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

---

Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rapamycin and its analogues are being tested as new antitumor agents. Rapamycin binds to FKBP-12 and this complex inhibits the activity of FRAP/mammalian target of rapamycin, which leads to dephosphorylation of 4EBP1 and p70 S6 kinase, resulting in blockade of translation initiation. We have found that RAP inhibits the growth of HER-2-overexpressing breast cancer cells. The phosphorylation of mammalian target of rapamycin, p70 S6 kinase, and 4EBP1 is inhibited by rapamycin and cells are arrested in the G1 phase, as determined by growth assays, fluorescence-activated cell sorting analysis, and bromodeoxyuridine incorporation studies. Rapamycin causes down-regulation of cyclin D3 protein, retinoblastoma hypophosphorylation, loss of cyclin-dependent kinase (cdk) 4, cdk6, and cdk2 activity. The half-life of cyclin D3 protein decreases after rapamycin treatment, but not its synthesis, whereas the synthesis or half-life of cyclin D1 protein is not affected by the drug. Additionally, rapamycin caused accumulation of ubiquitinated forms of cyclin D3 protein, proteasome inhibitors blocked the effect of rapamycin on cyclin D3, and rapamycin stimulated the activity of the proteasome, showing that the effect of rapamycin on cyclin D3 is proteasome proteolysis dependent. This effect depends on the activity of HER-2 because Herceptin, a neutralizing antibody against HER-2, is able to block both the induction of proteasome activity and the cyclin D3 down-regulation due to rapamycin. Furthermore, inhibition of HER-2 gene expression by using small interfering RNA blocked the rapamycin effects on cyclin D3. These data indicate that rapamycin causes a G1 arrest in HER-2-overexpressing breast cancer cells that is associated with a differential destabilization and subsequent down-regulation of cyclin D3 protein.
...
PMID:Cyclin D3 is down-regulated by rapamycin in HER-2-overexpressing breast cancer cells. 1698 50

The eukaryotic cell cycle is controlled by cyclin-dependent kinases (CDKs). Plants possess six types of CDK, among which the B-type CDK (CDKB) is expressed specifically from the late S- to the M-phase. We demonstrate that the expression of Arabidopsis CDKB2 is under the control of the protein degradation machinery. beta-Glucuronidase fused to a putative PEST motif of CDKB2 was unstable in tobacco Bright Yellow-2 cells and Arabidopsis plants, and its degradation was arrested by the proteasome inhibitor MG132. We propose that the abundance of CDKB2 protein is regulated not only at the transcriptional level, but also through proteasome-mediated protein degradation.
...
PMID:Expression of B2-type cyclin-dependent kinase is controlled by protein degradation in Arabidopsis thaliana. 1709 23

Curcumin, a well-known chemopreventive agent, has been shown to suppress the proliferation of a wide variety of tumor cells through a mechanism that is not fully understood. Cyclin E, a proto-oncogene that is overexpressed in many human cancers, mediates the G(1) to S transition, is a potential target of curcumin. We demonstrate in this report a dose- and time-dependent down-regulation of expression of cyclin E by curcumin that correlates with the decrease in the proliferation of human prostate and breast cancer cells. The suppression of cyclin E expression was not cell type dependent as down-regulation occurred in estrogen-positive and -negative breast cancer cells, androgen-dependent and -independent prostate cancer cells, leukemia and lymphoma cells, head and neck carcinoma cells, and lung cancer cells. Curcumin-induced down-regulation of cyclin E was reversed by proteasome inhibitors, lactacystin and N-acetyl-L-leucyl-L-leucyl-L-norleucinal, suggesting the role of ubiquitin-dependent proteasomal pathway. We found that curcumin enhanced the expression of tumor cyclin-dependent kinase (CDK) inhibitors p21 and p27 as well as tumor suppressor protein p53 but suppressed the expression of retinoblastoma protein. Curcumin also induced the accumulation of the cells in G1 phase of the cell cycle. Overall, our results suggest that proteasome-mediated down-regulation of cyclin E and up-regulation of CDK inhibitors may contribute to the antiproliferative effects of curcumin against various tumors.
...
PMID:Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines. 2698 69

In vitro manipulation of hematopoietic stem cells (HSCs) is a key issue in both transplantation therapy and regenerative medicine, and thus new methods are required to achieve HSC expansion with self-renewal. GATA2 is a transcription factor controlling pool size of HSCs. Of interest, continuous overexpression of GATA2 does not induce HSC proliferation. In this report, we demonstrate that GATA2 expression, in leukemic and normal hematopoietic cells, oscillates during the cell cycle, such that expression is high in S phase but low in G(1)/S and M phase. GATA2 binding to target Bcl-X gene also oscillates in accordance with GATA2 expression. Using a green fluorescent protein (GFP)-GATA2 fusion protein, we demonstrate cell-cycle-specific activity of proteasome-dependent degradation of GATA2. Immunoprecipitation/immunoblotting analysis demonstrated phosphorylation of GATA2 at cyclin-dependent kinase (Cdk)-consensus motifs, S/T(0)P(+1), and interaction of GATA2 with Cdk2/cyclin A2-, Cdk2/cyclin A2-, and Cdk4/cyclin D1-phosphorylated GATA2 in vitro. Mutants in phosphorylation motifs exhibited altered expression profiles of GFP-GATA2 domain fusion proteins. These results indicate that GATA2 phosphorylation by Cdk/cyclin systems is responsible for the cell-cycle-dependent regulation of GATA2 expression, and suggest the possibility that a cell-cycle-specific "on-off" response of GATA2 expression may control hematopoietic-cell proliferation and survival.
...
PMID:Cell-cycle-dependent oscillation of GATA2 expression in hematopoietic cells. 1725 59

Integrins may play important roles in many cellular events, such as cell proliferation, differentiation, and apoptosis. We showed previously that overexpression of integrin beta1 inhibits cell proliferation in SMMC-7721 cells. Here we reported that one of the cyclin-dependent kinase (CDK) inhibitors, p27(Kip1) was involved in proliferation-inhibition induced by overexpression of integrin beta1. Overexpression of integrin beta1 upregulated p27(Kip1) at the protein level, but not mRNA level. The knock-down of p27(Kip1) expression restored cell growth in integrin beta1-overexpressing cells. Cycloheximide (Chx) treatment and pulse-chase experiments revealed that overexpression of integrin beta1 prolonged the half-life of p27(Kip1) by inhibiting its degradation. Proteasome inhibitor (MG132) treatment of the cells indicated that proteasome mediated degradation of p27, and Skp2-dependent degradation might be prevented. Overexpression of integrin beta1 decreased Skp2 at mRNA level, which was regulated by cell adhesion and the subsequent adhesion-dependent signaling. Overexpression of integrin beta1 reduced cell adhesion, accordingly, inactivated the phosphoinositide 3-kinase (PI3K) signaling. PI3K inhibitor LY294002 upregulated p27(Kip1) at post-translational level and downregulate Skp2 at mRNA level, which could mimic the effects of integrin beta1 overexpression on p27(Kip1) and Skp2. Together, these results suggested that overexpression of integrin beta1 inhibited cell proliferation by preventing the Skp2-dependent degradation of p27(Kip1) via PI3K pathway.
...
PMID:Overexpression of integrin beta1 inhibits proliferation of hepatocellular carcinoma cell SMMC-7721 through preventing Skp2-dependent degradation of p27 via PI3K pathway. 1740 40

Therapy resistance represents a major problem for disease management in oncology. Histone deacetylase inhibitors (HDACi) have been shown to modulate the cell cycle, to induce apoptosis and to sensitize cancer cells for other chemotherapeutics. Our study shows that the HDACi valproic acid (VPA) and the ribonucleotide reductase inhibitor hydroxyurea (HU) potentiate the pro-apoptotic effects of each other towards several cancer cell lines. This correlates with the HU-induced degradation of the cyclin-dependent kinase inhibitors (CDKI) p21 and p27, mediated by the proteasome or caspase-3. Moreover, we found that caspase-3 activation is required for VPA-induced apoptosis. Remarkably, p21 and p27 can confer resistance against VPA and HU. Both CDKI interact with caspase-3 and compete with other caspase-3 substrates. Hence, p21 and p27 may contribute to chemotherapy resistance as apoptosis inhibitors. Since the biological effects of VPA and HU could be achieved at concentrations used in current treatment protocols, the combined application of these compounds might be considered as a potential strategy for cancer treatment.
...
PMID:Histone deacetylase inhibitors and hydroxyurea modulate the cell cycle and cooperatively induce apoptosis. 1765 85

Supernumerary centrosomes promote the assembly of abnormal mitotic spindles in many human tumors. In human cells, overexpression of the cyclin-dependent kinase (Cdk)2 partner cyclin A during a prolonged S phase produces extra centrosomes, called centrosome reduplication. Cdk2 activity protects the Mps1 protein kinase from proteasome-mediated degradation, and we demonstrate here that Mps1 mediates cyclin A-dependent centrosome reduplication. Overexpression of cyclin A or a brief proteasome inhibition increases the centrosomal levels of Mps1, whereas depletion of Cdk2 leads to the proteasome-dependent loss of Mps1 from centrosomes only. When a Cdk2 phosphorylation site within Mps1 (T468) is mutated to alanine, Mps1 cannot accumulate at centrosomes or participate in centrosome duplication. In contrast, phosphomimetic mutations at T468 or deletion of the region surrounding T468 prevent the proteasome-dependent removal of Mps1 from centrosomes in the absence of Cdk2 activity. Moreover, cyclin A-dependent centrosome reduplication requires Mps1, and these stabilizing Mps1 mutations cause centrosome reduplication, bypassing cyclin A. Together, our data demonstrate that the region surrounding T468 contains a motif that regulates the accumulation of Mps1 at centrosomes. We suggest that phosphorylation of T468 attenuates the degradation of Mps1 at centrosomes and that preventing this degradation is necessary and sufficient to cause centrosome reduplication in human cells.
...
PMID:Preventing the degradation of mps1 at centrosomes is sufficient to cause centrosome reduplication in human cells. 1780 18

In this study, we performed proteomic analysis of porcine oocytes during in vitro maturation. Comparison of oocytes at the initial and final stages of meiotic division characterized candidate proteins that were differentially synthesized during in vitro maturation. While the biosynthesis of many of these proteins was significantly decreased, we found four proteins with increased biosynthetic rate, which are supposed to play an essential role in meiosis. Among them, the ubiquitin C-terminal hydrolase-L1 (UCH-L1) was identified by mass spectrometry. To study the regulatory role of UCH-L1 in the process of meiosis in pig model, we used a specific inhibitor of this enzyme, marked C30, belonging to the class of isatin O-acyl oximes. When germinal vesicle (GV) stage cumulus-enclosed oocytes were treated with C30, GV breakdown was inhibited after 28 h of culture, and most of the oocytes were arrested at the first meiosis after 44 h. The block of metaphase I-anaphase transition was not completely reversible. In addition, the inhibition of UCH-L1 resulted in elevated histone H1 kinase activity, corresponding to cyclin-dependent kinase(CDK1)-cyclin B1 complex, and a low level of monoubiquitin. These results supported the hypothesis that UCH-L1 might play a role in metaphase I-anaphase transition by regulating ubiquitin-dependent proteasome mechanisms. In summary, a proteomic approach coupled with protein verification study revealed an essential role of UCH-L1 in the completion of the first meiosis and its transition to anaphase.
...
PMID:Proteomic analysis of porcine oocytes during in vitro maturation reveals essential role for the ubiquitin C-terminal hydrolase-L1. 1789 Feb 91

Recent work has suggested that statins may exert beneficial effects on patients suffering from Alzheimer's disease (AD). The pharmacological effects of statins extend beyond their cholesterol-lowering properties. Based on the antineoplastic and apoptotic effects of statins in several cell types, we hypothesized that statins may be able to protect neurons by controlling the regulation of cell cycle. A growing body of evidence indicates that neurodegeneration involves the activation of cell cycle machinery in postmitotic neurons. We and others have presented direct evidence to support the hypothesis that the failure of cell cycle control is not restricted to neurons in AD patients, but that it occurs in peripheral cells as well. For these reasons, we found it worthy to study the role of simvastatin on cell proliferation in immortalized lymphocytes from AD patients. We report here that simvastatin (SIM) inhibits the serum-mediated enhancement of cell proliferation in AD by blocking the events critical for G(1)/S transition. SIM induces a partial blockade of retinoblastoma protein phosphorylation and inhibition of cyclin E/cyclin-dependent kinase (CDK)2 activity associated with increased levels of the CDK inhibitors p21(Cip1) and p27(kip1). These effects of SIM on AD lymphoblasts are dependent on inhibition of the proteasome-mediated degradation of p21 and p27 proteins. The antiproliferative effect of this natural statin may provide a therapeutic approach for AD disease.
...
PMID:HMG-CoA reductase inhibitor simvastatin inhibits cell cycle progression at the G1/S checkpoint in immortalized lymphocytes from Alzheimer's disease patients independently of cholesterol-lowering effects. 1792 68

In animals and fungi, a group of proteins called the cyclin-dependent kinase inhibitors play a key role in cell cycle regulation. However, comparatively little is known about the role of these proteins in plant cell cycle regulation. To gain insight into the mechanisms by which the plant cell cycle is regulated, we studied the cyclin-dependent kinase inhibitor KRP1 in Arabidopsis. KRP1 interacts with the CDKA;1/CYCD2;1 complex in planta and functions in the G1-S transition of the cell cycle. Furthermore, we show that KRP1 is a likely target of the ubiquitin/proteasome pathway. Two different ubiquitin protein ligases, SCF(SKP2) and the RING protein RKP, contribute to its degradation. These results suggest that SCF(SKP2b) and RPK play an important role in the cell cycle through regulating KRP1 protein turnover.
...
PMID:Degradation of the cyclin-dependent kinase inhibitor KRP1 is regulated by two different ubiquitin E3 ligases. 1800 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---