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)

Lactacystin, a proteasome-inhibitor, has been shown to induce apoptosis of experimental gliomas in vitro. However, its systemic toxicity prevents further clinical use. To circumvent this problem, lactacystin can be delivered intratumorally. We tested the efficacy of lactacystin incorporated into controlled-release polymers for treating experimental gliomas. 9L-gliosarcoma and F98-glioma cell lines were treated with lactacystin (10-100 microg/ml) for 72 h in vitro. Cell-viability was measured with MTT-assays. Toxicity of lactacystin/polycarboxyphenoxypropane-sebacic-acid (pCPP : SA) polymers was tested in vivo using Fischer-344 rats intracranially implanted with lactacystin polymers loaded from 0.1 to 2% lactacystin by weight. The efficacy of 1, 1.3, 1.5 and 1.7% lactacystin/pCPP : SA polymers was determined in Fischer-344 rats intracranially challenged with 9L and treated either simultaneously or 5 days after tumor implantation. Lactacystin was cytotoxic in 9L cells, causing a 16 +/- 8% growth inhibition at 10-microg/ml that increased to 78 +/- 4% at 100-microg/ml. Similarly, lactacystin inhibited growth of F98 by 18 +/- 8% at 10-microg/ml and 74 +/- 2% at 100-microg/ml in vitro. Polymers released lactacystin for 21 days and intracranial implantation in rats neither generate local nor systemic toxicity at doses lower than 2%. Treatment with lactacystin/pCPP : SA polymers with loading concentrations of 1.0, 1.3, and 1.5% prolonged survival of animals intracranially challenged with 9L when polymers where inserted in the day of tumor implantation. In conclusion, lactacystin exhibits potent cytotoxic-activity against 9L and F98 in vitro, it can be efficiently incorporated and delivered using controlled-release polymers, and at the proposed concentrations lactacystin polymers are safe for CNS delivery and prolong survival in the 9L model.
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PMID:Lactacystin exhibits potent anti-tumor activity in an animal model of malignant glioma when administered via controlled-release polymers. 1660 37

Measurements of the response of thermoluminescent (TL) detectors after gamma ray doses high enough to observe signal saturation provide input to microdosimetric models which relate this gamma-ray response with the energy response after low doses of photons (gamma rays and low-energy X rays) and after high-LET irradiation. To measure their gamma ray response up to saturation, LiF:Mg,Ti (MTS-7 and MTT), LiF:Mg,Cu,P (MCP-7), CaSO4:Dy (KCD) and Al2O3:C detectors were irradiated with 60Co gamma rays over the range 1-5000 Gy. The X-ray photon energy response and TL efficiency (relative to gamma rays) after doses of beta rays and alpha particles, were also measured, for CaSO4:Dy and for Al2O3:C. Microdosimetric and track structure modelling was then applied to the experimental data. In a manner similar to LiF:Mg,Cu,P, the experimentally observed under response of alpha-Al2O3:C to X rays <100 keV, compared with cross-section calculations, is explained as a microdosimetric effect caused by the saturation of response of this detector without prior supralinearity (saturation of traps along the tracks). The enhanced X-ray photon energy response of CaSO4:Dy is related to the supralinearity observed in this material after high gamma ray doses, similarly to that in LiF:Mg,Ti. The discussed model approaches support the general rule relating dose-, energy- and ionisation density-responses in TL detectors: if their gamma ray response is sublinear prior to saturation, the measured photon energy response is lower, and if it is supralinear, it may be higher than that expected from the calculation of the interaction cross sections alone. Since similar rules have been found to apply to other solid-state detector systems, microdosimetry may offer a valuable contribution to solid-state dosimetry even prior to mechanistic explanations of physical phenomena in different TL detectors.
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PMID:On the relationship between dose-, energy- and LET-response of thermoluminescent detectors. 1664 68

A new method of thermoluminescence dosimetry of densely ionising radiation based on the ratio of different efficiency-LET functions of three thermoluminescent detectors (TLDs) has been developed. The applied TLD types are: MTS-7 ((7)LiF:Mg,Ti), MCP-7 ((7)LiF:Mg,Cu,P) and MTT-7 (a newly developed (7)LiF:Mg,Ti with modified activator composition and increased response to high-LET radiation). The tests of this method, performed with high-energy ion beams at the HIMAC accelerator within the ICCHIBAN project, proved that good agreement with the true dose values may be achieved even in very complicated mixed fields. The proposed method will be applied for analysis of several thousand TLDs used for the determination of organ doses in an anthropomorphic phantom orbiting outside the International Space Station within the MATROSHKA experiment.
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PMID:Dosimetry of densely ionising radiation with three LiF phosphors for space applications. 1673 89

Previous work in our laboratory has shown that acute exposure of primary rat hepatocyte cultures to non-toxic concentrations of arsenite causes major decreases in the DEX-mediated induction of CYP3A23 protein, with minor decreases in CYP3A23 mRNA. To elucidate the mechanism for these effects of arsenite, the effects of arsenite and proteasome inhibition, separately and in combination, on induction of CYP3A23 protein were compared. The proteasome inhibitor, MG132, inhibited proteasome activity, but also decreased CYP3A23 mRNA and protein. Lactacystin, another proteasome inhibitor, decreased CYP3A23 protein without affecting CYP3A23 mRNA at a concentration that effectively inhibited proteasome activity. This result, suggesting that the action of lactacystin is similar to arsenite and was post-transcriptional, was confirmed by the finding that lactacystin decreased association of DEX-induced CYP3A23 mRNA with polyribosomes. Both MG132 and lactacystin inhibited total protein synthesis, but did not affect MTT reduction. Arsenite had no effect on ubiquitination of proteins, nor did arsenite significantly affect proteasomal activity. These results suggest that arsenite and lactacystin act by similar mechanisms to inhibit translation of CYP3A23.
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PMID:Effect of proteasome inhibition on toxicity and CYP3A23 induction in cultured rat hepatocytes: comparison with arsenite. 1708 55

Red sea bream iridovirus (RSIV) is a causative agent of red sea bream iridoviral disease (RSIVD) in marine fish species in Japan. Fibroblast cells were developed from a tail fin of red sea bream, Pagrus major, and then underwent single cell cloning. The successful cloned cells were named CRF-1 cells. Most CRF-1 cells had a normal diploid karyotype with 2n=48 by chromosomal analysis. RSIV-infected CRF-1 cells showed typical morphological changes that were associated with apoptosis by EGFP-annexin V staining. The serial viral passages were successful in CRF-1 cells but failed in BF-2 cells as judged by MTT assay. The expression of three genes obviously decreased in BF-2 cells compared with CRF-1 cells and finally was below detectable level. Because the expression of 591R gene showed the fastest decrease among three transcripts, the suppression of IE transcript may be responsible for the restricted replication in BF-2 cells. MCP and ATPase phylogenetic trees showed that RSIV strain U-1 belongs to a distinct group from RSIV strain ehime-1. Therefore, possibly recent epizootics of RSIVD in Japan do not originate directly from RSIV strain ehime-1. Taken together, this study confirmed that RSIV strain U-1 is more closely related to Korean RSIV isolates.
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PMID:Characterization of a new fibroblast cell line from a tail fin of red sea bream, Pagrus major, and phylogenetic relationships of a recent RSIV isolate in Japan. 1733 26

The proteasome plays a pivotal role in controlling cell proliferation, apoptosis, and differentiation in a variety of tumor cells. Bortezomib is a boronic acid dipeptide derivative, which is a selective and potent inhibitor of the proteasome and has prominent effects in vitro and in vivo against several solid tumors. We examined the anti-proliferative and apoptotic effects of bortezomib in three gastric cancer cell lines (SNU638, MUGC-3 and MKN-28), along with its antitumor combination effects with other chemotherapeutic agents. Tumor cell growth inhibition and apoptosis was measured by MTT assay and FACS analysis, respectively. Apoptosis- and cell cycle-associated protein expression levels were measured by Western blot assay. Bortezomib induced the suppression of tumor cell growth and apoptosis in a dose-dependent manner with an inhibitory dose (ID)50 of approximately 0.5 microg/ml in all gastric cancer cell lines tested. Further combination treatment with cisplatin and docetaxel, in particular with docetaxel displayed dramatically increased tumor cell growth suppression in all three gastric cancer cell lines, as compared to single drug treatment alone. This was concomitant with the induction patterns of apoptotic cells. Bortezomib treatment increased the Bax protein expression. Moreover, combination treatment of bortezomib plus docetaxel resulted in a dramatic increase in the Bax expression. In contrast, Bcl-2 expression was decreased by combination treatment with bortezomib plus docetaxel in SNU638 cells. Finally, bortezomib, docetaxel and to a greater degree bortezomib plus docetaxel increased the expression levels of p27 proteins even without influencing p53 expression levels. Bortezomib has profound effects on tumor cell growth inhibition and induction of apoptosis in human gastric cancer cells, suggesting that bortezomib may be an effective therapeutic drug for patients with gastric cancer. Further combination studies with other chemotherapeutic drugs, in particular docetaxel showing more tumor cell growth inhibition and apoptosis suggest that combining bortezomib with docetaxel might be more effective for displaying tumor cell growth inhibitory effects in gastric cancer cells through regulation of Bcl-2, Bax and p27 proteins in vitro.
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PMID:Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapeutic agents in gastric cancer cell lines. 1835 92

Domoic acid (DA) is an excitatory amino acids (EAAs) analog which induced excitotoxicity lesion to central nervous system, but whether induced adult animal spinal cord is not known, furthermore, previous studies have shown that EAAs play an important role in spinal cord lesion, however, the molecular pathways in spinal cord lesion are not fully known. Therefore, a motor neuron-like cell culture system and a DA-induced spinal cord lesioned mice model were used to study the effect of DA on spinal cord in adult mice and the possible molecular pathways of EAAs in spinal cord lesions. Exposure of motor neuron-like cells NSC34 to DA dramatically increased reactive oxygen species (ROS) production by the DCF fluorescent oxidation assay, reduced mitochondrial function by MTT assay, cell viability by trypan blue exclusion assay, and was accompanied by an increase of cell apoptosis by histone protein release assay. In DA-induced spinal cord lesioned mice model, we showed that the decrease of proteasome activity, increase of UCP4 expression by immunohistochemistry and neural cell apoptosis by TUNEL staining, and was accompanied by an decrease of motor disturbance grade during the different stages of DA treatment. Taken together, the in vitro and in vivo data presented in the current report demonstrated that DA induces spinal cord lesions in adult mice, and the multiple molecular pathways promoted by EAAs in spinal cord lesions, at least partially was associated with ROS generation increase, mitochondrial dysfunction, proteasome activity decrease and UCP4 expression increase.
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PMID:Domoic acid induced spinal cord lesions in adult mice: evidence for the possible molecular pathways of excitatory amino acids in spinal cord lesions. 1853 81

To investigate the effect of proteasome inhibitor MG132 on the apoptosis of bovine lens epithelial cells (BLECs), the cells were treated with MG132 at different concentrations for 12, 24 and 36 h. The cell viability was analyzed by MTT assay and the effect of MG132 on the apoptosis of BLECs was assessed by flow cytometry (FCM). The results showed that after treatment for the same period, the inhibitory effect of MG132 on BLECs proliferation was enhanced with the increment of the concentration of MG132 (0, 2, 5, 10, mumol/L) (P<0.05). The 50% inhibiting concentration (IC(50)) was 2.03 mumol/L when the BLECs were treated with MG132 for 36 h. MG132 also induced the apoptosis of BLECs obviously. FCM showed that the apoptosis index of the cells treated by MG132 at 2 mumol/L for 12 h was (20.24+/-1.51)%, and that of the control was (0.98+/-0.20)% respectively (P<0.01, n=3). It was concluded that MG132 could lead to apoptosis of BLECs. The decrease of proteasome activity may play an important role in the formation and development of cataract.
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PMID:The apoptosis of bovine lens epithelial cells induced by proteasome inhibitor MG132. 1870 14

First-line therapy for patients with glioblastoma multiforme includes treatment with radiation and temozolomide (TMZ), an oral DNA alkylating chemotherapy. Sensitivity of glioma cells to TMZ is dependent on the level of cellular O(6)-methylguanine-DNA methyltransferase (MGMT) repair activity. Several common coding-region polymorphisms in the MGMT gene (L84F and the linked pair I143V/K178R) modify functional characteristics of MGMT and cancer risk. To determine whether these polymorphic changes influence the ability of MGMT to protect glioma cells from TMZ, we stably overexpressed enhanced green fluorescent protein (eGFP)-tagged MGMT constructs in U87MG glioma cells. We confirmed that the wild-type (WT) eGFP-MGMT protein is properly localized within the nucleus and found that L84F, I143V/K178R, and L84F/I143V/K178R eGFP-MGMT variants exhibited nuclear localization patterns indistinguishable from WT. Using MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] proliferation and clonogenic survival assays, we confirmed that WT cells expressing eGFP-MGMT are resistant to TMZ treatment compared with control U87MG cells, and that each of the polymorphic eGFP-MGMT variants confers similar resistance to TMZ. However, upon exposure to O(6)-benzylguanine (O(6)-BG), a synthetic MGMT inhibitor, the L84F and L84F/I143V/K178R variants were degraded more rapidly than WT or I143V/K178R in a proteasome-dependent manner. Despite the increased O(6)-BG- stimulated protein turnover caused by the L84F alteration, cells expressing L84F eGFP-MGMT did not exhibit altered sensitivity to the combination of O(6)-BG and TMZ compared with WT cells. In conclusion, we demonstrated that the L84F polymorphic variant has altered protein turnover without modifying sensitivity of U87MG cells to TMZ or combined TMZ and O(6)-BG. These findings may provide a clue to determining the clinical significance of MGMT coding-region polymorphisms.
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PMID:The L84F polymorphic variant of human O6-methylguanine-DNA methyltransferase alters stability in U87MG glioma cells but not temozolomide sensitivity. 1881 20

Ubiquitin carboxy terminal hydrolase-L1 (UCH-L1) belongs to the UCH proteases family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. Previous research showed that UCH-L1 was expressed in mouse retinal cells and testicular germ cells, and its function was associated with apoptosis. But it is still unclear whether UCH-L1 is concerned with apoptosis in tumor cells. In order to clarify the role of UCH-L1 in tumor cells, multi-drug resistance (MDR) human breast carcinoma cell line MCF7/Adr, that expresses relatively high UCH-L1, and its parental cell line MCF7, that expresses relatively low UCH-L1, were chosen for this study. We transfected pcDNA3.1-UCH-L1 plasmid and UCH-L1 siRNA into MCF7 and MCF7/Adr cells, respectively. Using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, western blot, Hoechst 33258 staining assay and flow cytometry, we found that over-expression of UCH-L1 in MCF7 cells induced apoptosis. On the other hand, silencing of UCH-L1 in MCF7/Adr cells led to the opposite effect. Moreover, to explore the mechanism underling these observations, we further investigated the expression of phospho-Akt and its downstream signal phospho-IkB-alpha and other signal molecules including Fas, Fas-L, Trail, DR4, DR5, Bax, cytochrome C, active caspase-3, phospho-p53, phospho-Mdm-2, Bcl-2, Bcl-xL, p21 and p27. The results indicated that the process of apoptosis triggered by UCH-L1 is, at least in part, probably through Phosphoinositide 3-kinase (PI3K)/Akt signal pathway. Our findings suggest that modulating the ubiquitination and deubiquitination pathway could be a novel method for tumor therapy.
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PMID:Over-expression of ubiquitin carboxy terminal hydrolase-L1 induces apoptosis in breast cancer cells. 1894 67


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