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)

Histone deacetylase inhibitors (HDACi) are a new class of anticancer agents that cause growth arrest, differentiation and/or apoptosis in many tumor cells. As acetylation regulates the activity of the anti-apoptotic transcription factor NF-kappaB, we investigated whether the proteasome inhibitor MG-132 would inhibit NF-kappaB activation and as a consequence potentiate HDACi-dependent apoptosis in breast cancer cells. We observed that the HDACi suberoylanilide hydroxamic acid (SAHA) or trichostatin A (TSA) induced cell death but also enhanced NF-kappaB-activity. This increase of NF-kappaB activity was strongly reduced by the addition of MG-132. Moreover, MG-132 potentiates the HDACi-induced cell death that was associated with caspase-3 activation, and PARP cleavage. Induction of the stress related kinases JNK and p38 and the up-regulation of p21 and p27 were also observed after co-treatment of cells with HDACi and MG-132. Disruption of the NF-kappaB pathway by BAY 11-7085 or IkappaB-SR mimicked the action of MG-132 in promoting HDACi-induced cell death. Thus, the combined treatment with HDACi and proteasome inhibitors potentiates apoptosis in breast cancer cells representing a novel strategy for breast cancer therapy.
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PMID:Inactivation of NF-kappaB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells. 1806 64

Argyrophilic grain disease (AGD) is a common sporadic neurodegenerative disease of old age characterized by the presence of argyrophilic grains (AGs)--dendritic-derived appendages as revealed with the Golgi method--together with pre-tangle neurons in the limbic system, which accounts for about 5% of all demented cases. AGs and pre-tangle neurons contain hyperphosphorylated 4R tau. This is associated with a typical 64 kDa and 68 kDa pattern, but also accompanied by tau truncated forms of low molecular mass, probably resulting from thrombin-mediated proteolysis. Hyperphosphorylated tau also accumulates in oligodendroglial-coiled bodies and in limbic astrocytes. Ballooning neurons in the amygdala are non-specific accompanying abnormalities. A new proposal for AG distribution considers four stages. Clinical symptoms largely depend on the extension of AGs together with the very common associated tauopathies, mainly Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and synucleinopathies. Pathogenesis of AG and related lesions herein proposed includes oxidative stress that is followed by increased expression of oxidative response markers, and activation of stress kinases (stress activated protein kinase and p38). These kinases together with glycogen synthase kinase 3beta co-localize with hyperphosphorylated tau deposits in neurons and glial cells, thus indicating a link between oxidative stress and tau phosphorylation in AGD. Hyperphosphorylated tau, in turn, co-localizes with p62/sequestosome 1 and ubiquitin, thus pointing to activation of protein aggregation and protein degradation pathways, respectively. Finally, AGs and tangles co-localize with mutant ubiquitin (UBB(+1)) resulting from molecular misreading of mRNA, thus supporting proteasome function impairment and, therefore, impelling accumulation of hyperphosphorylated tau in AGs and tangles. The sequestration of active kinases in AGs and tangles is an additional local cause of tau hyperphosphorylation.
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PMID:Argyrophilic grain disease. 1823 98

There is evidence that NO can regulate CO production, however less is known about CO regulation of NO synthesis. Our studies were undertaken to define how CO regulates iNOS in cultured hepatocytes. CO (250ppm) exposure resulted in a significant decrease in iNOS protein, nitrite production, level of active iNOS dimer and cytosolic iNOS activity in cells stimulated with cytokines (IL-1beta) or transfected with the human iNOS gene. However, IL-1beta-stimulated iNOS mRNA expression was unaffected by CO. These effects of CO on iNOS protein levels were inhibited when CO was scavenged using hemoglobin. HO-1 induction with an adenoviral vector carrying HO-1 showed a decrease in total iNOS protein, nitrite production, and iNOS dimer level from cells stimulated by IL-1beta. iNOS protein level was significantly higher in lung endothelial cells isolated from HO-1 knockout mice compared to wild type cultures stimulated with cytokines mixture. CO was found to increase p38 phosphorylation and p38 inhibition using SB203580 increased iNOS protein levels in response to IL-1beta. Interestingly, proteasome inhibitors (MG132 and Lactacystin) and an autophagy inhibitor (3-methyladenine) reversed CO influence iNOS levels. Our results imply that CO exposure decreases NO production by suppressing dimer formation and increasing iNOS degradation through a process involving p38 activation.
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PMID:Carbon monoxide decreases the level of iNOS protein and active dimer in IL-1beta-stimulated hepatocytes. 1831 11

We tested the hypothesis that treatment of rats with curcumin prevents sepsis-induced muscle protein degradation. In addition, we determined the influence of curcumin on different proteolytic pathways that are activated in septic muscle (i.e., ubiquitin-proteasome-, calpain-, and cathepsin L-dependent proteolysis) and examined the role of NF-kappaB and p38/MAP kinase inactivation in curcumin-induced inhibition of muscle protein breakdown. Rats were made septic by cecal ligation and puncture or were sham-operated. Groups of rats were treated with three intraperitoneal doses (600 mg/kg) of curcumin or corresponding volumes of solvent. Protein breakdown rates were measured as release of tyrosine from incubated extensor digitorum longus muscles. Treatment with curcumin prevented sepsis-induced increase in muscle protein breakdown. Surprisingly, the upregulated expression of the ubiquitin ligases atrogin-1 and MuRF1 was not influenced by curcumin. When muscles from septic rats were treated with curcumin in vitro, proteasome-, calpain-, and cathepsin L-dependent protein breakdown rates were reduced, and nuclear NF-kappaB/p65 expression and activity as well as levels of phosphorylated (activated) p38 were decreased. Results suggest that sepsis-induced muscle proteolysis can be blocked by curcumin and that this effect may, at least in part, be caused by inhibited NF-kappaB and p38 activities. The results also suggest that there is not an absolute correlation between changes in muscle protein breakdown rates and changes in atrogin-1 and MuRF1 expression during treatment of muscle wasting.
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PMID:The NF-kappaB inhibitor curcumin blocks sepsis-induced muscle proteolysis. 1838 75

The ubiquitin-proteasome and autophagy-lysosomal pathways are the two main routes of protein and organelle clearance in eukaryotic cells. The proteasome system is responsible for unfolded, short-lived proteins, which precludes the clearance of oligomeric and aggregated proteins, whereas macroautophagy, a process generally referred to as autophagy, mediates mainly the bulk degradation of long-lived cytoplasmic proteins, large protein complexes or organelles.(1) Recently, the autophagy-lysosomal pathway has been implicated in neurodegenerative disorders as an important pathway for the clearance of abnormally accumulated intracellular proteins, such as huntingtin, tau and mutant and modified alpha-synuclein.(1-6) Our recent study illustrated the induction of adaptive autophagy in response to mutant glial fibrillary acidic protein (GFAP) accumulation in astrocytes, in the brains of patients with Alexander disease (AxD), and in mutant GFAP knock-in mouse brains.(7) This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). The activation of p38 MAPK by GFAP accumulation is responsible for mTOR inactivation and the induction of autophagy. We also found that the accumulation of GFAP impairs proteasome activity.(8) In this commentary we discuss the potential compensatory relationship between an impaired proteasome and activated autophagy, and propose that the MLK-MAPK (mixed lineage kinase-mitogen-activated protein kinase) cascade is a regulator of this crosstalk.
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PMID:Adaptive autophagy in Alexander disease-affected astrocytes. 1841 43

Cadmium (Cd) is a ubiquitous environmental pollutant that has been associated with male reproductive toxicity in both humans and animal models. The underlying mechanism of this response, however, is still uncharacterized. To address this issue, we employed a recently developed and optimized three-dimensional primary Sertoli cell-gonocyte coculture system and examined the time- and dose-dependent effects of Cd on morphological alterations, cell viability, activation of stress signaling pathway proteins, and the disruption of the ubiquitin proteasome system (UPS). Our results demonstrated that Cd exposure lead to time- and dose-dependent morphological changes that are associated with the induction of apoptosis. In response to Cd, we also saw a disruption of the UPS as evaluated through the accumulation of high-molecular weight polyubiquitinated proteins (HMW-polyUb) as well as alterations in proteasome activity. Robust activation of cellular stress response, measured through the increased phosphorylation of stress-activated protein kinase/c-jun N-terminal kinase and p38, paralleled the accumulation of HMW-polyUb. In addition, p53, a key regulatory protein, was upregulated and underwent increased ubiquitination in response to Cd. To further characterize the role of the UPS in Cd cellular response, we compared the above changes with two classic proteasomal inhibitors, lactacystin, and MG132. The stress response and the accumulation of HWM-polyUb induced by Cd were consistent with the response seen with MG132 but not with lactacystin. In addition, Cd treatment resulted in a dose- and time-dependent effect on proteasome activity, but the overall Cd-induced proteasomal inhibition was unique as compared to MG132 and lactacystin. Taken together, our studies further characterize Cd-induced in vitro testicular toxicity and highlight the potential role of the UPS in this response.
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PMID:Cadmium-induced activation of stress signaling pathways, disruption of ubiquitin-dependent protein degradation and apoptosis in primary rat Sertoli cell-gonocyte cocultures. 1846 1

Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. Stress-induced overproduction of inflammatory cytokines, such as interleukin-8 (IL-8), is one of the early events of inflammation. The objective of this study was to elucidate mechanistic links between oxidative stress and overproduction of IL-8 in retinal pigment epithelial (RPE) cells. We found that exposure of RPE cells to H(2)O(2), paraquat, or A2E-mediated photooxidation resulted in increased expression and secretion of IL-8. All of these oxidative stressors also inactivated the proteasome in RPE cells. In contrast, tert-butylhydroperoxide (TBH), a lipophilic oxidant that did not stimulate IL-8 production, also did not inactivate the proteasome. Moreover, prolonged treatment of RPE cells with proteasome-specific inhibitors recapitulated the stimulation of IL-8 production. These data suggest that oxidative inactivation of the proteasome is a potential mechanistic link between oxidative stress and up-regulation of the proinflammatory IL-8. The downstream signaling pathways that govern the production of IL-8 include NF-kappaB and p38 MAPK. Proteasome inhibition both attenuated the activation and delayed the turnoff of NF-kappaB, resulting in biphasic effects on the production of IL-8. Prolonged proteasome inhibition (>2 h) resulted in activation of p38 MAPK via activation of MKK3/6 and increased the production of IL-8. Chemically inhibiting the p38 MAPK blocked the proteasome inhibition-induced up-regulation of IL-8. Together, these data indicate that oxidative inactivation of the proteasome and the related activation of the p38 MAPK pathway provide a potential link between oxidative stress and overproduction of proinflammatory cytokines, such as IL-8.
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PMID:Oxidative inactivation of the proteasome in retinal pigment epithelial cells. A potential link between oxidative stress and up-regulation of interleukin-8. 1850 48

Sodium 4-phenylbutyrate (4-PBA) has attracted a great deal of attention in cystic fibrosis (CF) pathology due to its capacity to traffic DeltaF508-cystic fibrosis transmembrane conductance regulator (CFTR) to the cell membrane and restore CFTR chloride function at the plasma membrane of CF lung cells in vitro and in vivo. Using two different DeltaF508-CFTR lung epithelial cell lines (CFBE41o- and IB3-1 cells, characterized with DeltaF508-homozygous and heterozygous genotype, respectively) in vitro, 4-PBA induced an increase of proinflammatory cytokine interleukin (IL)-8 production in a concentration-dependent manner. This 4-PBA-induced IL-8 production was associated with a strong reduction of proteasome and nuclear factor-kappaB transcriptional activities in the two DeltaF508-CFTR lung cells either in a resting state or after tumor necrosis factor-alpha stimulation. In contrast, a strong increase of activator protein-1 transcriptional activity was observed. The inhibition of extracellular signal-regulated protein kinase 1/2 (ERK1/2) by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (U0126) and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) and c-Jun-NH(2)-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) by anthra[1,9-cd] pyrazol-6 (2H)-one (SP600125), respectively, was associated with a reduction (2-3.5-fold) of IL-8 production in both DeltaF508-CFTR lung cell lines treated with 4-PBA. No significant change of IL-8 production was observed after an inhibition of p38 MAPK with 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl] phenol (SB202190). Therefore, we suggest that inhibition of both ERK1/2 and JNK signaling may be a means to strongly reduce 4-PBA-induced IL-8 production in combination with 4-PBA treatment to restore CFTR Cl(-) channel function in lung epithelial cells of patients with CF.
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PMID:Proinflammatory effect of sodium 4-phenylbutyrate in deltaF508-cystic fibrosis transmembrane conductance regulator lung epithelial cells: involvement of extracellular signal-regulated protein kinase 1/2 and c-Jun-NH2-terminal kinase signaling. 1857 3

Head and neck squamous cell carcinomas (HNSCC) exhibit constitutive activation of transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), which are modulated by the proteasome and promote resistance to cell death. HNSCC show variable sensitivity to the proteasome inhibitor bortezomib in vitro as well as in murine xenografts and patient tumors in vivo, and the mechanisms are not well understood. To address this question, the sensitivities of nine HNSCC cell lines to bortezomib were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and the potential relationship between the sensitivity and bortezomib effects on biological processes was examined in HNSCC lines of differential bortezomib sensitivity. The most sensitive cell line (UM-SCC-11B) underwent cell death at 10(-9) mol/L in vitro and tumor regression at a maximally tolerated dose of bortezomib in a murine xenograft model. The differential sensitivity between UM-SCC-11A and UM-SCC-11B cells corresponded to differences in the extent of suppression of proteasome activity, ubiquitinated protein degradation, and NF-kappaB and AP-1 activation. Lower concentrations of bortezomib transiently increased NF-kappaB and sustained AP-1 activation in UM-SCC-11A cells. AP-1 reporter activity and cell density of UM-SCC-11A were suppressed when bortezomib was combined with c-Jun NH(2)-terminal kinase and p38 kinase pathways inhibitors. Thus, the differential sensitivities to bortezomib corresponded to dissimilar effects on the proteasome, NF-kappaB and AP-1 activities. Inhibition of c-Jun NH(2)-terminal kinase and p38 pathways blocked AP-1 activity and enhanced the antitumor effects. These findings revealed molecular mechanisms of bortezomib sensitivity and resistance, which are under development as biomarkers for clinical trials in patients with HNSCC.
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PMID:Differential bortezomib sensitivity in head and neck cancer lines corresponds to proteasome, nuclear factor-kappaB and activator protein-1 related mechanisms. 1864 5

The conditional kinase DeltaMEKK3:ER allows activation of JNK, p38 and ERK1/2 without overt cellular stress or damage and has proved useful in understanding how these pathways regulate apoptosis and cell cycle progression. We have previously shown that activation of DeltaMEKK3:ER causes a sustained G(1) cell cycle arrest which requires p21(CIP1), with ERK1/2 and p38 cooperating to promote p21(CIP1) expression. In cells lacking p21(CIP1), DeltaMEKK3:ER causes only a transient delay in cell cycle re-entry. We now show that this delay in cell cycle re-entry is due to a reduction in cyclin D1 levels. Activation of DeltaMEKK3:ER promotes the proteasome-dependent turnover of cyclin D1; this requires phosphorylation of threonine 286 (T(286)) and expression of cyclin D1T(286)A rescues the delay in G(1)/S progression. DeltaMEKK3:ER-dependent phosphorylation of T(286) does not appear to be mediated by GSK3beta but requires activation of the ERK1/2 and p38 pathways. ERK1/2 can physically associate with cyclin D1 but activation of ERK1/2 alone is not sufficient for phosphorylation of T(286). Rather, cyclin D1 phosphorylation appears to require coincident activation of ERK1/2 and p38. Thus activation of DeltaMEKK3:ER promotes a sustained G(1) cell cycle arrest by a bipartite mechanism involving the rapid destruction of cyclin D1 and the slower more prolonged expression of p21(CIP1). This has parallels with the bipartite response to ionizing radiation and p53-independent mechanisms of G(1) cell cycle arrest in simple organisms such as yeast.
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PMID:ERK1/2 and p38 cooperate to delay progression through G1 by promoting cyclin D1 protein turnover. 1866 82


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