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-dependent proteolysis is required for cell cycle progression. Here, we demonstrate that the proteasome is activated during in vivo Xenopus egg activation, induced by treatment with the calcium ionophore A23187. It was found that activation is due to the calcium-induced assembly of the 26 S proteasome from the 20 S proteasome. We propose that proteasome activation is regulated by cell cycle calcium transients, which are controlled upstream by an endogenous cell cycle oscillator that is independent of the cyclin-dependent kinase cycle.
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PMID:Activation of the proteasome during Xenopus egg activation implies a link between proteasome activation and intracellular calcium release. 857 36

In budding yeast, cell division is initiated in late G1 phase once the Cdc28 cyclin-dependent kinase is activated by the G1 cyclins Cln1, Cln2, and Cln3. The extreme instability of the Cln proteins couples environmental signals, which regulate Cln synthesis, to cell division. We isolated Cdc53 as a Cln2-associated protein and show that Cdc53 is required for Cln2 instability and ubiquitination in vivo. The Cln2-Cdc53 interaction, Cln2 ubiquitination, and Cln2 instability all depend on phosphorylation of Cln2. Cdc53 also binds the E2 ubiquitin-conjugating enzyme, Cdc34. These findings suggest that Cdc53 is a component of a ubiquitin-protein ligase complex that targets phosphorylated G1 cyclins for degradation by the ubiquitin-proteasome pathway.
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PMID:Cdc53 targets phosphorylated G1 cyclins for degradation by the ubiquitin proteolytic pathway. 875 27

Proteases are known to play important roles in cell growth control, although the underlying mechanisms are still poorly understood. Here we show that the protease inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal induced cell cycle arrest in platelet-derived growth factor-stimulated human fibroblasts at the G1/S boundary of the cell cycle by inhibiting the proteasome. Inhibition of the proteasome resulted in accumulation of the tumor suppressor p53, which was followed by an increase in the amount of the cyclin-dependent kinase-inhibitor p21. As a consequence, both phosphorylation and activity of the cyclin-dependent kinase 2/cyclin E complex were inhibited. We further observed that the retinoblastoma gene product, pRb, remained in the hypophosphorylated state, thus preventing cells from progression into the S-phase. These studies strongly support the hypothesis that the proteasome is a key regulator in the G1-phase of cell cycle progression.
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PMID:p53-dependent cell cycle arrest induced by N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal in platelet-derived growth factor-stimulated human fibroblasts. 885 63

The cell cycle has been the object of extensive studies for the past years. A complex network of molecular interactions has been identified. In particular, a class of cell cycle inhibitory proteins has been cloned and characterized but details of the molecular mechanism of their action have yet to be resolved. These inhibitors regulate the progression through G1 and the G1/S transition via the inhibition of the cyclin-dependent kinase (Cdk) activity. The potential function of these negative regulators as tumor suppressors provides new insights into the link between the cell cycle and oncogenesis. p27 is a potent inhibitor of Cdks. In quiescent cells p27 accumulates without an increase in mRNA or protein synthesis. Cell cycle regulation of p27 levels, both in normal and transformed human cells, occurs via the ubiquitin-proteasome pathway and, compared to proliferating cells, quiescent cells contain a far lower amount of p27 ubiquitinating activity. The specific proteolysis of p27 is probably involved in the pathway of activation of Cdks. p27 is a phosphoprotein and its phosphorylation is cell cycle regulated. Often phosphorylation is a signal for ubiquitination. p27 is phosphorylated exclusively on serine by Erk1 and almost exclusively on threonine by Cdk1 in in vitro experiments. This finding raises the question of whether and how phosphorylation by these kinases is involved in the process of p27 proteolysis.
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PMID:Regulation of the cyclin-dependent kinase inhibitor p27 by degradation and phosphorylation. 906 71

The cell cycle has been the object of extensive studies for the past years. A complex network of molecular interactions has been identified. In particular, a class of cell cycle inhibitory proteins has been identified but details of the molecular mechanism of their action have yet to be resolved. These inhibitors regulate the progression through G1 and the G1/S transition via the inhibition of the cyclin-dependent kinase (Cdk) activity. The potential function of these negative regulators as tumor suppressors provides new insights into the link between the cell cycle and oncogenesis. Kip1 is a potent inhibitor of Cdks. In quiescent cells Kip1 accumulates without an increase in mRNA or protein synthesis. We demonstrated that cell cycle regulation of Kip1 levels, both in normal and transformed human cells, occurs via the ubiquitin-proteasome pathway. In a crude in vitro system, Kip1 is ubiquitinated and degraded in an ATP dependent manner and inhibition or depletion of the proteasome blocks Kip1 degradation. Human Ubc2 and Ubc3, the homologs of yeast Rad6 and Cdc34 gene products respectively, are specifically involved in the ubiquitination of Kip1. Compared to proliferating cells, quiescent cells contain a far lower amount of Kip1 ubiquitinating activity. These results represent the first demonstration that the ubiquitin-proteasome pathway plays a role in the regulation of a cell cycle protein in human cells, namely the Cdk inhibitor Kip1. The specific proteolysis of Kip1 may be involved in the pathway of inactivation of Cdks.
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PMID:Kip1 degradation via the ubiquitin-proteasome pathway. 920 91

In eukaryotes the activity of CDK1 (CDC2), a cyclin-dependent kinase that initiates the structural changes that culminate in the segregation of chromosomes at mitosis, is regulated by the synergistic and opposing activities of a cascade of kinases and phosphatases. Dephosphorylation of threonine 14 and tyrosine 15 of CDK1 by the CDC25 phosphatases is a key step in the activation of the CDK1-cyclin B protein kinase. Little is currently known about the role and the regulation of CDC25B. Here we report in vitro and in vivo data that indicate that CDC25B is degraded by the proteasome. This degradation is dependent upon phosphorylation by the CDK1-cyclin A complex but not by CDK1-cyclin B. These results indicate that CDK1-cyclin A phosphorylation targets CDC25B for degradation and that this might be an important component of cell cycle regulation at the G2/M transition.
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PMID:Phosphorylation of human CDC25B phosphatase by CDK1-cyclin A triggers its proteasome-dependent degradation. 940 44

In fission yeast, the cyclin-dependent kinase (CDK) inhibitor p25(rum1) is a key regulator of progression through the G1 phase of the cell cycle. We show here that p25(rum1) protein levels are sharply periodic. p25(rum1) begins to accumulate at anaphase, persists in G1 and is destroyed during S phase. p25(rum1 )is stabilized and polyubiquitinated in a mutant defective in the 26S proteasome, suggesting that its degradation normally occurs through the ubiquitin-dependent 26S proteasome pathway. Phosphorylation of p25(rum1 )by cdc2-cyclin complexes at residues T58 and T62 is important to target the protein for degradation. Mutation of one or both of these residues to alanine causes stabilization of p25(rum1) and induces a cell cycle delay in G1 and polyploidization due to occasional re-initiation of DNA replication before mitosis. The CDK-cyclin complex cdc2-cig1, which is insensitive to p25(rum1 )inhibition, seems to be the main kinase that phosphorylates p25(rum1). Phosphorylation of p25(rum1) in S phase and G2 serves as the trigger for p25(rum1) proteolysis. Thus, periodic accumulation and degradation of the CDK inhibitor p25(rum1 )in G1 plays a role in setting a threshold of cyclin levels important in determining the length of the pre-Start G1 phase and in ensuring the correct order of cell cycle events.
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PMID:Regulation of the G1 phase of the cell cycle by periodic stabilization and degradation of the p25rum1 CDK inhibitor. 943 Jun 40

A variety of studies have demonstrated the critical role of the Rb/E2F pathway in the control of cell growth and have highlighted a complexity in the accumulation of both the E2F family proteins and the Rb family of proteins. Whereas the Rb protein is found in both growing and quiescent cells, the accumulation of p130 and p107 is tightly regulated with respect to the growth state of the cell. The p130 protein is found in quiescent cells but not in growing cells, whereas the inverse is true for the p107 protein. Control of p130 accumulation is posttranscriptional, because p130 RNA is relatively constant in growing and quiescent cells. The disappearance of the p130 protein after stimulation of cell growth coincides with cyclin-dependent kinase-mediated phosphorylation and is blocked by inhibitors of the 26S proteasome. In contrast, the cell growth-dependent regulation of p107 expression reflects the transcriptional regulation of the p107 gene. Similar to several other growth-regulated genes, the control of p107 expression is largely the result of E2F-dependent repression in quiescent cells. These experiments thus demonstrate a control of Rb family member expression mediated through distinct mechanisms of both transcriptional and posttranslational control and also suggest an intimate relationship in which p130 controls the expression of p107.
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PMID:Distinct mechanisms control the accumulation of the Rb-related p107 and p130 proteins during cell growth. 956 49

MyoD is a basic helix-loop-helix transcription factor involved in the activation of genes encoding skeletal muscle-specific proteins. Independent of its ability to transactivate muscle-specific genes, MyoD can also act as a cell cycle inhibitor. MyoD activity is regulated by transcriptional and posttranscriptional mechanisms. While MyoD can be found phosphorylated, the functional significance of this posttranslation modification has not been established. MyoD contains several consensus cyclin-dependent kinase (CDK) phosphorylation sites. In these studies, we examined whether a link could be established between MyoD activity and phosphorylation at putative CDK sites. Site-directed mutagenesis of potential CDK phosphorylation sites in MyoD revealed that S200 is required for MyoD hyperphosphorylation as well as the normally short half-life of the MyoD protein. Additionally, we determined that turnover of the MyoD protein requires the proteasome and Cdc34 ubiquitin-conjugating enzyme activity. Results of these studies demonstrate that hyperphosphorylated MyoD is targeted for rapid degradation by the ubiquitin pathway. The targeted degradation of MyoD following CDK phosphorylation identifies a mechanism through which MyoD activity can be regulated coordinately with the cell cycle machinery (CDK2 and CDK4) and/or coordinately with the cellular transcriptional machinery (CDK7, CDK8, and CDK9).
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PMID:Phosphorylation of nuclear MyoD is required for its rapid degradation. 971 May 83

In proliferating cells the turnover rate of proteins responsible for regulation of the cell cycle progression, namely cyclins and inhibitors of the cyclin-dependent kinases (CDKs) and phosphatases, is rapid and their cellular level is modulated at the transcriptional, translational and/or degradation (via proteasome pathway) stages. Inhibition of proteasome function results in accumulation of rapidly turning over proteins and, thus, causes an imbalance of the cell cycle regulatory components, and loss of their regulatory function. Indeed, it has been shown that proteasome inhibitors perturb the cell cycle progression. Onconase, a novel RNase which has anti-tumor activity and is in clinical trials, has previously been shown to suppress protein synthesis, presumably by degradation of intracellular RNA, preferentially tRNA. By interfering with regulation of expression of cyclins and/or CDK-inhibitors, onconase also may induce the imbalance of these proteins and potentiate the effect of proteasome inhibitors. In the present study, we observed that the combinations of onconase with peptide-aldehyde inhibitors of calpain and proteasome such as the N-acetyl-leucinyl-leucinyl-norleucinal (LLnL) and the N-acetyl-leucinyl-valinyl-phenylalaninal (LVP), but not N-acetyl-leucinyl-leucinyl-methioninal (LLM), were synergistic in suppressing cell proliferation and inducing apoptosis in three human tumor cell lines: A-549 lung adenocarcinoma, DU-145 prostatic carcinoma, and MDA-MB-231 breast carcinoma. The observed cytotoxicity may also be a result of prevention of the induction of the 'survival' genes by the nuclear factor kappaB (NFkappaB) by onconase and proteasome inhibitors. The data indicate that such combinations should be further tested as potential anti-cancer regimens.
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PMID:Enhanced in vitro cytotoxicity and cytostasis of the combination of onconase with a proteasome inhibitor. 973 89


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