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

Some anticancer agents induce cell cycle arrest. We analyzed the effect of anticancer agents on cell-cycle regulators, such as CDK. Our data suggested that arresting cells in the G2-phase of the cell cycle by cisplatin might be regulated by dephosphorylation of cdc2 kinase. Butyrolactone I inhibits both cdc2 and CDK2 kinase in the cell-free system. The cytotoxic effect of paclitaxel shows mainly in the M-phase of the cell cycle. Suramin inhibits cdc2 kinase. UCN-01, a protein kinase-C inhibitor, also inhibits both cdc2 and CDK2 kinase. Some anticancer agents induce apoptosis.
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PMID:[Cell cycle regulation by anticancer agent]. 757 1

Butyrolactone I is a selective inhibitor of the cyclin-dependent kinase (cdk) family. It inhibits both cdk2 and cdc2 kinase, but scarcely affects C-kinase, A-kinase, casein kinases, MAP kinase or EGF receptor-tyrosine kinase (Kitagawa et al., 1993, Oncogene, 8, 2425-2432). We studied the effects of butyrolactone I on the cell cycle as well as on phosphorylation of retinoblastoma protein (pRB). Butyrolactone I inhibited phosphorylation of pRB catalyzed by cyclin A-cdk2 produced by baculovirus in vitro. Furthermore, it inhibited phosphorylation of pRB and cell cycle progression from G1 to S phase in WI38 cell cultures. WI38 cells arrested at the G0 phase by serum starvation progressed in the cell cycle after serum stimulation. pRB was phosphorylated after 10 h serum stimulation. Incorporation of [3H]thymidine into the cells began to increase after 16 h serum stimulation. These processes were inhibited by butyrolactone I. Flow cytometric analysis showed that exposure to butyrolactone I inhibited progression of the cell cycle from G1 to S phase. These data suggested that initiation of DNA synthesis was inhibited by butyrolactone I and that the cell cycle was arrested in the G1 phase. Butyrolactone I also inhibited H1 histone phosphorylation in human WI38 cells and their G2/M progression. tsFT210 cells, a temperature-sensitive cdc2 mutant cell line, were synchronized at G2/M at a nonpermissive temperature, butyrolactone I inhibited the cell cycle progression of these cells at G2/M at the permissive temperature. Thus butyrolactone I, a cyclin-dependent kinase family inhibitor, which prevented the phosphorylations of the cell cycle-regulating proteins pRB and H1 histone, inhibited the cell cycle at G1/S and G2/M, respectively. These results suggest that the phosphorylations of pRB and H1 histone may play crucial roles in G1/S and G2/M progression, respectively, although it is possible that phosphorylations of other proteins by cdks are involved in G1/S and G2/M progression.
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PMID:A cyclin-dependent kinase inhibitor, butyrolactone I, inhibits phosphorylation of RB protein and cell cycle progression. 805 18

We screened cdc2 kinase inhibitors from cultured mediums of micro organisms using purified mouse cyclin B-cdc2 kinase and a specific substrate peptide for cdc2 kinase. A selective inhibitor of cdc2 kinase was isolated from the cultured medium of Aspergillus species F-25799, and identified as butyrolactone I. Butyrolactone I inhibited cdc2 and cdk2 kinases but it had little effect on mitogen-activated protein kinase, protein kinase C, cyclic-AMP dependent kinase, casein kinase II, casein kinase I or epidermal growth factor-receptor tyrosine kinase. Its inhibitory effect was found to be due to competition with ATP. Butyrolactone I selectively inhibited the H1 histone phosphorylation in nuclear extracts. It also inhibited the phosphorylation of the product of retinoblastoma susceptibility gene in nuclear extracts and intact cells. Thus butyrolactone I should be very useful for elucidating the function of cdc2 and cdk2 kinases in cell cycle regulation.
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PMID:Butyrolactone I, a selective inhibitor of cdk2 and cdc2 kinase. 839 80

Butyrolactone I, which is a naturally occurring specific inhibitor of the cdc2 kinase family, showed antitumor effects on several non-small- and small-cell-lung cancer cell lines with IC50 values the order of 50 micrograms/ml on the former. No cross-resistance of several drug-resistant cell lines, including those with the multidrug-resistant phenotype and five cisplatin-resistant cell lines to butyrolactone I was observed. The cdc2 kinase activity of PC-14 cells was inhibited by treatment with 20 micrograms/ml butyrolactone I, a concentration comparable to the IC50 value, for 2 hours. Longer exposure to butyrolactone I (> 24 hours) reduced the cdc2 kinase protein level. Butyrolactone I arrested the cells at the G2/M phase in a concentration dependent manner. These results suggest that butyrolactone I actually acts on cdc2 kinase, rather than other cdk kinases, in PC-14 cells. Inhibition of DNA synthesis, determined by measuring thymidine uptake, occurred earlier (2 hours) after initiating exposure than the decrease in the cdc2 protein level and was concentration dependent, suggesting that butyrolactone I inhibited DN4 synthesis. Cell permeabilization by digitonin enhanced DN4 synthesis inhibition by butyrolactone I, suggesting that the permeability of the membrane to this agent was the limiting factor for its growth inhibitory effect. Many anticancer agents, such as alkylating agents and cisplatin, cause cells to accumulate at the G2/M phase of the cell cycle. We investigated whether butyrolactone I had any modulatory effect on the antitumor effects of several anticancer drugs in vitro. Butyrolactone I showed no modulatory effects on vindesine, paclitaxel, or etoposide, but exposure of PC-9 and PC-14 cells to butyrolactone I together with or prior to treatment with cisplatin reduced the cytotoxicity of the latter. Thin-layer chromatographic analysis revealed that butyrolactone I bound to cisplatin, which was a possible cause of the reduced cisplatin cytotoxicity in the presence of bytyrolactone I.
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PMID:Antitumor effects of butyrolactone I, a selective cdc2 kinase inhibitor, on human lung cancer cell lines. 904 96

CDK inhibitor, Butyrolactone I inhibited CDK1, 2 and 5 in CDKs. In syncronized human lung fibroblast WI38 cells, it inhibited G1/S transition by inhibiting the phosphorylation of RB protein and G2/M transition by inhibiting the phosphorylation of H1 histone. Also, it selectively inhibited the initiation of DNA replication. The MMP inhibitor, BE16627B, reversively inhibited metalloproteinases including MMPs. It showed the MMP-dependent inhibition of the growth and metastasis of human tumor cells in nude mice without any cytotoxicity and severe side effects. The MMP inhibitor, Marimastat, showed remarkable prolongation of the life span of patients with pancreatic tumors in clinical trials.
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PMID:[CDK and MMP inhibitors]. 930 54

As cells enter mitosis, gap junctional communication with neighboring cells decreases (H. Xie et al., J. Cell Biol., 137: 203-210, 1997). Phosphorylation of the gap junction protein, connexin43 (Cx43), has been implicated in reducing junctional permeability. Cx43 contains p34cdc2 phosphorylation consensus sites in its COOH-terminal region. Accordingly, we examined the role of p34cdc2/cyclin B in Cx43 phosphorylation. Purified p34cdc2/cyclin B, or p34cdc2/cyclin B complex immunoprecipitated from mitotic cells, phosphorylated GSTCx43 in vitro. The synthetic peptide, SDPYHATTGPLSPSKDCGSPK, corresponding to amino acids 241-264 of Cx43, was also phosphorylated by p34cdc2/cyclin B in vitro. Sites phosphorylated in vitro were phosphorylated in vivo. Butyrolactone I, an inhibitor of cdc2 kinase, inhibited increases in Cx43 phosphorylation during mitosis. We conclude that phosphorylation of Cx43 by p34cdc2/cyclin B may contribute to the increased Cx43 phosphorylation and reduced gap junctional communication observed during mitosis.
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PMID:Cdc2-mediated phosphorylation of the gap junction protein, connexin43, during mitosis. 943 84

Cyclin dependent kinases propel the cell cycle in collaboration with cyclins. We have examined the expression of cdk2/cdc2 in adenoma and focal carcinoma in adenomatous tissue to explore their role in tumorigenesis of colorectum. Immunohistochemical study revealed that cdk2/cdc2 was overexpressed in a subsets of adenoma (14/50; 28.0%) but this overexpression was much more obvious in focal carcinoma (13/15; 86.7%). These results suggest that cdk2/cdc2 is remarkably upregulated together with a malignant change. In an effort to demonstrate a significant role for cdk2/cdc2 in colon cancer, we investigated growth and apoptosis with butyrolactone I, a specific inhibitor for cdk2/cdc2, using 4 colon carcinoma cell lines (HCT116, LoVo, HT29, Colo 320DM). Butyrolactone I inhibited proliferation of all colon carcinoma cell lines at 100 microM and it induced apoptosis in LoVo cell line with induction of p53. Our findings suggest that inhibition of cdk2/cdc2 may be a useful strategy against colon cancer.
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PMID:Cdk2/cdc2 expression in colon carcinogenesis and effects of cdk2/cdc2 inhibitor in colon cancer cells. 966 16

Butyrolactone I is a selective inhibitor of the cyclin-dependent kinase (cdk) family, cdk2 and cdc2 kinase. In the present study, the effect of butyrolactone I on expression of the albumin and alpha-fetoprotein (AFP) genes was investigated in HuH-7 human hepatoma cells. Butyrolactone I inhibited cell growth and arrested cells predominantly in G2/M phase. By Northern blot analysis, the levels of both albumin and AFP mRNA were suppressed dose-dependently by butyrolactone I. In transient chloramphenicol acetyltransferase plasmid transfection experiments, the albumin promoter activity and the AFP promoter and enhancer activities were suppressed by butyrolactone I. Consistent with this, the transcripts of hepatocyte nuclear factor-1 (HNF-1), a liver-specific transcription factor which transactivates these promoter and enhancer regions were reduced by butyrolactone I in a dose-dependent manner. These results indicate that butyrolactone I down-regulates both the albumin and the AFP gene transcription through the reduction of HNF-1 expression.
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PMID:Suppression of albumin and alpha-fetoprotein gene expression by butyrolactone I, a selective inhibitor of the cdk family, in HuH-7 human hepatoma cells. 989 85

Trichostatin A (TSA, 17 nM), a specific and reversible inhibitor of histone deacetylase induced neurite network formation at and after 4 days. The networks were preserved for at least 3 weeks in the presence of TSA. Butyrolactone I (BLI, 23.6 microM), an inhibitor of cdc2 and cdk2 kinases, also induced neurite extension. Both compounds enhanced the acetylcholinesterase activity of the cells. Cell cycle progression of the cells was blocked by TSA (17 nM) at G1 phase alone. Furthermore, the level of histone hyperacetylation and p21(WAF1) expression in TSA-treated cells increased transiently. These findings suggest that the induction of the neuronal differentiation in Neuro 2a cells by these agents requires the cell cycle arrest at G1 phase, which is caused by inhibition of cycline dependent kinase, a target molecule of BLI and p21(WAF1).
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PMID:Neuronal differentiation of neuro 2a cells by inhibitors of cell cycle progression, trichostatin A and butyrolactone I. 1007 91

Two principal kinases, p34cdc2 kinase and MAP kinase play a pivotal role in maturation of mammalian oocytes. In the porcine and bovine oocytes both kinases are activated around the time of germinal vesicle breakdown (GVBD). Butyrolactone I (BL I), a specific inhibitor of cdk kinases, prevents effectively and reversibly resumption of meiosis in the porcine and bovine oocytes. Neither p34cdc2 kinase nor MAP kinase are activated in oocytes inhibited in the GV stage. The bovine oocytes maintained for 48 h in the medium supplemented with BL I, progress subsequently to metaphase II in 91%, their cumuli expand optimally and after in vitro fertilization they possess two pronuclei. When the cdc2 kinase is blocked in the porcine oocytes by BL I, MAP kinase, activated by okadaic acid treatment, is able to substitute cdc2 kinase and induce GVBD. The histone H1 kinase activity sharply decreases in the metaphase II oocytes treated by BL I and one or two female pronuclei are formed. These data indicate that BL I is a useful tool either for the two step in vitro culture of mammalian oocytes or for their activation in nuclear transfer experiments.
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PMID:Interplay between CDC2 kinase and MAP kinase pathway during maturation of mammalian oocytes. 1073 27


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