Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), the key regulatory enzyme in the mevalonate (MVA) pathway, is rapidly degraded in mammalian cells supplemented with sterols or MVA. This accelerated turnover was blocked by N-acetyl-leucyl-leucyl-norleucinal (ALLN), MG-132, and lactacystin, and to a lesser extent by N-acetyl-leucyl-leucyl-methional (ALLM), indicating the involvement of the 26 S proteasome. Proteasome inhibition led to enhanced accumulation of high molecular weight polyubiquitin conjugates of HMGR and of HMGal, a chimera between the membrane domain of HMGR and beta-galactosidase. Importantly, increased amounts of polyubiquitinated HMGR and HMGal were observed upon treating cells with sterols or MVA. Cycloheximide inhibited the sterol-stimulated degradation of HMGR concomitantly with a marked reduction in polyubiquitination of the enzyme. Inhibition of squalene synthase with zaragozic acid blocked the MVA- but not sterol-stimulated ubiquitination and degradation of HMGR. Thus, similar to yeast, the ubiquitin-proteasome pathway is involved in the metabolically regulated turnover of mammalian HMGR. Yet, the data indicate divergence between yeast and mammals and suggest distinct roles for sterol and nonsterol metabolic signals in the regulated ubiquitination and degradation of mammalian HMGR.
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PMID:The ubiquitin-proteasome pathway mediates the regulated degradation of mammalian 3-hydroxy-3-methylglutaryl-coenzyme A reductase. 1096 18

Proteasome-dependent degradation of ubiquitinated proteins plays a key role in many important cellular processes. Ubiquitination requires the E1 ubiquitin activating enzyme, an E2 ubiquitin conjugating enzyme, and frequently a substrate-specific ubiquitin protein ligase (E3). One class of E3 ubiquitin ligases has been shown to contain a common zinc-binding RING finger motif. We have previously shown that herpes simplex virus type 1 ICP0, itself a RING finger protein, induces the proteasome-dependent degradation of several cellular proteins and induces the accumulation of colocalizing conjugated ubiquitin in vivo. We now report that both full-length ICP0 and its isolated RING finger domain induce the accumulation of polyubiquitin chains in vitro in the presence of E1 and the E2 enzymes UbcH5a and UbcH6. Mutations within the RING finger region that abolish the in vitro ubiquitination activity also cause severe reductions in ICP0 activity in other assays. We conclude that ICP0 has the potential to act as an E3 ubiquitin ligase during viral infection and to target specific cellular proteins for destruction by the 26S proteasome.
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PMID:Herpes simplex virus type 1 immediate-early protein ICP0 and is isolated RING finger domain act as ubiquitin E3 ligases in vitro. 1175 73

To determine the effect of dietary protein intake on lean body wasting in adult canines a study was undertaken to investigate the Ubiquitin Proteasome (UP) pathway and concurrent changes in lean and fat body mass of canines fed variable sources and concentrations of dietary protein. Purpose-bred, intact female canines (56) between the ages of 2 and 3 years were fed either 12 or 28% protein diet for 10 weeks. Each diet contained variable amounts of corn gluten meal and chicken protein sources in ratios of 100 : 0, 67 : 33, 33 : 67 and 0 : 100 per cent (w/w), respectively. All diets were isocaloric with calories coming from protein : fat : carbohydrate at the respective ratios of 12 : 40 : 48% for the 12% diets, and 28 : 40 : 32% for the 28% diets. Standard dual energy X-ray absorptiometry was performed to assess total body lean and fat mass at weeks 0 and 10 of the dietary trial. Muscle biopsies were also taken and processed for protein determination and standard gel electrophoresis with subsequent Western blotting for 20S proteasome and PA700 regulatory cap subunit p31. Statistical analysis revealed a moderate degree of correlation between increasing quantities of corn gluten, which is low in essential amino acids (i.e. lysine, tryptophan), and increasing loss of lean body mass over the 10-week study (R = 0.56). Furthermore, a moderate degree of correlation was observed between increasing concentrations of corn gluten protein and decreased expression of the p31 subunit of the 26S proteasome (R = 0.49). Additionally, the dogs consuming the 12% protein diets had a significant increase in fat mass regardless of the protein source. These findings suggest that lean body wasting in adult canines can be associated with the consumption of low protein diets consisting of predominantly corn gluten, which is likely due to imbalances or subclinical deficiencies of specific essential amino acids, and that low protein diets may augment accumulation of adipose tissue. Although the mechanisms remain unclear, alteration of molecular targets of skeletal muscle proteolysis, specifically involving the UP pathway occur.
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PMID:Effect of dietary protein on lean body wasting in dogs: correlation between loss of lean mass and markers of proteasome-dependent proteolysis. 1463 50

The breast and ovarian cancer suppressor BRCA1 acquires significant ubiquitin ligase activity when bound to BARD1 as a RING heterodimer. Although the activity may well be important for the role of BRCA1 as a tumor suppressor, the biochemical consequence of the activity is not yet known. Here we report that BRCA1-BARD1 catalyzes Lys-6-linked polyubiquitin chain formation. K6R mutation of ubiquitin dramatically reduces the polyubiquitin products mediated by BRCA1-BARD1 in vitro. BRCA1-BARD1 preferentially utilizes ubiquitin with a single Lys residue at Lys-6 or Lys-29 to mediate autoubiquitination of BRCA1 in vivo. Furthermore, mass spectrometry analysis identified the Lys-6-linked branched ubiquitin fragment from the polyubiquitin chain produced by BRCA1-BARD1 using wild type ubiquitin. The BRCA1-BARD1-mediated Lys-6-linked polyubiquitin chains are deubiquitinated by 26 S proteasome in vitro, whereas autoubiquitinated CUL1 through Lys-48-linked polyubiquitin chains is degraded. Proteasome inhibitors do not alter the steady state level of the autoubiquitinated BRCA1 in vivo. Hence, the results indicate that BRCA1-BARD1 mediates novel polyubiquitin chains that may be distinctly edited by 26 S proteasome from conventional Lys-48-linked polyubiquitin chains.
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PMID:Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase. 1463 90

Proteasomes play important roles in a variety of cellular processes such as cell cycle progression, signal transduction and immune responses. Proteasome activity is important in maintaining rapid turnover of short-lived proteins, as well as preventing accumulation of misfolded or damaged proteins. Alteration in ubiquitin-proteasome function may be detrimental to its crucial role in maintaining cellular homeostasis. Here, we have found that treatment of pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, resulted in the accumulation of several proteasome substrates including p53 and p21 in HeLa cells. The PDTC effect was due to an extended half-life of these proteins through the mobilization of zinc. PDTC and/or zinc also increased fluorescence intensity of Ub(G76V)-GFP fusion protein that is degraded rapidly by the ubiquitin-proteasome system. Treatment of cells with zinc induced formation of ubiquitinated inclusions in the centrosome, a histological marker of proteasome inhibition. Western blotting showed zinc-induced increase in laddering bands of polyubiquitin-conjugated proteins. In vitro study, zinc inhibited the ubiquitin-independent proteasomal degradations of p21 and alpha-synuclein. These results suggest that zinc may modulate cell functions through its action on the turnover of proteins that are susceptible to proteasome-dependent proteolysis.
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PMID:Pyrrolidine dithiocarbamate and zinc inhibit proteasome-dependent proteolysis. 1524 77

Ubiquitin is a key regulatory molecule in diverse cellular events. How cells determine the outcome of ubiquitylation remains unclear; however, a likely determinant is the specificity of ubiquitin receptor proteins for polyubiquitin chains of certain length and linkage. Proteasome subunit S5a contains two ubiquitin-interacting motifs (UIMs) through which it recruits ubiquitylated substrates to the proteasome for their degradation. Here, we report the structure of S5a (196-306) alone and complexed with two monoubiquitin molecules. This construct contains the two UIMs of S5a and we reveal their different ubiquitin-binding mechanisms and provide a rationale for their unique specificities for different ubiquitin-like domains. Furthermore, we provide direct evidence that S5a (196-306) binds either K63-linked or K48-linked polyubiquitin, and in both cases prefers longer chains. On the basis of these results we present a model for how S5a and other ubiquitin-binding proteins recognize polyubiquitin.
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PMID:Structure of S5a bound to monoubiquitin provides a model for polyubiquitin recognition. 1582 67

Proteasome is protein complex with proteolytic activity. Proteasomes are in addition to lysosomes the main proteolytic machinery of the eukaryotic cell. Proteins destined for degradation in proteasomes are marked by ubiquitinylation, which consists in attachment of polyubiquitin to relevant protein. The transport of polyubiquitinylated protein follows to proteasome, where protein is cleaved into small peptides. Besides polyubiquitin attachment to protein, monoubiquitinylation of proteins exists and has an important role in DNA repair, transcription of genes, endocytosis and signal transduction. The function of an important transcription factor NF-kappaB is connected with proteasome. NF-kappaB is activated after the proteolysis of its inhibitor IkappaB in proteasome. Ubiqutinylation and degradation of protein in proteasome and the activation of NF-kappaB play significant roles in taking proteins away and in expression of great numbers of genes important for the regulation of the cell cycle and apoptosis of cells. The inhibition of proteasomes has antiproliferative and antiinflammatory effects and opens new therapeutic approaches to a treatment of cancer and some inflammatory diseases. We divided the review into three parts: I. Ubiquitin-proteasome system and the transcription factor NF-kappaB, II. Sumoylation and neddylation as post-translational modification of proteins similar to ubiquitinylation and their significance and lastly III. Using of the knowledge of ubiquitin-proteasome system in cancer and other diseases therapy.
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PMID:[Ubiquitins, proteasomes, sumoylation and therapeutic application today and in future for cancer and other diseases. I. Ubiquitin-proteasome system and the transcription factor NF-kappaB]. 1675 93

We previously reported that L-leucine suppresses myofibrillar proteolysis in chick skeletal muscles. In the current study, we compared the effects of L- and D-enantiomers of leucine on myofibrillar proteolysis in skeletal muscle of chicks. We also assessed whether leucine itself or its metabolite, alpha-ketoisocaproate (alpha-KIC), mediates the effects of leucine. Food-deprived (24 h) chicks were orally administered 225 mg/100 g body weight L-leucine, D-leucine or alpha-KIC and were sacrificed after 2 h. L-Leucine administration had an obvious inhibitory effect on myofibrillar proteolysis (plasma N(tau)-methylhistidine concentration) in chicks while D-leucine and alpha-KIC were much more effective. We also examined the expression of the proteolytic-related genes (ubiquitin, proteasome, m-calpain and cathepsin B) by real-time PCR of cDNA in chick skeletal muscles. Ubiquitin mRNA expression was decreased by D-leucine and alpha-KIC but not L-leucine. Proteasome and m-calpain mRNA expressions as well as cathepsin B mRNA expression were likewise decreased by L-leucine, D-leucine and alpha-KIC. These results indicate that D-leucine and alpha-KIC suppress proteolytic-related genes, resulting in an decrease in myofibrillar proteolysis while L-leucine is much less effective in skeletal muscle of chicks, may be explain by conversion of D-leucine to alpha-KIC.
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PMID:Suppression of myofibrillar proteolysis in chick skeletal muscles by alpha-ketoisocaproate. 1699 14

The Ubiquitin Proteasome System is a multi-enzymatic pathway which degrades polyubiquinated soluble cytoplasmic proteins. This biochemical machinery is impaired both in sporadic and inherited forms of Parkinsonism. In the present paper we focus on the role of the pre-synaptic protein alpha-synuclein in altering the proteasom based on the results emerging from experimental models showing a mechanistic chain of events between altered alpha-synuclein, proteasome impairment and formation of neuronal inclusions and catecholamine cell death.
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PMID:A short overview on the role of alpha-synuclein and proteasome in experimental models of Parkinson's disease. 1701 16

Ubiquitin-dependent protein degradation is essential for cells to survive many environmental stresses. Thus, it may be necessary to buffer ubiquitin and proteasome pools against fluctuation. Proteasome levels are tightly regulated, and proteasome deficiency stimulates a stress response. Here we report a novel pathway of cellular response to ubiquitin depletion. Unlike proteasome stress, ubiquitin stress does not upregulate proteasome abundance. Instead, ubiquitin stress alters proteasome composition. The proteasome-associated deubiquitinating enzyme Ubp6, which spares ubiquitin from proteasomal degradation, is induced by ubiquitin deficiency. This enhances loading of proteasomes with Ubp6, thereby altering proteasome function. A catalytically inactive mutant of Ubp6 fails to recycle ubiquitin and also inhibits proteasome function directly, thus inducing both ubiquitin stress and proteasome stress. These results show that homeostatic control of the ubiquitin-proteasome pathway can be achieved through signal-dependent, subunit-specific regulation of the proteasome, and indicate a dual role of Ubp6 in regulating ubiquitin levels and proteasome function.
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PMID:A ubiquitin stress response induces altered proteasome composition. 1751 1


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