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)

Ubiquitin-proteasome-dependent protein degradation plays a central role in sepsis-induced muscle wasting. Because the proteasome degrades proteins into small peptides rather than free amino acids, it is likely that additional mechanisms downstream of the proteasome are involved in sepsis-induced muscle proteolysis. Recent studies suggest that the extralysosomal peptidase tripeptidyl-peptidase II (TPP II) degrades peptides generated by the proteasome. We hypothesized that TPP II expression and activity are increased in skeletal muscle during sepsis. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. TPP II activity was determined by using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin (AAF-AMC). TPP II protein and gene expression were determined by Western blot and real-time PCR, respectively. Sepsis resulted in increased activity and protein and gene expression of TPP II in extensor digitorum longus muscles. This result was blunted by the glucocorticoid receptor antagonist RU 38486, indicating that glucocorticoids participate in the upregulation of TPP II in skeletal muscle during sepsis. The results suggest that proteolytic mechanisms downstream of the proteasome may be important for the complete degradation of muscle proteins during sepsis.
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PMID:Tripeptidyl-peptidase II expression and activity are increased in skeletal muscle during sepsis. 1214 24

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

Spinal and bulbar muscular atrophy (SBMA) is a heritable neurodegenerative disease caused by the expansion of a polyglutamine [poly(Q)] repeat within the androgen receptor (AR) protein. We studied SBMA in Drosophila using an N-terminal fragment of the human AR protein. Expression of a pathogenic AR protein with an expanded poly(Q) repeat in Drosophila results in nuclear and cytoplasmic inclusion formation, and cellular degeneration, preferentially in neuronal tissues. We have studied the influence of ubiquitin-dependent modification and the proteasome pathway on neural degeneration and AR protein fragment solubility. Compromising the ubiquitin/proteasome pathway enhances degeneration and decreases poly(Q) protein solubility. Our data further suggest that Hsp70 and the proteasome act in an additive manner to modulate neurodegeneration. Through the over-expression of a mutant of the SUMO-1 activating enzyme Uba2, we further show that poly(Q)-induced degeneration is intensified when the cellular SUMO-1 protein conjugation pathway is altered. These data suggest that post-translational protein modification, including the ubiquitin/proteasome and the SUMO-1 pathways, modulate poly(Q) pathogenesis.
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PMID:Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. 1239 1

NF-kappaB activation is classically defined as a transient response initiated by the degradation of IkappaB inhibitor proteins leading to nuclear import of NF-kappaB and culminating with the resynthesis of IkappaBalpha and subsequent inactivation of the transcription factor. Although this type of regulation is considered the paradigm for NF-kappaB activation, other regulatory profiles are known to exist. By far the most common of these is chronic or persistent activation of NF-kappaB. In comparison, regulation of NF-kappaB in a biphasic manner represents a profile that is scarcely documented and whose biological significance remains poorly understood. Here we show using differentiated skeletal muscle cells, that tumor necrosis factor (TNF) induces NF-kappaB activation in a biphasic manner. Unlike the first transient phase, which is terminated within 1 h of cytokine addition, the second phase persists for an additional 24-36 h. Biphasic activation is mediated at both the levels of NF-kappaB DNA binding and transactivation function, and both phases are dependent on the IKK/26 S proteasome pathway. We find that regulation of the first transient phase is mediated by the degradation and subsequent resynthesis of IkappaBalpha, as well as by a TNF-induced expression of A20. Second phase activity correlates with persistent down-regulation of both IkappaBalpha and IkappaBbeta proteins, derived from a continuous TNF signal. Finally, we demonstrate that inhibition of NF-kappaB prior to initiation of the second phase of activity inhibits cytokine-mediated loss of muscle proteins. We propose that the biphasic activation of NF-kappaB in response to TNF may play a key regulatory role in skeletal muscle wasting associated with cachexia.
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PMID:Tumor necrosis factor-regulated biphasic activation of NF-kappa B is required for cytokine-induced loss of skeletal muscle gene products. 1243 91

The object of this study was to summarize information on catabolic factors produced by tumours which lead to tissue catabolism in cancer cachexia and to use this information for the development of effective therapy. The study population was made up of patients with cancer cachexia and weight loss greater than 1 kg month(-1). They had a varied range of carcinomas, particularly pancreatic, but also of the breast, ovary, lung, colon and rectum. Cachectic factors were isolated by standard biochemical methods, and the mechanism of tissue catabolism was evaluated in vitro and in vivo. We isolated a 24-kDa sulphated glycoprotein produced by cachexia-inducing murine and human tumours, which induces catabolism of myofibrillar proteins in skeletal muscle and for this reason has been named proteolysis-inducing factor (PIF). PIF was shown to be present in a diverse range of carcinomas in patients whose rate of weight loss exceeded 1.0 kg month(-1). Administration of PIF to normal mice produced a rapid decrease in body weight, which arose primarily from a loss of skeletal muscle, accompanied by increased mRNA levels for ubiquitin, the ubiquitin-carrier protein (E2(14k)), and proteasome subunits. This suggests that PIF induces protein catabolism through an increased expression of the key components of the ATP-ubiquitin-dependent proteolytic pathway. The action of PIF was attenuated both in vitro and in vivo by eicosapentaenoic acid (EPA). Oral EPA has been found to stabilize the body weight of patients with advanced pancreatic cancer and, when combined with an energy- and protein-rich nutritional supplement, to produce weight gain arising solely from an increase in lean body mass. Nutritional supplementation alone is unable to reverse the process of muscle wasting in cancer patients, since this arises from activation of the ubiquitin proteasome pathway by PIF, which is independent of nutrient intake. EPA is able to down-regulate the increased expression of this pathway and prevents muscle wasting in cancer patients.
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PMID:The 'cancer cachectic factor'. 1256 Sep 34

Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes'. Aggresome formation is an active cellular response that involves trafficking of the offending protein along microtubules, reorganization of intermediate filaments and recruitment of components of the ubiquitin proteasome system. Whether aggresomes are benevolent or noxious is unknown, but they are of particular interest because of the appearance of similar inclusions in protein deposition diseases. Here we present evidence that aggresomes serve a cytoprotective function and are associated with accelerated turnover of mutant proteins. We show that mutant androgen receptor (AR), the protein responsible for X-linked spinobulbar muscular atrophy, forms insoluble aggregates and is toxic to cultured cells. Mutant AR was also found to form aggresomes in a process distinct from aggregation. Molecular and pharmacological interventions were used to disrupt aggresome formation, revealing their cytoprotective function. Aggresome-forming proteins were found to have an accelerated rate of turnover, and this turnover was slowed by inhibition of aggresome formation. Finally, we show that aggresome-forming proteins become membrane-bound and associate with lysosomal structures. Together, these findings suggest that aggresomes are cytoprotective, serving as cytoplasmic recruitment centers to facilitate degradation of toxic proteins.
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PMID:Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. 1265 70

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR). The nuclear inclusions consisting of the mutant AR protein are characteristic and combine with many components of ubiquitin-proteasome and molecular chaperone pathways, raising the possibility that misfolding and altered degradation of mutant AR may be involved in the pathogenesis. We have reported that the overexpression of heat shock protein (HSP) chaperones reduces mutant AR aggregation and cell death in a neuronal cell model (Kobayashi et al., 2000). To determine whether increasing the expression level of chaperone improves the phenotype in a mouse model, we cross-bred SBMA transgenic mice with mice overexpressing the inducible form of human HSP70. We demonstrated that high expression of HSP70 markedly ameliorated the motor function of the SBMA model mice. In double-transgenic mice, the nuclear-localized mutant AR protein, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 overexpression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, probably caused by enhanced mutant AR degradation. Our study may provide the basis for the development of an HSP70-related therapy for SBMA and other polyQ diseases.
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PMID:Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein. 1265 79

Muscle atrophy is a common consequence of catabolic conditions like kidney failure, cancer, sepsis, and acute diabetes. Loss of muscle protein is due primarily to activation of the ubiquitin-proteasome proteolytic system. The proteolytic responses to catabolic signals include increased levels of mRNA that encode various components of the system. In the case of two genes, the proteasome C3 subunit and ubiquitin UbC, the higher levels of mRNA result from increased transcription but the mechanisms of transactivation differ between them. This review summaries the evidence that cachectic signals activate a program of selective transcriptional responses in muscle that frequently occurs coordinately with increased protein destruction.
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PMID:Increased transcription of ubiquitin-proteasome system components: molecular responses associated with muscle atrophy. 1267 54


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