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)

gamma-Aminobutyric acid type A receptors (GABA(A)Rs) mediate fast synaptic inhibition in brain and spinal cord. They are ligand-gated ion channels composed of numerous distinct subunit combinations. For efficient synaptic transmission, GABA(A)Rs need to be localized to and anchored at postsynaptic sites in precise apposition to presynaptic nerve terminals that release the neurotransmitter GABA. Neurons therefore require distinct mechanisms to regulate intracellular vesicular protein traffic, plasma membrane insertion, synaptic clustering and turnover of GABA(A)Rs. The GABA(A) receptor-associated protein GABARAP interacts with the gamma2 subunit of GABA(A)Rs and displays high homology to proteins involved in membrane fusion underlying Golgi transport and autophagic processes. The binding of GABARAP with NSF, microtubules and gephyrin together with its localization at intracellular membranes suggests a role in GABA(A)R targeting and/or degradation. Growth factor tyrosine kinase receptor activation is involved in the control of GABA(A)R levels at the plasma membrane. In particular insulin recruits GABA(A)Rs to the cell surface. Furthermore, the regulation of GABA(A)R surface half-life can also be the consequence of negative modulation at the proteasome level. Plic-1, a ubiquitin-like protein binds to both the proteasome and GABA(A)Rs and the Plic1-GABA(A)R interaction is important for the maintenance of GABA-activated current amplitudes. At synaptic sites, GABA(A)Rs are clustered via gephyrin-dependent and gephyrin-independent mechanisms and may subsequently become internalized via clathrin-mediated endocytosis underlying receptor recycling or degradation processes. This article discusses these recent data in the field of GABA(A)R dynamics.
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PMID:Dynamic regulation of GABA(A) receptors at synaptic sites. 1208 9

Insulin-like growth factor binding protein (IGFBP)-3, a p53-response gene, can induce apoptosis in an IGF-independent manner. Here we demonstrate that IGFBP-3 mediates p53-induced apoptosis during serum starvation using two foil neoplastic cell models: one which introduces p53 activity and one which eliminates it. We created a doxycycline-inducible p53 model from the p53-negative PC-3 prostate cancer cell line. Doxycycline treatment increased both p53 and IGFBP-3 levels. It also augmented apoptosis, but not during insulin-like growth factor-I co-treatment. In a second model, lung carcinoma H460 cells expressing fully functional p53 were stably transfected with E6, which targets p53 for degradation. H460-E6 cells contained less p53 and IGFBP-3 than control neo-transfected cells, and proteasome blockade restored both. In serum deprivation, H460-E6 cells had enhanced growth and less apoptosis than did H460-neo cells. Reductions in H460-neo apoptosis, comparable in magnitude to H460-E6, were achieved by adding anti-IGFBP-3-antibody or IGFBP-3 antisense oligomers, but not non-specific immunoglobulin or IGFBP-3 sense oligomers. In summary, turning p53 in two foil neoplastic cell models induced IGFBP-3 expression and increased apoptosis during serum starvation, an effect inhibited by insulin-like growth factor-I treatment and specific IGFBP-3 blockade. This is the first demonstration of inhibition of p53 action by antagonizing IGFBP-3.
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PMID:IGFBP-3 mediates p53-induced apoptosis during serum starvation. 1211 29

Insulin rapidly stimulates the tyrosine kinase activity of its receptor, resulting in the phosphorylation of insulin receptor substrates (IRS), which in turn associates and activates PI 3-kinase, leading to an increase in glucose uptake. Phosphorylation of IRS proteins and activation of downstream kinases by insulin are transient and the mechanisms for the subsequent downregulation of their activity are largely unknown. We report here that the insulin-induced IRS-1 tyrosine phosphorylation and PI 3-kinase association to IRS-1 were strongly sustained by the proteasome inhibitors, MG132 and lactacystin. In contrast, no effect was detected on the insulin receptor and IRS-2 tyrosine phosphorylation. Interestingly, lactacystin also preserved PKB activation and insulin-induced glucose uptake. In contrast, calpeptin, a calpain inhibitor, was ineffective. Tyrosine phosphatase assays were also performed, showing that lactacystin was not functioning directly as a tyrosine phosphatase inhibitor "in vitro." In conclusion, proteasome inhibitors can regulate the tyrosine phosphorylation of IRS-1 and the downstream insulin signaling pathway, leading to glucose transport.
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PMID:Proteasome inhibitors regulate tyrosine phosphorylation of IRS-1 and insulin signaling in adipocytes. 1220 9

When isolated mouse fat pads were incubated with insulin or sodium orthovanadate (vanadate) for up to 4h, the intracellular leptin content was increased by insulin, while it was decreased by vanadate. Bupranolol, a beta3-adrenergic receptor antagonist, prevented both effects of vanadate, i.e., the decrease in intracellular leptin and increase in cellular cAMP content, while BRL 37344, a beta3-adrenergic receptor antagonist mimicked the action of vanadate. H-89 prevented the vanadate-induced decrease in intracellular leptin, suggesting the involvement of a cAMP-dependent protein kinase (PKA). No detectable difference in the incorporation of [3H]leucine into leptin was observed between incubations of the fat pads with and without vanadate, suggesting that the action of vanadate is independent of decreasing synthesis. Similar concentrations of MG-132, a membrane-permeable proteasome inhibitor, prevented the vanadate-induced decrease in both intracellular leptin content and leptin secretion, suggesting the involvement of the proteasome in the vanadate action. The proteasome fraction separated from the vanadate-treated fat pads increased the degradation of exogenous [125I]leptin in the presence of an ATP-regenerating system together with an ubiqutination system. The endopeptidase activity against Cbz-Leu-Leu-Glu-beta-naphthylamine also was increased by the proteasome fraction. MG-132 prevented both increased effects. The 8-Br-cAMP-treated proteasome fraction increased the degradation of the exogenous leptin. H-89 prevented the effect of 8-Br-cAMP. These results indicate that vanadate decreases the intracellular leptin content by increased degradation via a cAMP/PKA-dependent process involving proteasome activation.
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PMID:Orthovanadate decreases the leptin content in isolated mouse fat pads via proteasome activation. 1236 13

The catabolic response to sepsis, severe injury, and burn is characterized by whole-body protein loss, mainly reflecting increased breakdown of muscle proteins, in particular myofibrillar proteins. Glucocorticoids and various proinflammatory cytokines are important regulators of muscle proteolysis in stressed patients. There is evidence that breakdown of proteins by the ubiquitin-proteasome pathway plays an important role in muscle cachexia, although other mechanisms may participate, such as calcium- and calpain-dependent release of myofilaments from the sarcomere. Three types of treatments have been used to reduce or prevent the catabolic response to injury and sepsis: 1). nutritional, 2). hormonal, and 3). pharmacologic. With regard to nutrition support, it is generally believed that enteral feeding is superior to parenteral feeding and that early feeding is better than late feeding. Although "immune-enhancing" enteral nutrition has been shown in several recent studies to improve outcome in critically ill patients, the specific effects of these treatments on the catabolic response in muscle are not known. In addition to nutrition support, various hormones, including insulin, growth hormone, and insulin-like growth factor-1, may blunt the catabolic response in patients with stress. Experimental studies have indicated that other treatments may become available in the future, including cytokine antibodies, calcium antagonists, and induction of heat shock response. Methods to prevent or reduce the catabolic response to stress are important considering the significant clinical consequences of muscle cachexia.
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PMID:Catabolic response to stress and potential benefits of nutrition support. 1243 20

p21(WAF1/CIP1) Contributes to positive and negative growth control on multiple levels. We previously mapped phosphorylation sites within the C-terminal domain of p21 that regulate proliferating cell nuclear antigen binding. In the current study, a kinase has been fractionated from mammalian cells that stoichiometrically phosphorylates p21 at the Ser146 site, and the enzyme has been identified as an insulin-responsive atypical protein kinase C (aPKC). Expression of PKCzeta or activation of the endogenous kinase by 3-phosphoinositide dependent protein kinase-1 (PDK1) decreased the half-life of p21. Conversely, dnPKCzeta or dnPDK1 increased p21 protein half-life, and a PDK1-dependent increase in the rate of p21 degradation was mediated by aPKC. Insulin stimulation gave a biphasic response with a rapid transient decrease in p21 protein levels during the initial signalling phase that was dependent on phosphatidylinositol 3- kinase, PKC and proteasome activity. Thus, aPKC provides a physiological signal for the degradation of p21. The rapid degradation of p21 protein during the signalling phase of insulin stimulation identifies a novel link between energy metabolism and a key modulator of cell cycle progression.
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PMID:PDK1-dependent activation of atypical PKC leads to degradation of the p21 tumour modifier protein. 1248 98

Okadaic acid (OA) decreased the leptin content in isolated mouse fat pads in a time and dose-dependent manner. MG-132, a membrane-permeable proteasome inhibitor, prevented the decrease by OA, suggesting the involvement of proteasome in the OA action. No significant decrease in the incorporation of [(3)H]leucine into leptin was observed with a 4-h incubation, although the amino acid incorporation was stimulated by insulin and decreased by cycloheximide. These results suggest that the OA action is independent of the decrease in protein synthesis. The proteasome fraction, which had been separated from the fat pads pretreated with OA, enhanced the proteolytic degradation of exogenous [(125)I]leptin in the presence of an ATP-regenerating system together with an ubiquitination system. No enhancement of hydrolytic activity against Suc-Leu-Leu-Val-Tyr-AMC was detected in the OA-treated proteasome fraction, suggesting that the activation of proteasome is not involved in the OA action. The OA-treated proteasome fraction had decreased phosphatase activity against p-nitrophenyl phosphate, suggesting that OA entering the cells may exert its action by preventing dephosphorylation of key molecules. OA may reduce the intracellular leptin content through the increased ubiquitination and proteolytic turnover of leptin by the proteasome, based on the decreased phosphatase activity.
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PMID:Okadaic acid decreases the leptin content in isolated mouse fat pads. 1252 Jan 67

Highly active antiretroviral therapy, which includes a combination of protease inhibitors, is highly successful in controlling human immunodeficiency virus (HIV) infection and reducing the morbidity and mortality of autoimmune deficiency syndrome (AIDS). However, the benefits of HIV protease inhibitors are compromised by numerous undesirable side effects. These include peripheral fat wasting and excessive central fat deposition (lipodystrophy), overt hyperlipidemia, and insulin resistance. The mechanism associated with protease inhibitor-induced metabolic abnormalities is multifactorial. One major effect of the protease inhibitor is its suppression of the breakdown of the nuclear form of sterol regulatory element binding proteins (nSREBP) in the liver and adipose tissues. Hepatic accumulation of nSREBP results in increased fatty acid and cholesterol biosynthesis, whereas nSREBP accumulation in adipose tissue causes lipodystrophy, reduces leptin expression, and promotes insulin resistance. The HIV protease inhibitors also suppress proteasome-mediated breakdown of nascent apolipoprotein (apo) B, thus resulting in the overproduction and secretion of triglyceride-rich lipoproteins. Finally, protease inhibitor also suppresses the inhibition of the glucose transporter GLUT-4 activity in adipose and muscle. This latter effect also contributes directly to insulin resistance and diabetes. These adverse effects need to be alleviated for long-term use of protease inhibitor therapy in treatment of HIV infection.
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PMID:Effects of HIV protease inhibitor therapy on lipid metabolism. 1254 52

The central role of the ubiquitin-proteasome system in the loss of skeletal muscle protein in many wasting conditions has been well established. However, it is unclear what factors are responsible for the suppression of this system during periods of protein gain. Thus, the aim of these studies was to examine the short-term effects of insulin release and nutrients on skeletal muscle protein turnover in young rats starved for 48 h, and then infused intravenously with amino acids (AA), or fed an oral diet. Forty-eight hours of starvation (i.e. prolonged starvation in young rats) decreased muscle protein synthesis and increased proteasome-dependent proteolysis. Four-hour AA infusion and 4 h of refeeding increased plasma insulin release and AA concentrations, and stimulated muscle protein synthesis, but had no effect on either total or proteasome-dependent proteolysis, despite decreased plasma corticosterone concentrations. Both muscle proteasome-dependent proteolysis and the rate of ubiquitination of muscle proteins were not suppressed until 10 h of refeeding. The temporal response of these two measurements correlated with the normalised expression of the 14-kDa E2 (a critical enzyme in substrate ubiquitination in muscle) and the expression of the MSS1 subunit of the 19S regulatory complex of the 26S proteasome. In contrast, the starvation-induced increase in mRNA levels for 20S proteasome subunits was normalised by refeeding within 24 h in muscle, and 6 h in jejunum, respectively. In conclusion, unlike protein synthesis, skeletal muscle proteasome-dependent proteolysis is not acutely responsive in vivo to insulin, AA, and/or nutrient intake in refed starved rats. This suggests that distinct and perhaps independent mechanisms are responsible for the nutrient-dependent regulation of protein synthesis and ubiquitin-proteasome-dependent proteolysis following a prolonged period of catabolism. Furthermore, factors other than the expression of ubiquitin-proteasome pathway components appear to be responsible for the suppression of skeletal muscle proteasome-dependent proteolysis by nutrition.
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PMID:Ubiquitin-proteasome-dependent muscle proteolysis responds slowly to insulin release and refeeding in starved rats. 1256 2

Insulin action in target tissues involved precise regulation of gene expression. To define the set of insulin-regulated genes in human skeletal muscle, we analyzed the global changes in mRNA levels during a 3-h hyperinsulinemic euglycemic clamp in vastus lateralis muscle of six healthy subjects. Using 29,308 cDNA element microarrays, we found that the mRNA expression of 762 genes, including 353 expressed sequence tags, was significantly modified during insulin infusion. 478 were up-regulated and 284 down-regulated. Most of the genes with known function are novel targets of insulin. They are involved in the transcriptional and translational regulation (29%), intermediary and energy metabolisms (14%), intracellular signaling (12%), and cytoskeleton and vesicle traffic (9%). Other categories consisted of genes coding for receptors, carriers, and transporters (8%), components of the ubiquitin/proteasome pathways (7%) and elements of the immune response (5.5%). These results thus define a transcriptional signature of insulin action in human skeletal muscle. They will help to better define the mechanisms involved in the reduction of insulin effectiveness in pathologies such as type 2 diabetes mellitus, a disease characterized by defective regulation of gene expression in response to insulin.
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PMID:Microarray profiling of human skeletal muscle reveals that insulin regulates approximately 800 genes during a hyperinsulinemic clamp. 1262 Oct 37


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