pro-apoptotic and tumor suppressor functions.
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PMID:ERK and the F-box protein betaTRCP target STAT1 for degradation. 2960 81

In this study we examined whether established signal transduction cascades, p44/42 mitogen-activated protein kinase (ERK1/2) and Jun N-terminal kinases (JNK) pathways, are altered in N2a neural cells in response to proteasome inhibition. Additionally, we sought to elucidate the relative contribution of these signal transduction pathways to the multiple downstream effects of proteasome inhibition. Our data indicate that ERK1/2 and JNK are activated in response to proteasome inhibition. Washout of proteasome inhibitor (MG132) results in an enhancement of ERK1/2 activation and amelioration of JNK activation. Treatment with an established MAPK inhibitor resulted in an increase in proteasome inhibitor toxicity, and incubation with JNK inhibitor was observed to attenuate proteasome inhibitor toxicity significantly. Subsequent studies demonstrated that inhibition of ERK1/2 and JNK activity does not alter the gross increase in ubiquitinated protein following proteasome inhibitor administration. Similarly, ERK1/2 and JNK activity do not appear to play a role in the disruption of polysomes following proteasome inhibitor administration in neural cells. Together these data indicate that ERK1/2 and JNK activation may play differential roles in modulating neurochemical disturbances and neurotoxicity induced by proteasome inhibition.
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PMID:Proteasome inhibition modulates kinase activation in neural cells: relevance to ubiquitination, ribosomes, and survival. 1956 57


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