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)

The muscle protein catabolism present in rats with insulin-dependent diabetes and other catabolic conditions is generally associated with increased glucocorticoid production and mRNAs encoding components of the ubiquitin-proteasome system. The mechanisms that increase ubiquitin (UbC) expression have not been identified. We studied the regulation of UbC expression in L6 muscle cells because dexamethasone stimulates the transcription of this gene and others encoding components of the ubiquitin-proteasome pathway. Results of in vivo genomic DNA footprinting experiments indicate that a protein(s) binds to Sp1 sites approximately 50 bp upstream from the UbC transcription start site; dexamethasone changes the methylation pattern at these sites. Sp1 binds to DNA probes corresponding to the rat or human UbC promoter, and treating cells with dexamethasone increases this binding. Deletion and mutation analyses of the rat and human UbC promoters are consistent with an important role of Sp1 in UbC induction by glucocorticoids. Dexamethasone-induced ubiquitin expression is blocked by mithramycin, an inhibitor of Sp1 binding. UO126, a pharmacologic inhibitor of MEK1, also blocks UbC transcriptional activation by dexamethasone; L6 cells transfected to express constitutively active MEK1 exhibit increased UbC promoter activity. Thus, glucocorticoids increase UbC expression in muscle cells by a novel transcriptional mechanism involving Sp1 and MEK1.
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PMID:Ubiquitin (UbC) expression in muscle cells is increased by glucocorticoids through a mechanism involving Sp1 and MEK1. 1187 50

Muscle wasting in cancer cachexia is associated with increased levels of malondialdehyde (MDA) in gastrocnemius muscles, suggesting an increased oxidative stress. To determine whether oxidative stress contributes to muscle protein catabolism, an in vitro model system, consisting of C2C12 myotubes, was treated with either 0.2 mM FeSO4, 0.1 mM H2O2, or both, to replicate the rise in MDA content in cachexia. All treatments caused an increased protein catabolism and a decreased myosin expression. There was an increase in the proteasome chymotrypsin-like enzyme activity, while immunoblotting showed an increased expression of the 20S proteasome alpha-subunits, p42, and the ubiquitin-conjugating enzyme, E214k. These results show that mild oxidative stress increases protein degradation in skeletal muscle by causing an increased expression of the major components of the ubiquitin-proteasome pathway.
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PMID:Induction of protein catabolism and the ubiquitin-proteasome pathway by mild oxidative stress. 1191 72

Both exercise and insulin-like growth factor I (IGF-I) are known to have major hypertrophic effects in skeletal muscle; however, the interactive effect of exogenous IGF-I and exercise on muscle protein turnover or the ubiquitin-proteasome pathway has not been reported. In the present study, we have examined the interaction between endurance exercise training and IGF-I treatment on muscle protein turnover and the ubiquitin-proteasome pathway in the postexercise period. Adult male rats (270-280 g) were randomized to receive 5 consecutive days of progressive treadmill exercise and/or IGF-I treatment (1 mg. kg body wt(-1). day(-1)). Twenty-four hours after the last bout of exercise, the rate of protein breakdown in incubated muscles was significantly reduced compared with that in unexercised rats. This was associated with a significant reduction in the chymotrypsin-like activity of the proteasome and the rate of ubiquitin-proteasome-dependent casein hydrolysis in muscle extracts from exercised compared with unexercised rats. In contrast, the muscle expression of the 20S proteasome subunit beta-1, ubiquitin, and the 14-kDa E2 ubiquitin-conjugating enzyme was not altered by exercise or IGF-I treatment 24 h postexercise. Exercise had no effect on the rates of total mixed muscle protein synthesis in incubated muscles 24 h postexercise. IGF-I treatment had no effect on muscle weights or the rates of protein turnover 24 h after endurance exercise. These results suggest that a suppression of the ubiquitin-proteasome proteolytic pathway after endurance exercise may contribute to the acute postexercise net protein gain.
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PMID:IGF-I has no effect on postexercise suppression of the ubiquitin-proteasome system in rat skeletal muscle. 1201 37

The mechanism of muscle protein catabolism induced by proteolysis-inducing factor, produced by cachexia-inducing murine and human tumours has been studied in vitro using C(2)C(12) myoblasts and myotubes. In both myoblasts and myotubes protein degradation was enhanced by proteolysis-inducing factor after 24 h incubation. In myoblasts this followed a bell-shaped dose-response curve with maximal effects at a proteolysis-inducing factor concentration between 2 and 4 nM, while in myotubes increased protein degradation was seen at all concentrations of proteolysis-inducing factor up to 10 nM, again with a maximum of 4 nM proteolysis-inducing factor. Protein degradation induced by proteolysis-inducing factor was completely attenuated in the presence of cycloheximide (1 microM), suggesting a requirement for new protein synthesis. In both myoblasts and myotubes protein degradation was accompanied by an increased expression of the alpha-type subunits of the 20S proteasome as well as functional activity of the proteasome, as determined by the 'chymotrypsin-like' enzyme activity. There was also an increased expression of the 19S regulatory complex as well as the ubiquitin-conjugating enzyme (E2(14k)), and in myotubes a decrease in myosin expression was seen with increasing concentrations of proteolysis-inducing factor. These results show that proteolysis-inducing factor co-ordinately upregulates both ubiquitin conjugation and proteasome activity in both myoblasts and myotubes and may play an important role in the muscle wasting seen in cancer cachexia.
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PMID:Development of an in-vitro model system to investigate the mechanism of muscle protein catabolism induced by proteolysis-inducing factor. 1208 14

Under microgravity conditions similar to those in space, it is known that various nutritional and physiological changes in the body are induced. Especially in the aspect of nutrition, muscle atrophy is a characteristic phenomenon accompanying weightlessness. This study was conducted to investigate the ameliorated effect of muscle atrophy caused by suspension hypokinesia by using the soy protein isolate (SPI) as the protein source in comparison with casein. Male Wistar strain rats (8 wk old) were divided into two groups, each suspended with a suspension harness, and fed on a 20% SPI diet or a 20% casein diet for 10 d. The body weights of the suspended rats fed casein or SPI decreased similarly. The weight of the gastrocnemius and soleus muscle were decreased by suspension hypokinesia; however, the degree of the decrease of the muscle weights, especially soleus muscles, of rats fed the SPI diet was smaller than that of rats fed the casein diet. Serum Ntau-methylhistidine concentration was significantly lower in rats fed the SPI diet than in rats fed the casein diet. Similarly, the activities of muscle protein-degrading enzymes such as calpain and proteasome were significantly lower in rats fed the SPI diet than in rats fed the casein diet. Cathepsin B+L activities were not affected by the SPI or the casein diet. Therefore it is suggested that SPI caused a reduction of the proteolysis of myofibrillar protein in skeletal muscles through a reduction of calpain and proteasome activities, in consequence to ameliorate the muscle atrophy.
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PMID:Effect of different dietary protein composition on skeletal muscle atrophy by suspension hypokinesia/hypodynamia in rats. 1217 31

The ascites hepatoma Yoshida AH-130 induces loss of body weight and tissue waste. Tumour necrosis factor alpha (TNF-alpha) plays a pivotal role in the pathogenesis of muscle wasting in this model system, but other cytokines, such as interleukin-6, may be involved. In order to verify whether a combined anticytokine treatment may synergistically counteract muscle protein degradation, tumour bearing rats were treated with pentoxyfilline (PTX, an inhibitor of TNF-alpha synthesis), or with suramin (SUR, an antiprotozoal drug blocking the peripheral action of several cytokines including IL-6 and TNF-alpha), or both the drugs, and the effects on muscle proteolytic systems were assessed. Muscle protein loss in the AH-130-bearing rats was associated with increased activity of both the ATP-ubiquitin- and the calpain- dependent proteolytic pathways (246% and 230% of controls, respectively). Both PTX and SUR, either alone or in combination, prevented the depletion of muscle mass and significantly reduced the activity of muscle proteolytic systems. In particular, treatment with SUR, either alone or with PTX, induced a decrease in enzymatic activities to values similar to those of controls. The results obtained in the present paper demonstrate that: (i) muscle depletion in this model is indeed associated with increased proteasome- and calpain-dependent proteolysis, as previously suggested by increased mRNA expression of molecules pertaining to both pathways; (ii) anticytokine treatments effectively reduce muscle protein loss by down-regulating the activity of at least two major proteolitic systems; (iii) SUR is more effective than PTX in reducing the activity of proteolytic systems, possibly because of its multiple anticytokine action.
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PMID:Anticytokine treatment prevents the increase in the activity of ATP-ubiquitin- and Ca(2+)-dependent proteolytic systems in the muscle of tumour-bearing rats. 1220 Jan 6

Negative nitrogen balance and accelerated muscle protein breakdown are characteristics of burn injury. The mechanism by which muscle proteolysis occurs may be activation of the ubiquitin-proteasome pathway, but needs to be further elucidated. The aim of this study was to gain more insight into the role of ubiquitin-proteasome pathway in muscle proteolysis, after burn injury in a rat burn injury model. The proteolytic rates and mRNA expression of ubiquitin, E2-14K, and subunit RC2 in extensor digital longus (EDL) and soleus (SOL) muscle were determined by amino acid analyzer and Northern blot, respectively. The results were as follows: the total and myofibrillar proteolytic rate of EDL muscle increased markedly, especially at 12 and 24h post-burn. The levels of 2.4kb mRNA for ubiquitin, 1.2kb mRNA for E2-14K (a rate-limiting and regulated enzyme for conjugation of ubiquitin with protein substrate) and mRNA for subunit RC2 (the largest subunit of 20S proteasome) predominantly increased in EDL muscle after the stimulation of burn injury. No significant changes in proteolytic rate and transcription of ubiquitin, E2-14K, and subunit RC2 in SOL muscle were observed. There was a significantly positive correlation between the proteolytic rate and the levels of 2.4kb mRNA for ubiquitin, 1.2kb mRNA for E2-14K, or mRNA for subunit RC2. The results indicated that muscle wasting after burn injury was mainly due to the accelerated breakdown of myofibrils, and EDL muscle was more sensitive to burn injury than SOL muscle. The activation of ubiquitin-proteasome pathway was one reason for the enhanced protein catabolism in skeletal muscle. This is the first demonstration of upregulated expression of E2-14K and subunit RC2 in muscle, in response to burn injury, and it provides a clue to reduce muscle wasting by specifically inhibiting the specific enzymes or subunits involved in the enhancement of the activity of ubiquitin-proteasome pathway after burn injury.
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PMID:The relationship between skeletal muscle proteolysis and ubiquitin-proteasome proteolytic pathway in burned rats. 1222 Sep 9

Previous studies suggest that insulin-like growth factor-I (IGF-I) inhibits burn-induced muscle wasting mainly by reducing muscle protein degradation. The intracellular mechanisms of this effect of IGF-I are not known. In the present study, we examined the influence of IGF-I on individual proteolytic pathways in muscles from burned rats. Extensor digitorum longus muscles from burned rats were incubated with specific blockers of lysosomal, calcium-calpain-dependent, and ubiquitin-proteasome-dependent proteolytic pathways in the absence or presence of IGF-I. In addition, cathepsin B and L activities and 20S proteasome activity were determined. IGF-I inhibited lysosomal and ubiquitin-proteasome-dependent protein breakdown in skeletal muscle from burned rats by 70 and 90%, respectively, but did not influence calcium-calpain-dependent protein breakdown. The hormone blocked the burn-induced increase in cathepsin B and L activities but did not reduce 20S proteasome activity. Results are important because they provide novel information about intracellular mechanisms by which IGF-I inhibits the catabolic response to burn injury in skeletal muscle.
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PMID:Insulin-like growth factor-I inhibits lysosomal and proteasome-dependent proteolysis in skeletal muscle after burn injury. 1235 32

The interaction between testosterone and exogenous amino acids was studied in older men before and after 6 months of testosterone administration. Twelve healthy older male subjects were randomly assigned in double-blind fashion to receive either testosterone enanthate [T; n = 7; 68 +/- 3 (+/-SE) yr] or placebo (n = 5; 67 +/- 3 yr) for 6 months. Muscle protein kinetics were determined using stable isotope methodology, arterial-venous difference across leg muscle, and muscle biopsies. In addition, ubiquitin-proteasome activity was measured in muscle biopsies as an indicator of muscle protein breakdown. T improved fasting net protein balance, although it remained significantly negative. The improvement in net balance was due to a decrease in muscle protein breakdown, as protein synthesis was unchanged. Ubiquitin-proteasome activity was also decreased with T. Exogenous amino acids increased protein synthesis in both placebo and T groups, but to a lesser degree after 6 months of T treatment. These results indicate that prolonged T administration increases net protein balance in the fasted state, but no additive effect is demonstrated when combined with amino acid feedings. Taken together, however, these diverse stimulatory effects can increase lean body mass and muscle strength over time.
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PMID:Differential anabolic effects of testosterone and amino acid feeding in older men. 1251 77

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


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