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)

Mounting evidence supports Harman's hypothesis that aging is caused by free radicals and oxidative stress. Although it is known that oxidant species are produced during metabolic reactions, it is largely unknown which factor(s), of physiological or pathophysiological significance, modulate their production in vivo. In this hypothesis paper, it is postulated that hyperinsulinemia may have such function and therefore promote aging, independently of elevations of glycemia. Hyperinsulinemia is secondary to impaired insulin stimulated glucose metabolism at the level of skeletal muscle (insulin resistance) and is seen in about one third of glucose tolerant humans following dietary carbohydrate intake. If other insulin-stimulated (or inhibited) pathways retain normal sensitivity to the hormone, hyperinsulinemia could, by its effects on antioxidative enzymes and on free radical generators, enhance oxidative stress. Other proaging effects of insulin involve the inhibition of proteasome and the stimulation of polyunsaturated fatty acid (PUFA) synthesis and of nitric oxide (NO). The hypothesis that hyperinsulinemia accelerates aging also offers a metabolic explanation for the life-prolonging effect of calorie restriction and of mutations decreasing the overall activity of insulin-like receptors in the nematode Caenorhabditis elegans.
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PMID:Hyperinsulinemia: the missing link among oxidative stress and age-related diseases? 1111 20

Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The non-obese diabetic (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse lymphocytes that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect both prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor kappaB (NF-kappaB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor alpha (TNF-alpha). The proteasome dysfunction is both tissue and developmental stage specific and likely contributes to disease pathogenesis and tissue targeting.
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PMID:A role for NF-kappaB and the proteasome in autoimmunity. 1114 Apr 62

Multiple lines of evidence suggest that the ubiquitin-proteasome-dependent proteolytic pathway is the major degradative process responsible for the loss of muscle proteins seen in various pathological states and following food deprivation. The first step in this pathway is the covalent attachment of polyubiquitin chains to protein substrates. This signal targets the substrates for subsequent hydrolysis into peptides by the 26S proteasome. Several metabolic abnormalities (reduced food intake, impaired mobility, and perturbations in the production or responsiveness of catabolic and anabolic hormones, cytokines and/or proteolysis inducing factors) act in concert to contribute to muscle wasting in disease states. We cite recent evidence that insulin, glucocorticoids, thyroid hormones, and nutrients regulate the rates of ubiquitinylation of protein substrates and of proteasome-dependent proteolysis in skeletal muscle.
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PMID:Nutritional and hormonal control of protein breakdown. 1115 73

Loss of muscle mass is a risk factor for mortality in chronic renal failure (CRF). Catabolic signals (eg, acidosis, glucocorticoids, insulin resistance) present in CRF stimulate the ubiquitin-proteasome proteolytic pathway in muscle but the activation mechanism(s) have been elusive. We have identified distinct mechanisms that may work in concert to increase the degradation of muscle proteins. Glucocorticoids increase the transcription of genes encoding components of the ubiquitin-proteasome pathway, thereby increasing the proteolytic capacity of muscle cells. Another signal could be a decreased response to insulin because acute diabetes is a potent stimulus for protein degradation by the ubiquitin-proteasome pathway and CRF impairs insulin signaling in muscle. Together, these responses increase the breakdown of muscle, contributing to protein malnutrition in CRF.
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PMID:Molecular mechanisms regulating protein turnover in muscle. 1115 74

PA28 or 11S REG is a proteasome activator composed of homologous alpha- and beta-subunits and predominantly found in the cytosol. A homologous protein originally known as the Ki antigen but now called PA28gamma or REGgamma is predominantly localized in the nucleus. To further characterize the biochemical properties of PA28gamma, we expressed and purified homogenous recombinant human protein with and without an N-terminal 6-His extension. PA28gamma is a heptamer based on the molecular masses of the native and monomeric proteins. The heptameric 6-His fusion protein can dimerize. Recombinant PA28y stimulates the proteasome-mediated hydrolysis of synthetic substrates containing hydrophobic, basic, and acidic amino acids in the P1 position. Stimulation is dependent on substrate size. PA28y only minimally stimulates degradation of the oxidized B chain of insulin. PA28gamma may facilitate the later stages of protein metabolism in the nucleus and/or have a more specialized role in controlling the levels of biologically active peptides in the nucleus.
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PMID:Properties of the nuclear proteasome activator PA28gamma (REGgamma). 1118 62

Widespread utilization of highly active antiretroviral therapy (HAART) for HIV-infection, primarily protease inhibitors in combination with nucleoside analogue reverse transcriptase inhibitors, has recently led to a sustained reduction in the morbidity and mortality of this disease. However, administration of HAART is frequently associated with the development of lipid disorders. The severity and prevalence of dyslipidaemia vary, depending on the type of HAART, nutritional status, HIV disease stage, and concomitant presence of lipodystrophy and insulin resistance (two additional adverse effects of HAART). The mechanism that is responsible for HAART-associated dyslipidaemia remains incompletely understood. Recent data indicate that this effect may be, at least in part, accounted for by protease inhibitor-mediated inhibition of the proteasome activity and accumulation of the active portion of sterol regulatory element-binding protein-1c in liver cells and adipocytes. Whether lipid disorders in HIV-infected patients receiving HAART translate into an increased cardiovascular risk, and the indications for lipid-lowering interventions in this population, remain to be established.
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PMID:Antiretroviral therapy-associated hyperlipidaemia in HIV disease. 1135 35

In muscle cells, protein degradation occurs by lysosomal and nonlysosomal mechanisms but the mechanism by which insulin inhibits protein degradation is not well understood. Using cultured L6 myotubes, the effect of insulin on muscle cell protein degradation was examined. Cells were labeled for 18 h with [3H]leucine or [3H]tyrosine and protein degradation measured by release of TCA-soluble radioactivity. Incubation with insulin for 0.5, 1, 2, or 3 h produced 0, 6, 12, and 13% inhibition, respectively, at 10(-7) M. If the cells were incubated for 3 h prior to the addition of insulin to remove short-lived proteins, the effect of insulin was enhanced, producing 26% inhibition. Very long-lived protein degradation (cells labeled for 48 h, chased for 24 h before the addition of insulin) was only inhibited 17% by insulin. This was due to serum starvation during the chase since the addition of serum to the chase medium produced a subsequent inhibition of 38% by insulin. Thus insulin had a greater effect on the degradation of longer-lived proteins. Use of inhibitors suggested that insulin requires internalization and degradation to produce inhibition of protein degradation and acts through both the proteasome and lysosomes. There appears to be no interaction with the calpains.
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PMID:Characterization of the inhibition of protein degradation by insulin in L6 cells. 1136 17

The effect of heat shock protein 90 (Hsp-90) and several other proteins on the catalytic activities of the 20 S proteasome (MPC) was examined. The chymotrypsin-like (ChT-L) and peptidylglutamyl-peptide hydrolyzing (PGPH) activities of the pituitary MPC were inhibited by Hsp-90 with IC50 values of 8 and 28 nM, respectively. Bovine serum albumin and two other proteins tested inhibited the same activities with much higher IC50 values. The trypsin-like and branched-chain amino-acid-preferring activities were not affected by any of the proteins. None of the activities of the bovine spleen MPC, an enzyme form in which the X, Y, and Z subunits are virtually completely replaced by the LMP2, LMP7, and LMP10 subunits, was affected by either Hsp-90 or the other proteins tested. Hsp-90 inhibited the degradation of the oxidized B-chain of insulin by the pituitary MPC but not by its spleen counterpart. The PA28 activator (11 S regulator; REG) of the proteasome abolished the inhibitory effect of Hsp-90 and other proteins on the ChT-L and PGPH activities of the pituitary MPC. It is suggested that Hsp-90 induces conformational changes that affect the ChT-L and PGPH activities expressed by the X and Y subunits, respectively, but does not affect the activities expressed by LMP subunits.
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PMID:Heat shock protein-90 and the catalytic activities of the 20 S proteasome (multicatalytic proteinase complex). 1136 78

In NOD (nonobese diabetic) mice, a model of autoimmune diabetes, various immunomodulatory interventions prevent progression to diabetes. However, after hyperglycemia is established, such interventions rarely alter the course of disease or allow sustained engraftment of islet transplants. A proteasome defect in lymphoid cells of NOD mice impairs the presentation of self antigens and increases the susceptibility of these cells to TNF-alpha-induced apoptosis. Here, we examine the hypothesis that induction of TNF-alpha expression combined with reeducation of newly emerging T cells with self antigens can interrupt autoimmunity. Hyperglycemic NOD mice were treated with CFA to induce TNF-alpha expression and were exposed to functional complexes of MHC class I molecules and antigenic peptides either by repeated injection of MHC class I matched splenocytes or by transplantation of islets from nonautoimmune donors. Hyperglycemia was controlled in animals injected with splenocytes by administration of insulin or, more effectively, by implantation of encapsulated islets. These interventions reversed the established beta cell-directed autoimmunity and restored endogenous pancreatic islet function to such an extent that normoglycemia was maintained in up to 75% of animals after discontinuation of treatment and removal of islet transplants. A therapy aimed at the selective elimination of autoreactive cells and the reeducation of T cells, when combined with control of glycemia, is thus able to effect an apparent cure of established type 1 diabetes in the NOD mouse.
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PMID:Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. 1143 53

Chronic metabolic acidosis stimulates the catabolism of bone and muscle in experimental animals and humans. The toxicity caused by acidosis involves changes in endocrine function and toxicity arising from the homeostatic responses that are activated by the body to maintain pH near normal levels. Glucocorticoids, insulin, insulin-like growth factor-1, and parathyroid hormone play important roles in the homeostatic responses of bone and muscle to acid. Bone buffering of acid and the resulting increase in renal calcium excretion leads to negative calcium balance. Activation of the ubiquitin-proteasome proteolytic system and branched-chain ketoacid dehydrogenase in muscle, along with hepatic glutamine synthesis in the liver and renal glutamine uptake, are homeostatic mechanisms that cause negative nitrogen balance and loss of muscle mass. Treating the acidosis of chronic renal insufficiency improves both bone and muscle metabolism by reducing the loss of calcium and protein and amino acids in the two organs, respectively. Thus, treating acidosis suppresses both bone and muscle catabolism in patients with normal and reduced renal function.
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PMID:Catabolism in uremia: the impact of metabolic acidosis. 1144 73


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