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)

HIV protease inhibitors (HPIs), which have been used to treat HIV patients since the mid 1990s, have been shown to downregulate the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Because this pathway is frequently activated in human malignancies and associated with resistance to ionizing radiation, we investigated and confirmed that HPIs could radiosensitize cells. However, the mechanism underlying this downregulation was unclear, prompting the investigations in this report. In this paper we show that nelfinavir inhibits proteasome activity. Inhibition of the proteasome leads to endoplasmic reticulum-based stress with accumulation of misfolded proteins, which triggers the unfolded protein response (UPR). As part of the UPR, the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) is phosphorylated, resulting in a decrease in global protein synthesis and induction of the feedback regulator growth arrest and DNA damage-inducible protein (GADD34), which acts as a phosphatase in complex with protein phosphatase 1. This complex dephosphorylates eIF2alpha; however, our data also suggest that this phosphatase activity can dephosphorylate Akt. Furthermore, our data indicate that nelfinavir decreases Akt phosphorylation by triggering this response. These findings may have important implications in understanding how nelfinavir may increase radiation sensitivity and also result in downregulation of the PI3K/Akt pathway.
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PMID:The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. 1746 Jul 71

The roles of individual eukaryotic translation initiation factor 3 (eIF3) subunits are largely unclear, although some are essential, while others are thought to have regulatory roles. The 'e' subunit, also known as Int-6/Int6, is a candidate for a regulatory subunit as it is not essential for translation initiation in yeasts. eIF3e associates with the COP9 signalosome, and localizes to the nucleus in certain tissues. To further elucidate the roles of eIF3e, we have taken a genetic approach using Arabidopsis as a model system. Overexpression of eIF3e results in defects similar to mutations in the COP9 signalosome. eIF3e protein, but not transcript, over accumulates in csn mutants, and eIF3e is degraded in a proteasome-dependent fashion. In vitro and in vivo assays suggest that excess eIF3e inhibits translation. We conclude that the COP9 signalosome maintains a precise regulation of eIF3e levels, which is necessary for normal development in Arabidopsis.
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PMID:Arabidopsis eIF3e is regulated by the COP9 signalosome and has an impact on development and protein translation. 1806 29

Efficiency of nutrient utilization is high in neonates with normal birth weights but is reduced in those with intrauterine growth restriction (IUGR). However, the underlying mechanisms are largely unknown. This study was conducted with the piglet model and proteomics technology to test the hypothesis that IUGR affects expression of key proteins that regulate growth and development of the small intestine, liver, and muscle, the major organs involved in the digestion, absorption, and metabolism of dietary nutrients. Jejunum, liver, and gastrocnemius muscle were obtained from IUGR and normal birth-weight piglets at birth for analysis of proteomes using the 2-dimensional-PAGE MS technology. The results indicate that IUGR decreased the levels of proteins that regulate immune function (immunoglobulins and annexin A1), oxidative defense (peroxiredoxin 1, transferrin, and zeta-crystallin), intermediary metabolism (creatine kinase, alcohol dehydrogenase, L-lactate dehydrogenase, prostaglandin F synthase, apolipoprotein AI, catecho O-methyltransferase, and phosphoglycerate kinase 1), protein synthesis (eukaryotic translation initiation factor-3), and tissue growth (beta-actin, desmin, and keratin 10) in a tissue-specific manner. In addition, IUGR increased the levels of proteins that are involved in proteolysis (proteasome alpha-5 and alpha-1 subunits), response to oxidative stress (scavenger-receptor protein and alpha-1 acid glycoprotein), and ATP hydrolysis (F1-ATPase). These novel findings suggest that cellular signaling defects, redox imbalance, reduced protein synthesis, and enhanced proteolysis may be the major mechanisms responsible for abnormal absorption and metabolism of nutrients, as well as reduced growth and impaired development of the small intestine, liver, and muscle in IUGR neonates.
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PMID:Intrauterine growth restriction affects the proteomes of the small intestine, liver, and skeletal muscle in newborn pigs. 1815 5

Recent evidence indicates that the protein synthesis inhibitor cycloheximide triggers selective macrophage death in rabbit atheroma-like lesions without affecting smooth muscle cells (SMCs) or the endothelium, thereby favoring a stable plaque phenotype. In this study, we report that puromycin, a protein synthesis inhibitor with a different mode of action but with similar ability to inhibit de novo protein synthesis, did not reveal plaque-stabilizing effects. The macrophage and the SMC content readily decreased in puromycin-treated atheroma-like lesions in rabbit carotid arteries. Moreover, puromycin induced apoptosis in macrophages and SMCs in vitro. Puromycin-treated SMCs showed signs of endoplasmic reticulum (ER) stress, as demonstrated by CCAAT/enhancer-binding protein homologous protein (CHOP) protein expression, splicing of X-box-binding protein 1 mRNA, and phosphorylation of eukaryotic translation initiation factor 2alpha. The ER stress inducer thapsigargin up-regulated CHOP protein expression in SMCs without affecting their viability, indicating that ER stress not necessarily results in cell death. Puromycin, but not thapsigargin, activated the ER stress-related caspase-12. Treatment of SMCs with a combination of cycloheximide and puromycin inhibited ER stress and partially improved SMC viability. In addition, puromycin, but not cycloheximide or thapsigargin, induced intracellular accumulation of polyubiquitinated proteins in SMCs, whereas the proteasome function was not affected. Taken together, puromycin, in contrast to cycloheximide, induces SMC apoptosis, thereby favoring an unstable plaque phenotype. SMC death upon puromycin treatment could only be partially prevented by cycloheximide, which completely blocked ER stress. However, other or additional mechanisms, such as increased polyubiquitination of proteins, might be involved in puromycin-induced SMC death.
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PMID:Differential effect of the protein synthesis inhibitors puromycin and cycloheximide on vascular smooth muscle cell viability. 1832 49

In response to cancer, AIDS, sepsis and other systemic diseases inducing muscle atrophy, the E3 ubiquitin ligase Atrogin1/MAFbx (MAFbx) is dramatically upregulated and this response is necessary for rapid atrophy. However, the precise function of MAFbx in muscle wasting has been questioned. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome. Ectopic expression of MAFbx in myotubes induces atrophy and degradation of eIF3-f. Conversely, blockade of MAFbx expression by small hairpin RNA interference prevents eIF3-f degradation in myotubes undergoing atrophy. Furthermore, genetic activation of eIF3-f is sufficient to cause hypertrophy and to block atrophy in myotubes, whereas genetic blockade of eIF3-f expression induces atrophy in myotubes. Finally, eIF3-f induces increasing expression of muscle structural proteins and hypertrophy in both myotubes and mouse skeletal muscle. We conclude that eIF3-f is a key target that accounts for MAFbx function during muscle atrophy and has a major role in skeletal muscle hypertrophy. Thus, eIF3-f seems to be an attractive therapeutic target.
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PMID:The initiation factor eIF3-f is a major target for atrogin1/MAFbx function in skeletal muscle atrophy. 1835 98

Regulating gene expression is an effective way for cells to deal with various stresses. The outcome of this regulation differs with the type of stress, and can promote either cell survival or cell death depending on the severity of the injury incurred. Gene expression can be controlled at several steps, including transcription, translation and degradation. An extensively studied protein involved in translational control is the eukaryotic translation initiation factor 2 (eIF2). When eIF2 becomes phosphorylated on a specific serine residue located within the alpha (alpha) subunit, global protein synthesis is halted. This phosphorylation occurs following periods of environmental stress, and plays a significant role in the cellular response to these events. The eIF2alpha kinase family consists of four members, which are each activated in response to different stimuli. Our group has recently discovered that two members of this family, the protein kinase activated by double-stranded RNA (PKR) and the PKR-like endoplasmic reticulum (ER) kinase (PERK) can also regulate the expression of specific proteins by promoting their degradation by the 26S proteasome. Specifically, we demonstrated that degradation of the cell cycle regulator cyclin D1, and the tumour suppressor p53 was promoted by PERK and PKR during periods of ER stress. This novel function may allow the eIF2alpha kinases to affect a larger number of cellular processes than previously believed.
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PMID:PERK and PKR: old kinases learn new tricks. 1841 49

Int6 is a proto-oncogene implicated in various types of cancer, but the mechanisms underlying its activity are not clear. Int6 encodes a subunit of the eukaryotic translation initiation factor 3, and interacts with two related complexes, the proteasome, whose activity is regulated by Int6 in S. pombe, and the COP9 signalosome. The COP9 signalosome regulates the activity of Cullin-Ring Ubiquitin Ligases via deneddylation of their cullin subunit. We report here the generation and analysis of two Drosophila mutants in Int6. The mutants are lethal demonstrating that Int6 is an essential gene. The mutant larvae accumulate high levels of non-neddylated Cul1, suggesting that Int6 is a positive regulator of cullin neddylation. Overexpression in Int6 in cell culture leads to accumulation of neddylated cullins, further supporting a positive role for Int6 in regulating neddylation. Thus Int6 and the COP9 signalosome play opposing roles in regulation of cullin neddylation.
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PMID:The proto-oncogene Int6 is essential for neddylation of Cul1 and Cul3 in Drosophila. 1849 98

Benzo[a]pyrene (B[a]P) is an ubiquitous environmental carcinogen produced during incomplete combustion of organic substances. Anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), is the most carcinogenic form of the ultimate metabolites of B[a]P. The goal of this study was to investigate the responses of human amniotic epithelial FL cells to BPDE at different time intervals after exposure and to find potential biomarkers involved in these responses. Cells were treated with 0.05 microM BPDE for 2 h and incubated for another 3, 12, and 24 h to obtain protein extracts which were resolved by 2-DE and visualized by silver staining. Sixty-four spots were up-regulated while 66 were down-regulated following BPDE exposure. These altered spots were excised from the gels and analyzed by MALDI-TOF-MS. The analysis led to the identification of 84 proteins affected by BPDE. These proteins were involved in regulation of transcription, cell cycle, apoptosis, transport, signal transduction, metabolism,and so forth. Among them, subunits of eukaryotic translation initiation factor 3 (EIF3) including EIF3S2, EIF3S3, EIF3S12, and EIF5A, component proteins of ubiquitin-proteasome system (ubiquitin carboxyl-terminal esterase L3, proteasome beta 4 subunit, and proteasome beta 3 subunit) and 14-3-3 proteins (14-3-3 zeta and epsilon) have not been previously associated with a response to BPDE exposure. All these results aid our understanding of the mechanism of BPDE induced cell defensive responses and hazardous effects as well as providing the possibility of the establishment of potential biomarkers.
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PMID:Translation initiation proteins, ubiquitin-proteasome system related proteins, and 14-3-3 proteins as response proteins in FL cells exposed to anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide. 1875 15

We recently presented evidence that the subunit eIF3-f of the eukaryotic initiation translation factor eIF3 that interacts with the E3-ligase Atrogin-1/muscle atrophy F-box (MAFbx) for polyubiquitination and proteasome-mediated degradation is a key target that accounts for MAFbx function during muscle atrophy. To understand this process, deletion analysis was used to identify the region of eIF3-f that is required for its proteolysis. Here, we report that the highly conserved C-terminal domain of eIF3-f is implicated for MAFbx-directed polyubiquitination and proteasomal degradation. Site-directed mutagenesis of eIF3-f revealed that the six lysine residues within this domain are required for full polyubiquitination and degradation by the proteasome. In addition, mutation of these six lysines (mutant K(5-10)R) displayed hypertrophic activity in cellulo and in vivo and was able to protect against starvation-induced muscle atrophy. Taken together, our data demonstrate that the C-terminal modifications, believed to be critical for proper eIF3-f regulation, are essential and contribute to a fine-tuning mechanism that plays an important role for eIF3-f function in skeletal muscle.
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PMID:MAFbx/Atrogin-1 controls the activity of the initiation factor eIF3-f in skeletal muscle atrophy by targeting multiple C-terminal lysines. 1907 96

Focal segmental glomerulosclerosis (FSGS) may be associated with glomerular epithelial cell (GEC; podocyte) apoptosis due to acquired injury or mutations in alpha-actinin-4. This study addresses how FSGS-associated mutant alpha-actinin-4 may induce GEC injury, focusing on endoplasmic reticulum (ER) stress and metabolism of mutant alpha-actinin-4 via the ubiquitin-proteasome system. In a model of experimental FSGS induced by expression of an alpha-actinin-4 K256E transgene in podocytes, we show induction of ER stress, including upregulation of ER chaperones (bip, grp94), phosphorylation of the eukaryotic translation initiation factor-2alpha subunit, and induction of the proapoptotic gene C/EBP homologous protein-10 (CHOP). To address mechanisms of ER stress, we studied signaling in cultured GEC and COS cells expressing alpha-actinin-4 K256E. Previously, we showed that expression of this alpha-actinin-4 mutant in GEC increased apoptosis. In the present study, we show that alpha-actinin-4 K256E upregulates grp94 and CHOP expression in COS cells and significantly exacerbates induction of bip and CHOP in GEC in the presence of tunicamycin. ER stress was associated with aggregation and ubiquitination of alpha-actinin-4 K256E and impairment of the ubiquitin-proteasome system. In addition, alpha-actinin-4 K256E exacerbated apoptosis in the context of mild proteasome inhibition. Thus alpha-actinin-4 K256E triggers several metabolic abnormalities, which may lead to GEC injury and glomerulosclerosis.
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PMID:Glomerular epithelial cell injury associated with mutant alpha-actinin-4. 1964 Sep 5


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