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)

Ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, is the most rapidly turned over mammalian enzyme. We have shown that its degradation is accelerated by ODC antizyme, an inhibitory protein induced by polyamines. This is a new type of enzyme regulation and may be a model for selective protein degradation. Here we report the identification of the protease responsible for ODC degradation. Using a cell-free degradation system, we demonstrate that immunodepletion of proteasomes from cell extracts causes almost complete loss of ATP- and antizyme-dependent degradation of ODC. In addition, purified 26S proteasome complex, but not the 20S proteasome, catalyses ODC degradation in the absence of ubiquitin. These results strongly suggest that the 26S proteasome, widely viewed as specific for ubiquitin-conjugated proteins, is the main enzyme responsible for ODC degradation. The 26S proteasome may therefore have a second role in ubiquitin-independent proteolysis.
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PMID:Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. 133 32

Proteasomes are large, unique protein complexes catalyzing energy- and ubiquitin-dependent proteolysis. Recent studies have revealed that these complexes are involved in two important cellular functions. One is to make antigen fragments for major histo-compatibility complex (MHC) class I-restricted antigen presentation and the other is to regulate the cell cycle by proteolysis. Here we review only the latter function of proteasomes. Proteasomes are widely distributed in eukaryotic cells, but their levels have been shown to be particularly high in various immature cells, such as cancerous, fetal and lymphoblastic cells, and agents including cell differentiation were found to suppress their expression. These conditions also regulate the expression of ubiquitin genes in a similar way, suggesting that proteasomes act ubiquitin-dependently in their 26S form in immature cells. High levels of proteasomes were found immunochemically in the nuclei of rapidly growing cells, indicating that proteasomes are important for eukaryotic cell growth. Indeed, gene disruptions of most subunits of proteasomes in yeast resulted in total suppression of cell growth and cell death. Short-lived regulatory factors of the cell cycle, such as Fos, p53, Mos, and cyclins are degraded by the proteasome-ubiquitin pathway under phosphorylated or dephosphorylated conditions. Ornithine decarboxylase, which is also a short-lived enzyme and is involved in the early phase of cell growth, is quickly degraded by proteasomes with antizyme, but without ubiquitination. Recently, we found that one of the regulatory factors of 26S proteasomes, p31, is a homologue of Nin1p, whose mutation caused inhibition of the cell cycle in yeast. These results indicate that proteasomes play important roles in regulation of the cell cycle in eukaryotes.
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PMID:Roles of proteasomes in cell growth. 756 64

Ornithine decarboxylase (ODC) of African trypanosomes is an important target for anti-trypanosomal chemotherapy because of its remarkable stability in vivo. The in vivo activity and stability of mammalian ODC are regulated by polyamines. Polyamines induce antizyme, which inactivates ODC by tight association and promotes degradation of ODC by the mammalian 26 S proteasome. Here we found, in contrast to mammalian cells, that polyamines caused no reduction of ODC activity in Trypanosoma brucei. Mouse ODC expressed in T. brucei was also unaffected by exogenous polyamines, suggesting that a mammalian antizyme equivalent may be absent in T. brucei. The rat antizyme expressed in T. brucei was found capable of inhibiting mouse ODC activity by the formation of rat antizyme-mouse ODC complex. However, complex formation did not lead to degradation of mouse ODC in T. brucei. Further in vitro experiments suggested the presence of an inhibitory factor(s) in trypanosome, which interferes with the degradation of mouse ODC. We also demonstrated the presence of proteasomes in T. brucei. But the mobility of the trypanosomal proteasome on native gel is different from that of the mammalian proteasome. Thus, the absence of antizyme, the presence of inhibitory factor(s), and the differences between trypanosomal and mammalian proteasome may account for the stability of mouse ODC in T. brucei cells.
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PMID:Rat antizyme inhibits the activity but does not promote the degradation of mouse ornithine decarboxylase in Trypanosoma brucei. 773 Mar 30

Ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines, is an extremely short-lived protein. This attribute is important for the regulation of the activity of the enzyme and implies that the mechanisms involved in its degradation play an important role in the control of the cellular processes in which the enzyme is involved. Recently, it has been shown that ODC is degraded by the 26S proteasome complex in a process that requires antizyme, but not ubiquitin. With one reported exception, ODC, the 26S complex recognizes and degrades specifically ubiquitinated proteins. Their unconjugated counterparts are not targeted. The 26S complex is composed of a core catalytic unit, the 20S proteasome complex, and two additional, and apparently distinct, subcomplexes. The two additional subcomplexes are regulatory subunits that are required in order to confer specificity and control. In this study, we demonstrate that, like the degradation of ubiquitin-conjugated proteins, ubiquitin-independent degradation of ODC also requires prior assembly of the mammalian 26S proteasome from all the three subunits, the 20S proteasome and the two subcomplexes. The combination of any two subunits does not support generation of a proteolytically active complex. This is also true for the yeast 26S complex. Like the mammalian 20S proteasome, the yeast 20S complex can cleave short peptides in an ATP-independent mode, but cannot degrade ODC or ubiquitin-conjugated proteins. These proteins are degraded only following addition of the regulatory subunits and generation of the high-molecular-mass 26S complex. In a distinct, but related, set of experiments, we demonstrate that the degradation of ODC by the assembled 26S proteasome in vitro reproduces faithfully proteolysis of the enzyme in the intact cell. Namely, (a) a C-terminal-deleted mouse ODC and trypanosome ODC are stable both in vitro and in vivo, and (b) like proteolysis in the intact cell, degradation in the reconstituted cell-free system is also dependent upon the addition of antizyme.
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PMID:Degradation of ornithine decarboxylase by the mammalian and yeast 26S proteasome complexes requires all the components of the protease. 774 41

Previously we reported that ornithine decarboxylase (ODC) is degraded ATP-dependently by the 26 S proteasome in the presence of antizyme (AZ), an ODC inhibitor (Murakami, Y., Matsufuji, S., Kameji, T., Hayashi, S., Igarashi, K., Tamura, T., Tanaka, K., and Ichihara, A. (1992) Nature 360, 597-599). Here we examined the cleavage of ODC by the 26 S proteasome. When ODC purified from ODC-overproducing cells was incubated with the 26 S proteasome and with AZ fused with maltose-binding protein (MBP) in the presence of ATP, ODC was degraded specifically without appreciable breakdown of MBP-AZ. The major degradation products of ODC, which were separated by high performance liquid chromatography on a reverse-phase column, were identified by N-terminal amino acid sequencing. The 26 S proteasome generated a variety of short peptides of 5-11 amino acid residues derived from regions throughout the ODC sequence. No detectable amounts of free amino acid residues were produced, indicating endoproteolytic degradation of ODC by the 26 S proteasome. Their major sites for cleavage of ODC by the 26 S proteasome were on the carboxyl sides of neutral/hydrophobic amino acid residues, but a few were on those of acidic or basic amino acid residues. These results demonstrate that the 26 S proteasome causes exhaustive endoproteolysis of the naturally occurring short-lived protein ODC in a multicatalytic and ATP-dependent manner.
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PMID:ATP- and antizyme-dependent endoproteolysis of ornithine decarboxylase to oligopeptides by the 26 S proteasome. 802 Dec 37

Ornithine decarboxylase (ODC) degradation in a freshly prepared reticulocyte lysate was examined. Immunodepletion of proteasomes from the reticulocyte lysate resulted in almost complete loss of ODC degradation. In contrast with the previously reported degradation in extracts of hepatoma tissue-culture (HTC) and Chinese-hamster ovary (CHO) cells or that by the purified 26 S proteasome, efficient degradation of ODC was observed in the lysate without exogenous antizyme, an ODC protein inhibitor induced by polyamines, owing to the presence of a significant amount of antizyme in the lysate. The degradation of ODC in the lysate was strongly suppressed on inactivation of antizyme in the lysate with antizyme inhibitor, a protein which binds to the antizyme and releases ODC from the ODC-antizyme complex. Thus the main pathway for ODC degradation in a reticulocyte lysate was essentially the same as that characterized previously in extracts of HTC and CHO cells, namely an ATP- and antizyme-dependent 26 S proteasome-catalysed pathway that is presumed to be responsible for ODC degradation in whole cells.
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PMID:Involvement of the proteasome and antizyme in ornithine decarboxylase degradation by a reticulocyte lysate. 821 32

Regulated degradation of ornithine decarboxylase (ODC) is mediated by its association with the inducible protein antizyme. The N terminus of antizyme (NAZ), although unneeded for the interaction with ODC, must be present to induce degradation. We report here that covalently grafting NAZ to ODC confers lability that normally results from the non-covalent association of native antizyme and ODC. To determine whether NAZ could act similarly as a modular functional domain when grafted to other proteins, we fused it to a region of cyclin B (amino acids 13-90) capable of undergoing degradation or to cyclin B (amino acids 13-59), which is not subject to degradation. The association with NAZ made both NAZ-cyclin B13-90 and NAZ-cyclin B13-59 unstable. Furthermore, NAZ and cyclin B 13-59 were together able to induce in vitro degradation of Trypanosoma brucei ODC, a stable protein. The ODC-antizyme complex bound to the 26 S protease but not the 20 S proteasome, consistent with the observation that ODC degradation is mediated by the 26 S protease. The association was shown to be independent of NAZ, suggesting that NAZ does not act as a recognition signal.
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PMID:The N terminus of antizyme promotes degradation of heterologous proteins. 862 96

The degradation of ornithine decarboxylase (ODC) catalyzed by the 26 S proteasome is accelerated by antizyme, an ODC inhibitory protein induced by polyamines. Previously, we have found another possible regulatory protein of ODC degradation, antizyme inhibitor. Antizyme inhibitor binds to the antizyme with a higher affinity than that of ODC, releasing ODC from ODC-antizyme complex. We report here the cDNA sequence of rat heart antizyme inhibitor. The deduced sequence of the protein is highly similar to, but distinct from, sequences of ODCs from various species. Antizyme inhibitor contains amino acid residues required for formation of active sites of ODC, but it completely lacks ODC activity. Antizyme inhibitor has no homology with peptide sequence in the mammalian ODC carboxyl terminus, which is needed for rapid turnover of ODC. It inhibits antizyme-dependent ODC degradation, but, unlike ODC, its degradation is not accelerated by antizyme.
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PMID:Cloning of antizyme inhibitor, a highly homologous protein to ornithine decarboxylase. 863 29

Ornithine decarboxylase (ODC) is degraded in an ATP-dependent manner in vitro by the 26 S proteasome in the presence of antizyme, an ODC destabilizing protein induced by polyamines. In the present study we examined whether the proteasome catalyses ODC degradation in living mammalian cells. Lactacystin, the most selective proteasome inhibitor, strongly inhibited the degradation of ODC that had been induced in hepatoma tissue-culture (HTC) cells by refeeding with fresh medium. Furthermore the inhibitor inhibited the rapid degradation of ODC that had been induced by hypotonic shock. Interestingly, hypertonic shock was found to increase the proportion of OD present as a complex with antizyme (the ratio of ODC-antizyme complex to total ODC). Cycloheximide, which partly inhibited rapid ODC degradation caused by hypertonic shock, also part inhibited the increase in the ratio of ODC-antizyme complex total ODC. These results suggest that a common ODC degradation pathway, namely the antizyme-dependent and 26 proteasome-catalysed ODC degradation pathway, is also operating in intact cells for osmoregulated ODC degradation.
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PMID:Proteasome pathway operates for the degradation of ornithine decarboxylase in intact cells. 869 89

DH23b cells, a variant of the HTC line selected for their resistance to difluoromethylornithine, exhibit defective feedback regulation of ornithine decarboxylase (ODC) stability and polyamine transport, and accumulate ODC protein to > 1000 times normal concentrations. The components of the polyamine feedback regulation system have been examined in an attempt to understand these unusual responses. Southern-blot analysis revealed an amplification (approx. 10-fold) in ODC DNA sequence without any concomitant increase in antizyme. Moreover, the amplified ODC sequence contains a single base substitution that results in the conversion of Cys-441 into Trp. This modification has previously been shown to cause ODC stability in HMOA cells. Although antizyme activity has not been noted in DH23b cells, Western-blot analysis revealed the accumulation of antizyme protein to > 50 times that induced in parental HTC cells. This increase is consistent with a 6-9-fold increase in the half-life of antizyme in these cells, a consequence of the inability of the mutant ODC-antizyme complex to be degraded by 26 S proteasome. Associated with the stabilization of antizyme in both DH23b and HMOA cells is the appearance of two additional forms of antizyme protein with apparent molecular masses of 22 and 18.5 kDa. It is suggested that these result from proteolytic removal of discrete fragments from the N-terminal end of antizyme, perhaps an indication of an initial step in rapid antizyme turnover.
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PMID:Overproduction of stable ornithine decarboxylase and antizyme in the difluoromethylornithine-resistant cell line DH23b. 876 Mar 67


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