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 role of cardiac lysosomal and nonlysosomal protease alterations in the development of the cardiomyopathy that occurs in genetically diabetic C57BL/KsJ db/db mice has been examined. The db/db mice and age-matched controls were sacrificed between 7 and 24 weeks of age. Cathepsin D activity, myofibrillar alkaline protease (MAP) activity (including serine protease activity), and Ca2+-activated protease activity were determined by using [3H]acetyl-casein as substrate. There is a significant decrease in cathepsin D, MAP, and serine protease activities in the myocardium of 7- to 20-week old diabetic mice with a rebound of these activities toward normal levels by 24 weeks of age. Cathepsin D and MAP activities are inversely related to heart weight in diabetic mice with the higher levels being recorded in association with the most pronounced decrease in heart weight. In contrast, Ca2+-activated protease activity in the hearts of diabetic mice does not differ significantly from controls throughout the period of observation. The results suggest that both lysosomal cathepsin D and nonlysosomal MAP may mediate the accelerated cardiac muscle degradation that occurs in the late stage of diabetic cardiomyopathy in the db/db mice.
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PMID:Lysosomal and nonlysosomal proteolytic activities in experimental diabetic cardiomyopathy. 632 62

Two-kidney, one clip Goldblatt hypertension of 2, 4 and 8 weeks duration was induced in 100-g male Wistar-Kyoto rats. Nucleic acid content was determined in the isolated cardiac muscle cells from the left ventricle. The profile for several major proteolytic activities in either isolated cardiac muscle cells or left ventricle preparations was also studied, using [3H]acetyl-casein as substrate. From the soluble fraction of the tissue or cell preparation, a pH 6 proteolytic activity, two forms of calcium-activated protease as well as cathepsin D were identifiable by inhibitor assay or DEAE-cellulose chromatography. From the myofibrillar fraction of the same preparation, two kinds of proteolytic activity were detected at alkaline pH: a phenylmethylsulfonyl fluoride (PMSF) inhibitable activity that was serine protease-like and the other a N-ethylmaleimide (NEM) inhibitable activity that resembled Ca2+-activated protease. At 2 weeks of hypertension, there was a significant increase in the pH 6 proteolytic activity as well as the calcium-activated protease I and the NEM-inhibitable alkaline protease activities, while the other identifiable proteolytic activities remained unchanged. Lysosomal cathepsin D showed a rise in activity only after 8 weeks of hypertension. These results may be related to the development of myocyte necrosis and lysis that occur in this model of hypertensive cardiomyopathy.
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PMID:Proteolytic activities in hypertensive cardiomyopathy of rats. 634 96

Regulated proteolysis has been postulated to be critical for proper control of cell functions. Muscle development, in particular, involves a great deal of structural adaptation and remodeling mediated by proteases. The transcription factor YY1 represses muscle-restricted expression of the sarcomeric alpha-actin genes. Consistent with this repressor function of YY1, the nuclear regulator is down-regulated at the protein level during skeletal as well as cardiac muscle cell differentiation. However, the YY1 message remains relatively unaltered throughout the myoblast-myotube transition, implicating a post-translational regulatory mechanism. We show that YY1 can be a substrate for cleavage by the calcium-activated neutral protease calpain II (m-calpain) and the 26 S proteasome. The calcium ionophore A23187 destabilized YY1 in cultured myoblasts, and the decrease in YY1 protein levels could be prevented by calpain inhibitor II and calpeptin. Treatment with the proteasome inhibitors MG132 and lactacystin resulted in the stabilization of YY1 protein, which is consistent with the finding that YY1 is readily polyubiquitinated in reticulocyte lysates. We further show that proteolytic targeting by calpain II and the proteasome involves different structural elements of YY1. This study thus illustrates two proteolytic pathways through which the transcriptional regulator can be differentially targeted under different cell growth conditions.
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PMID:Proteolytic regulation of the zinc finger transcription factor YY1, a repressor of muscle-restricted gene expression. 950 62

Cardiac myofibrillar proteins, like all other intracellular proteins, are in a dynamic state of continual degradation and resynthesis. The balance between these opposing metabolic processes ultimately determines the number of functional contractile units within each cardiac muscle cell. Although alterations in myofibrillar protein degradation have been shown to contribute to cardiac growth and remodeling, the intracellular proteolytic systems responsible for degrading myofibrillar proteins to their constitutive amino acids are currently unknown. Lactacystin, a recently developed, highly specific proteasome inhibitor, was used in this study to examine the role of the proteasome in myosin heavy chain (MHC) degradation in cultured neonatal rat ventricular myocytes. Cells were treated with growth medium alone or with lactacystin (1-50 microM) for up to 48 h. Lactacystin significantly increased the total protein/DNA ratio and markedly prolonged MHC half-life. Other proteasome inhibitors, namely carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (10 microM) and N-acetyl-L-leucyl-L-leucyl-norleucinal (100 microM), were also effective in suppressing MHC degradation. Lactacystin and other proteasome inhibitors also suppressed the markedly accelerated MHC degradation associated with Ca2+ channel blockade but did not prevent the disassembly and loss of myofibrils that accompanied contractile arrest. Thus, sarcomere disassembly precedes the degradation of MHC, which is at least in part mediated by the proteasome.
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PMID:Sarcomeric myosin heavy chain is degraded by the proteasome. 1037 Jan 41

Both regular physical exercise and low levels of H(2)O(2) administration result in increased resistance to oxidative stress. We measured the accumulation of reactive carbonyl derivatives and the activities of proteasome complex and DT-diaphorase in cardiac muscle of trained and untrained rats after chronic i.p. administration of 1 ml t-butyl H(2)O(2) (1 mmol/kg for 3 weeks every second day). Twenty-four rats were randomly assigned to a control group administered with saline, control administered with H(2)O(2), and exercised administered either saline or H(2)O(2). The activity of DT-diaphorase significantly increased in H(2)O(2) administered and exercised groups, indicating that an increase in H(2)O(2) levels stimulate the activity of this enzyme. The cardiac muscle of H(2)O(2) administered nonexercised animals accumulated significantly more carbonyl than control group (P < 0.05). The exercise and H(2)O(2) administration resulted in less oxidatively modified protein than found in nonexercised groups (P < 0.05). The peptide-like activity of proteasome complex was induced by the treatment of H(2)O(2) and exercise and exercise potentiate the effect of H(2)O(2). On the other hand, the chymotrypsin-like and trypsin-like activities were stimulated only by physical training and H(2)O(2) administration. The data suggest that chronic administration of H(2)O(2) after exercise training decreases the accumulation of carbonyl groups below the steady-state level and induces the activity of proteasome and DT-diaphorase. Hence, the stimulating effect of physical exercise on free radical generation is an important phenomenon of the exercise-induced adaptation process since it increases resistance to oxidative stress. Regular exercise training is a valuable physiological means of preconditioning the myocardium to prolonged oxidative stress.
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PMID:Exercise preconditioning against hydrogen peroxide-induced oxidative damage in proteins of rat myocardium. 1077 9

The restriction of viral receptors and coreceptors to the basolateral surface of airway epithelial cells has been blamed for the inefficient transfer of viral vectors to the apical surface of this tissue. We now report, however, that differentiated human airway epithelia internalize rAAV type-2 virus efficiently from their apical surfaces, despite the absence of known adeno-associated virus-2 (AAV-2) receptors or coreceptors at these sites. The dramatically lower transduction efficiency of rAAV infection from the apical surface of airway cells appears to result instead from differences in endosomal processing and nuclear trafficking of apically or basolaterally internalized virions. AAV capsid proteins are ubiquitinated after endocytosis, and gene transfer can be significantly enhanced by proteasome or ubiquitin ligase inhibitors. Tripeptide proteasome inhibitors increased persistent rAAV gene delivery from the apical surface >200-fold, to a level nearly equivalent to that achieved with basolateral infection. In vivo application of proteasome inhibitor in mouse lung augmented rAAV gene transfer from undetectable levels to a mean of 10.4 +/- 1.6% of the epithelial cells in large bronchioles. Proteasome inhibitors also increased rAAV-2-mediated gene transfer to the liver tenfold, but they did not affect transduction of skeletal or cardiac muscle. These findings suggest that tissue-specific ubiquitination of viral capsid proteins interferes with rAAV-2 transduction and provides new approaches to circumvent this barrier for gene therapy of diseases such as cystic fibrosis.
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PMID:Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus. 1084 16

The ubiquitin-proteasome system is thought to play a major role in normal muscle protein turnover and to contribute to diabetes-induced protein wasting in skeletal muscle. However, its importance in cardiac muscle is not clear. We measured heart muscle mRNA for ubiquitin and for the C2 and C8 proteasomal subunits, the amount of free ubiquitin and the proteasome chymotrypsin-like proteolytic activity in control and diabetic rats. Results were compared to those in skeletal muscle (rectus). Heart ubiquitin, C2 and C8 subunit mRNA and proteolytic activity were significantly greater than in skeletal muscle (P </= 0.05). This suggests that the ubiquitin proteasomal pathway may also be important for normal heart muscle turnover. Diabetes increased ubiquitin mRNA by approximately 50% in heart (P < 0.03) and by approximately 100% in skeletal muscle (P < 0.005). It remained high after 3 days of insulin treatment in both tissues. C2 and C8 subunit mRNA did not change with diabetes or insulin treatment. Diabetes did not change the amount of free ubiquitin or the proteasomal (lactacystin-inhibitable) chymotrypsin-like peptidase activity in heart or skeletal muscle. In conclusions, gene expression for several components of the ubiquitin-proteasome proteolytic pathway is significantly higher in cardiac than in skeletal muscle, as is the proteasome chymotrypsin-like peptidase activity. Diabetes increases the expression of ubiquitin but not C2 or C8 subunit mRNA, nor does it significantly alter the amount of free ubiquitin or the proteasome chymotrypsin-like peptidase activity. The rate-limiting step of enhanced protein degradation in diabetic rat heart and skeletal muscle may be located at ubiquitin conjugation and/or its binding to proteasome, not at the ubiquitin availability or the proteasome itself.
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PMID:The ubiquitin-proteasome proteolytic pathway in heart vs skeletal muscle: effects of acute diabetes. 1102 19

Emerin is a nuclear membrane protein that interacts with lamin A/C at the nuclear envelope. Mutations in either emerin or lamin A/C cause Emery-Dreifuss muscular dystrophy (EDMD). The functions of emerin are poorly understood, but EDMD affects mainly skeletal and cardiac muscle. We used a high-stringency yeast two-hybrid method to screen a human heart cDNA library, with full-length emerin as bait. Four out of five candidate interactors identified were nuclear proteins: lamin A, splicing factor YT521-B, proteasome subunit PA28 gamma and transcription factor vav-1. Specific binding between emerin and the functional C-terminal domain of YT521-B was confirmed by pull-down assays and biomolecular interaction analysis (BIAcore). Inhibition by emerin of YT521-B-dependent splice site selection in vivo suggests that the interaction is physiologically significant. A 'bipartite' binding site for YT521-B in emerin was identified using alanine substitution or disease-associated mutations in emerin. The transcription factor GCL (germ cell-less) has previously been shown to bind to the same site. The results are consistent with an emerging view that lamins and lamina-associated proteins, like emerin, have a regulatory role, as well as a structural role in the nucleus. YT521-B joins a growing list of candidates for a role in a gene expression model of the pathogenesis of EDMD.
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PMID:Emerin interacts in vitro with the splicing-associated factor, YT521-B. 1275 1

Chronic arthritis is a catabolic state associated with an inhibition of the IGF system and a decrease in body weight. Cachexia and muscular wasting is secondary to protein degradation by the ubiquitin-proteasome pathway. The aim of this work was to analyze the effect of adjuvant-induced arthritis on the muscle-specific ubiquitin ligases muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) as well as on IGF-I and IGF-binding protein-5 (IGFBP-5) gene expression in the skeletal muscle. We also studied whether the synthetic ghrelin receptor agonist, growth hormone releasing peptide-2 (GHRP-2), was able to prevent arthritis-induced changes in the skeletal muscle. Arthritis induced an increase in MuRF1, MAFbx (P < 0.01), and tumor necrosis factor (TNF)-alpha mRNA (P < 0.05) in the skeletal muscle. Arthritis decreased the serum IGF-I and its gene expression in the liver (P < 0.01), whereas it increased IGF-I and IGFBP-5 gene expression in the skeletal muscle (P < 0.01). Administration of GHRP-2 for 8 days prevented the arthritis-induced increase in muscular MuRF1, MAFbx, and TNF-alpha gene expression. GHRP-2 treatment increased the serum concentrations of IGF-I and the IGF-I mRNA in the liver and in the cardiac muscle and decreased muscular IGFBP-5 mRNA both in control and in arthritic rats (P < 0.05). GHRP-2 treatment increased muscular IGF-I mRNA in control rats (P < 0.01), but it did not modify the muscular IGF-I gene expression in arthritic rats. These data indicate that arthritis induces an increase in the activity of the ubiquitin-proteasome proteolytic pathway that is prevented by GHRP-2 administration. The parallel changes in muscular IGFBP-5 and TNF-alpha gene expression with the ubiquitin ligases suggest that they can participate in skeletal muscle alterations during chronic arthritis.
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PMID:Ghrelin receptor agonist GHRP-2 prevents arthritis-induced increase in E3 ubiquitin-ligating enzymes MuRF1 and MAFbx gene expression in skeletal muscle. 1603 67

The regulation of cell size depends on a delicate balance between protein synthesis and breakdown. Skeletal and cardiac muscle adapt to hormonal and neuronal stimuli and can rapidly hypertrophy and atrophy; however, the extent to which these processes occur in smooth muscle is less clear. Atrophy in striated muscle results from enhanced protein breakdown and is associated with a common transcriptional profile and activation of the ubiquitin-proteasome pathway, including induction of the muscle-specific ubiquitin protein ligases atrogin-1 and muscle ring-finger protein 1 (MuRF-1). Here we show that atrogin-1 is also expressed in smooth muscle, and that both atrogin-1 and MuRF-1 are upregulated in the uterus following delivery, as rapid involution occurs. While these two genes are similarly induced in all types of muscle during rapid loss of cell mass, other striated muscle atrophy-specific transcriptional changes are not observed during uterine involution, suggesting different underlying molecular mechanisms. These results raise the possibility that activation of atrogin-1 and MuRF-1 may be a common general adaptation in cells undergoing a rapid reduction in size.
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PMID:Atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 are associated with uterine smooth muscle involution in the postpartum period. 1700 54


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