Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown earlier that the cell growth inhibitory activity of interferon (IFN) is significantly enhanced by tunicamycin (TM) (Maheshwari et al., Science 219, 1339-1341, 1983). In this report, we investigated various regulatory points of synergistic action between TM and IFN-alpha/beta that inhibit cell growth in NIH 3T3 cells. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) viability assays showed a dose-dependent increase in percentage inhibition of the cells when treated with either TM or IFN. When doses of TM and IFN that had no significant inhibition on cell viability were used in combination, there was a pronounced suppression of DNA synthesis (tritiated thymidine incorporation). Flow cytometry studies revealed that individual treatments with either IFN or TM that did not alter the cell cycle profile, when combined, resulted in an impaired cell cycle by inhibiting G1/S progression. The blockage of G1/S transition was associated with reduction of cyclin-dependent kinase (CDK4) activity. The mRNA (analyzed by ribonuclease protection assay) and protein levels (assayed by Western blotting) of cyclins D1, D3, and CDK4 were downregulated by combined treatment with IFN and TM. An increase in the expression of p27/kipl, an inhibitor of CDK4, was observed in cells that were treated with both IFN and TM. These studies suggest that insufficient formation of the active cyclin/CDK complex could possibly be deferring the cells from normal cycling and may be responsible for the ability of TM to enhance cell growth inhibition induced by IFN.
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PMID:Tunicamycin enhances the anticellular activity of interferon by inhibiting G1/S phase progression in 3T3 cells. 1076 75

To assess the role of 8-oxoguanine glycosylase (OGG1) in the cell defense against radiation injury, the radiation-induced cytotoxicities were compared between the mutant type KG-1 featuring a loss of OGG1 activity due to a homozygous mutation of Arg 229 Gln, and the wild type U937. While the following three obvious toxicities were displayed in KG-1, they were observed only minimally in U937. These were: a dramatic arrest at the G2/M phase indicated by a marked increase in both the number of G2/M cells and the expression of cyclin B1, cdc2, and mitotic phosphoprotein monoclonal-2 (MPM-2)-reactive proteins; a severe apoptosis shown by a marked increase in the number of cells with hypo-diploid DNA and DNA fragmentation; and as a result, a severe inhibition of cell growth and proliferation measured by the MTT test and [(3)H]-thymidine uptake assay. As expected, KG-1 exhibited a significant increase in the 8-hydroxyguanine level in DNA whereas U937 did not. However, the level of irradiation-induced lipid peroxidation was almost the same in both cell lines. All of these symptoms shown by KG-1 were observed in Molt-4 and CEM-CM3, which were also found to feature low OGG1 activity. These findings suggest that OGG1 plays an important role in cell survival from radiation-induced damage and are also indicative of the capability of 8-hydroxyguanine in DNA to induce cellular toxicities.
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PMID:Radiation sensitivity depends on OGG1 activity status in human leukemia cell lines. 1182 46

Past research indicated that methylseleninic acid (MSA) is an excellent tool for investigating the cancer chemopreventive action of selenium in vitro. The present study was designed to examine the cellular and molecular effects of MSA in the MCF10AT1 and MCF10AT3B premalignant human breast cells. After exposure to MSA, both cell lines exhibited a dose- and time-dependent growth-inhibitory response as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay. Further characterization of cellular and molecular changes was carried out only with the MCF10AT1 cells. Flow cytometry analysis showed that MSA blocked cell cycle progression at the G(0)-G(1) phase. Induction of apoptosis was also observed with the use of either the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) or the annexin V binding method. cDNA microarray analyses with cell cycle- and apoptosis-targeted arrays were then applied to profile the gene expression changes mediating these two cellular events. The analyses were conducted at 6 and 12 h of MSA treatment using synchronized cells. The expression signals of 30 genes were found to be significantly altered by MSA. These genes fall into three categories: cell cycle checkpoint controllers (e.g., cyclins, cdcs, cdks, E2F family proteins, and serine/threonine kinases), apoptosis regulatory genes (e.g., Apo-3, c-jun, and cdk5/cyclin D1), and signaling molecules [e.g., mitogen-activated protein (MAP)/extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3'-kinase (PI3k) cascade genes]. The expression changes of 15 genes were selected for verification by Western or semiquantitative reverse transcription-PCR analyses. An agreement rate of 60% (9 of 15) was obtained from these confirmation experiments. On the basis of the above findings, tentative signaling pathways mediating the outcome of selenium-induced cell cycle arrest and apoptosis are proposed. The present study thus demonstrated the feasibility of applying cDNA microarray technology in delineating the mechanisms of the action of selenium and in pinpointing molecular targets as potential biomarkers for evaluating the efficacy of selenium intervention.
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PMID:Identification of molecular targets associated with selenium-induced growth inhibition in human breast cells using cDNA microarrays. 1183 May 24

This study was undertaken to investigate whether kainic acid (KA) may regulate the expression of several proteins which plays an important role in cell-cycle progression in cerebellar granule neurons (CGNs). KA induced decrease in MTT values in a concentration dependent way. Flow cytometric analysis showed that KA was able to induce 30% apoptosis in CGNs. Apoptotic nuclear condensation were detected 24 h of exposure to KA (200 microM). An associated marked increase in DNA synthesis, measured by BrdU incorporation, was observed. Western blot analysis showed that KA induced an increase in the expression of Cdk2, cyclin E and E2F-1. It is proposed that, in post-mitotic cells like CGNs, re-entry cell cycle could be responsible for the apoptotic effect of KA.
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PMID:Kainic acid-induced apoptosis in cerebellar granule neurons: an attempt at cell cycle re-entry. 1193 Jan 51

1. Previous studies have suggested that neuronal apoptosis is the result of an abortive attempt to re-enter the cell cycle, and more recently the cyclin-dependent (CDKs) and the mitogen-activated protein (MAP) kinases, two superfamilies of kinases that influence and control cell cycle progression, have been implicated in neuronal apoptosis. 2. Here, to examine whether CDK/MAPK related pathways are involved in excitotoxicity, we studied the actions of various kinase inhibitors on apoptosis induced by the ionotropic glutamate (Glu) receptor agonist, kainate (KA), in primary cultures of murine cerebellar granule cells (CGCs). 3. KA-mediated neurotoxicity was concentration-dependent, as determined by a cell viability assay monitoring the reduction of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and largely apoptotic in nature, as shown by morphological examination and labelling of DNA fragmentation in situ using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP digoxigenin nick-end labelling (TUNEL). 4. KA-mediated neurotoxicity and apoptosis was completely attenuated by the mixed CDK and MAP kinase inhibitor, olomoucine, in a concentration-dependent manner (50 - 600 microM), and partially by roscovitine (1 - 100 microM), a more selective CDK inihibitor. 5. The p38 MAP kinase inhibitor, SB203580 (1 - 100 microM), partially attenuated KA receptor-mediated apoptosis, as did the MAP kinase kinase inhibitors PD98509 (1 - 100 microM) and U0126 (1 - 100 microM). 6. These findings provide new evidence for a complex network of interacting pathways involving CDK/MAPK that control apoptosis downstream of KA receptor activation in excitotoxic neuronal cell death.
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PMID:Kainate receptor-mediated apoptosis in primary cultures of cerebellar granule cells is attenuated by mitogen-activated protein and cyclin-dependent kinase inhibitors. 1193 14

We investigated the anti-proliferative effects of luteolin and apigenin, isolated from Ixeris sonchifolia Hance, on HepG2 human hepatocellular carcinoma cells. In MTT assay luteolin showed more efficient anti-proliferative effects on cells than apigenin did. According to propidium iodide staining and flow cytometry studies, we postulated that these effects might be a result of cell cyde arrest. Hence we examined the changes of protein expressions related to cell cycle arrest. Western blotting data demonstrated that the down-regulated expression of CDK4 was correlated to the increase of p53 and CDK inhibitor p21(WAF1/CIP1) protein. These data suggest that luteolin may have potential as an anti-cancer agent.
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PMID:Inhibitory effects of luteolin isolated from Ixeris sonchifolia Hance on the proliferation of HepG2 human hepatocellular carcinoma cells. 1264 93

Evodiamine, isolated from a Chinese herbal drug named Wu-Chu-Yu, possesses many biological functions. Recently, it has been reported that Wu-Chu-Yu exerts an antiproliferative effect on several cancers. Prostate carcinoma initially occurs as an androgen-dependent tumor and is the second leading cause of cancer death in American males. In the present study, the effect of evodiamine on the growth of androgen-dependent prostate cancer cell line LNCaP in vitro was examined. Based on [3-(4,5-dimethylthiazol-2-yle)2,5-diphenyltetrazolium bromide] (MTT) assay, evodiamine significantly inhibited the growth of LNCaP cells in a concentration-dependent manner. A significant and concentration-dependent inhibitory effect of evodiamine on LNCaP cell growth was observed at 24 hr and persisted for 96 hr. The examination of lactate dehydrogenase (LDH) assay showed that the cytotoxic effects of evodiamine on LNCaP cells were concentration dependent. Furthermore, we examined the influences of evodiamine on cell death and cell cycle. The flow cytometric analysis of evodiamine-treated cells indicated a block of G2/M phase and an elevated level of DNA fragmentation. The G2/M arrest reached a maximum at 24 hr after evodiamine treatment. The G2/M arrest was accompanied by an elevated p34(cdc2) kinase activity and an increase in the protein expression of cyclin B1 and phosphorylated form of p34(cdc2) (Thr 161). Examination of TUNEL showed that evodiamine-induced apoptosis was observed at 24 hr and extended for 72 hr. Evodiamine elevated caspase-3, and caspase-9 activities and the processing of caspase-3 and caspase-9. These results suggested that evodiamine inhibits the growth of prostate cancer cell line, LNCaP, through an accumulation of cell cycle at G2/M phase and an induction of apoptosis.
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PMID:Inhibitory effects of evodiamine on the growth of human prostate cancer cell line LNCaP. 1514 52

Experimental data implicate calpain activation in the pathways involved in neuronal apoptosis. Indeed, calpain inhibitors confer neuroprotection in response to various neurotoxic stimuli. However, the pathways involved in calpain activation-induced apoptosis are not well known. We demonstrate that apoptosis (40%) induced by serum/potassium (S/K) withdrawal on cerebellar granule cells (CGNs) is inhibited by selective calpain inhibitors PD150606 (up to 15%) and PD151746 (up to 29%), but not PD145305 in CGNs. zVAD-fmk, a broad spectrum inhibitor of caspases, attenuates apoptosis (up to 20%) mediated by S/K deprivation and protects against cell death, as measured by MTT ([3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium]) assay. PD150606 and PD151746 prevented apoptosis mediated by S/K withdrawal through inhibition of calpain. Furthermore, PD151746 was able to inhibit caspase-3 activity. After S/K withdrawal, we observed an increase in cdk5/p25 formation and MEF2 phosphorylation that was prevented by 40 microM PD150606 and PD151746. This indicates that calpain inhibition may be an upstream molecular target that prevents neuronal apoptosis in vitro. Taken together, these data suggest an apoptotic route in S/K withdrawal in CGNs mediated by calpain activation, cdk5/p25 formation and MEF2 inhibition. Calpain inhibitors may attenuate S/K withdrawal-induced apoptosis and may provide a potential therapeutic target for drug treatment in a neurodegenerative process.
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PMID:Inhibition of the cdk5/MEF2 pathway is involved in the antiapoptotic properties of calpain inhibitors in cerebellar neurons. 1591 27

Thallium acetate is a known neurotoxic agent. In this study, we investigated the mechanisms by which thallium acetate induces cell cycle arrest and cell apoptosis in cultured LC6 glioma cells. Exposure of C6 glioma cells to thallium acetate decreased cell viability as demonstrated by the MTT assay. Incubation of thallium acetate arrested cell cycle progression at the G2/M phase and caused cellular apoptosis at 300 microM as determined by trypan blue exclusion and flow cytometric analysis. The G2/M arrest was associated with a decrease in expression of CDK2 protein and an upregulation of p53 and the CDK inhibitor p21(Cip1), but not p27(Kip1). Thallium acetate did not alter the protein levels of cyclin A and B; cyclin D1, D2, and D3; and CDK4 expression in C6 glioma cells. Incubation of C6 glioma cells with thallium acetate upregulated the expression of proapoptotic proteins Bad and Apaf and downregulated the expression of anti-apoptotic proteins Bcl-xL and Bcl-2. In conclusion, these data suggest that thallium acetate inhibits cell cycle progression at G2/M phase by suppressing CDK activity through the p53-mediated induction of the CDK inhibitor p21(Cip1). Impairment of cell cycle progression may trigger the activation of a mitochondrial pathway and shifts the balance in the Bcl-2 family toward the proapoptotic members, promoting the formation of the apoptosome and, consequently, apoptosis.
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PMID:Thallium acetate induces C6 glioma cell apoptosis. 1596 99

The second open reading frame of avian reovirus S1 gene segment encodes a 17 kDa non-structural protein, named p17. The biological role of p17 is fully unknown so far. Using trypan blue dye exclusion and MTT assay, we demonstrated that the ectopic expression of p17 results in the reduction of viable cell number and cell proliferation rate of Vero, BHK, 293, and HeLa cells. Measurement of LDH activity and DNA fragmentation analysis revealed that p17 expression did not cause cell death or apoptosis. These data indicated that the p17 possessed the growth retardation function. Semi-quantitative RT-PCR and Western blotting revealed that p17-expressing cells induced the expression of CDK inhibitor p21cip1/waf1 in a time- and dose-dependent manner, but the transcripts of CDK inhibitor p15INK4b, p16INK4a, or p27kip were not altered. In the presence of p17, the p53 protein level and p53-driven reporter activity were elevated significantly. Dominant negative p53 alleviated the p21 accumulation, p53 activation, and growth inhibition effect induced by p17. Taken together, these studies revealed a possible intrinsic function of p17 in growth regulation through the activation of p53 and p21cip1/waf1.
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PMID:Retardation of cell growth by avian reovirus p17 through the activation of p53 pathway. 1614 10


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