Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

After chromosome replication, the intertwined sister chromatids are disentangled by topoisomerases. The integrity of this process is monitored by the chromatid decatenation checkpoint. Here, we describe small molecule modulators of the human chromatid decatenation checkpoint identified using a cell-based, chemical genetic modifier screen. Similar to 1,2,7-trimethylyxanthine (caffeine), these small molecules suppress the G(2)-phase arrest caused by ICRF-193, a small molecule inhibitor of the enzymatic activity of topoisomerase II. Analysis of specific suppressors, here named suptopins for suppressor of Topoisomerase II inhibition, revealed distinct effects on cell cycle progression, microtubule stability, nucleocytoplasmic transport of cyclin B1, and no effect on the chromatin deacetylation checkpoint induced by trichostatin A. The suptopins provide new molecular tools for dissecting the role of topoisomerases in maintaining genomic stability and determining whether inhibiting the chromatid decatenation checkpoint sensitizes tumor cells to chemotherapeutics.
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PMID:Small molecule modulation of the human chromatid decatenation checkpoint. 1470 Jun 34

Camptothecin and Adriamycin are clinically important inhibitors for topoisomerase (Topo) I and Topo II, respectively. The ataxia-telangiectasia mutated (ATM) product is essential for ionizing radiation-induced DNA damage responses, but the role of ATM in Topo poisons-induced checkpoints remains unresolved. We found that distinct mechanisms are involved in the activation of different cell cycle checkpoints at different concentrations of Adriamycin and camptothecin. Adriamycin promotes the G(1) checkpoint through activation of the p53-p21(CIP1/WAF1) pathway and decrease of pRb phosphorylation. Phosphorylation of p53(Ser20) after Adriamycin treatment is ATM dependent, but is not required for the full activation of p53. The G(1) checkpoint is dependent on ATM at low doses but not at high doses of Adriamycin. In contrast, the Adriamycin-induced G(2) checkpoint is independent on ATM but sensitive to caffeine. Adriamycin inhibits histone H3(Ser10) phosphorylation through inhibitory phosphorylation of CDC2 at low doses and down-regulation of cyclin B1 at high doses. The camptothecin-induced intra-S checkpoint is partially dependent on ATM, and is associated with inhibitory phosphorylation of cyclin-dependent kinase 2 and reduction of BrdUrd incorporation after mid-S phase. Finally, apoptosis associated with high doses of Adriamycin or camptothecin is not influenced by the absence of ATM. These data indicate that the involvement of ATM following treatment with Topo poisons differs extensively with dosage and for different cell cycle checkpoints.
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PMID:Topoisomerase poisons differentially activate DNA damage checkpoints through ataxia-telangiectasia mutated-dependent and -independent mechanisms. 1514 Oct 20

Ellipticine, a cytotoxic plant alkaloid, is known to inhibit topoisomerase II. Here we report the mechanism of apoptosis induction and cell cycle arrest by ellipticine in human breast MDA-MB-231 cancer cells. Ellipticine treatment arrested MDA-MB-231 cells at the G2/M phase after 6 h of treatment. This effect was strongly associated with a concomitant decrease in the level of cyclin B1, Cdc25 and Cdc2, and increase in phospho-Cdc2 (Tyr15). In addition, ellipticine also induced apoptosis in MDA-MB-231 cells, as determined by using both DNA fragmentation and Annexin-V staining assay. Ellipticine increased the expression of Bax, but decreased the level of Bcl-2, Bcl-XL and X-linked inhibitor of apoptosis protein (XIAP), and subsequently triggered the mitochondrial apoptotic pathway (release of cytochrome c, and activation of caspase-9 and -3). In addition, pre-treatment of cells with caspase-9 inhibitor inhibited ellipticine-induced cell proliferation and apoptosis, indicating that caspase-9 activation was involved in MDA-MB-231 cell apoptosis induced by ellipticine. Taken together, our study suggests that the inhibition of cell cycle progression signaling and initiation of the mitochondrial apoptotic system may participate in the anti-proliferative activity of ellipticine in MDA-MB-231 cells.
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PMID:The anti-proliferative inhibition of ellipticine in human breast mda-mb-231 cancer cells is through cell cycle arrest and apoptosis induction. 1602 29

The ability of the immune system to magnify the appearance of disease by generating relatively large amounts of antibody in response to small amounts of disease makes it a natural biosensor, and serum antibodies have emerged as promising biomarkers for the detection of cancer. This review summarizes recent progress in targeting serum antibodies for cancer diagnosis, with a particular focus on colorectal cancer (CRC). Several serum antibodies have been detected at increased levels in CRC patients, including p53, carcinoembryonic antigen, Ras, topoisomerase II-alpha, histone deacetylase 3 and 5, ubiquitin C-terminal hydrolase L3, tropomyosin and cyclin B1. As each antibody is only present in a limited proportion of patients (usually < 40%), a combination of serum antibodies that defines the 'immunological signature' of cancer needs to be developed. High-throughput methods to identify new serum antibodies for cancer diagnosis are also reviewed.
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PMID:Targeting serum antibody for cancer diagnosis: a focus on colorectal cancer. 1722 37

How plant organs grow to reach their final size is an important but largely unanswered question. Here, we describe an Arabidopsis thaliana mutant, brassinosteroid-insensitive4 (bin4), in which the growth of various organs is dramatically reduced. Small organ size in bin4 is primarily caused by reduced cell expansion associated with defects in increasing ploidy by endoreduplication. Raising nuclear DNA content in bin4 by colchicine-induced polyploidization partially rescues the cell and organ size phenotype, indicating that BIN4 is directly and specifically required for endoreduplication rather than for subsequent cell expansion. BIN4 encodes a plant-specific, DNA binding protein that acts as a component of the plant DNA topoisomerase VI complex. Loss of BIN4 triggers an ATM- and ATR-dependent DNA damage response in postmitotic cells, and this response coincides with the upregulation of the cyclin B1;1 gene in the same cell types, suggesting a functional link between DNA damage response and endocycle control.
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PMID:BIN4, a novel component of the plant DNA topoisomerase VI complex, is required for endoreduplication in Arabidopsis. 1805 5

Earlier studies have shown that ICP22 and the U(L)13 protein kinase but not the U(S)3 kinase are required for optimal expression of a subset of late (gamma(2)) genes exemplified by U(L)38, U(L)41, and U(S)11. In primate cells, ICP22 mediates the disappearance of inactive isoforms of cdc2 and degradation of cyclins A and B1. Active cdc2 acquires a new partner, the viral DNA synthesis processivity factor U(L)42. The cdc2-U(L)42 complex recruits and phosphorylates topoisomerase IIalpha for efficient expression of the gamma(2) genes listed above. In uninfected cells, the cdc25C phosphatase activates cdc2 by removing two inhibitory phosphates. The accompanying report shows that in the absence of cdc25C, the rate of degradation of cyclin B1 is similar to that occurring in infected wild-type mouse embryo fibroblast cells but the levels of cdc2 increase, and the accumulation of a subset of late proteins and virus yields are reduced. This report links ICP22 with cdc25C. We show that in infected cells, ICP22 and U(S)3 protein kinase mediate the phosphorylation of cdc25C at its C-terminal domain. In in vitro assays with purified components, both U(L)13 and U(S)3 viral kinases phosphorylate cdc25C and ICP22. cdc25C also interacts with cdc2. However, in infected cells, the ability of cdc25C to activate cdc2 by dephosphorylation of the inactive cdc2 protein is reduced. Coupled with the phosphorylation of cdc25C by the U(S)3 kinase, the results raise the possibility that herpes simplex virus 1 diverts cdc25C to perform functions other than those performed in uninfected cells.
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PMID:The interaction of herpes simplex virus 1 regulatory protein ICP22 with the cdc25C phosphatase is enabled in vitro by viral protein kinases US3 and UL13. 1827 72

Earlier studies have shown that in herpes simplex virus 1-infected cells, ICP22 upregulates the accumulation of a subset of gamma(2) proteins exemplified by the products of the U(L)38, U(L)41, and U(S)11 genes. The ICP22-dependent process involves degradation of cyclins A and B1, the stabilization and activation of cdc2, physical interaction of activated cdc2 with the U(L)42 DNA synthesis processivity factor, and recruitment and phosphorylation of topoisomerase IIalpha by the cdc2/U(L)42 complex. Activation of cdc2, the first step in the process, is a key function of the mitotic phosphatase cdc25C. To define the role of cdc25C, we probed some features of the ICP22-dependent pathway of upregulation of gamma(2) genes in cdc25C(-/-) cells and in cdc25C(+/+) cells derived from sibling mice. We report that cyclin B1 turned over in cdc25C(+/+) or cdc25C(-/-) cells at the same rate, that cdc2 increased in amount, and that U(S)11 and U(L)38 proteins and infectious virus accumulated in smaller amounts than in wild-type infected cells. The reduction in U(L)38 protein accumulation and virus was greater in cdc25C(-/-) cells infected with virus lacking ICP22 than in cells infected with wild-type virus. We conclude that cdc25C phosphatase plays a role in viral replication and that this role extends beyond its function of activating cdc2 for initiation of the ICP22-dependent cascade for upregulation of gamma(2) gene expression.
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PMID:Role of cellular phosphatase cdc25C in herpes simplex virus 1 replication. 1827 75

Despite major advances in the molecular biology of the cancer cell over the past two decades, the great majority of patients are still treated by conventional cytotoxic drugs. The chemotherapy regimens employed frequently include platinating agents, taxanes, intercalating agents and topoisomerase inhibitors. Attempts to predict the therapeutic efficacy of such drugs by molecular profiling (theranostics) have up to the present time had limited success. Genes responsible for the control of cell division, senescence and apoptosis whose normal functions become corrupted during carcinogenesis, might potentially play a part in determining chemotherapeutic response. Here we have examined the relationships between the chemoresponsiveness of 18 human in vitro cancer cell lines and proteomic expression of Ras, cyclins B1 and D1 and cyclin-dependent kinases Cdk1 and Cdk4. When all 18 cell lines were examined as a single group, proteomic expression did not provide any helpful theranostic predictors. Clear relationships between proteomic expression and drug efficacy emerged, however, when Ras, cyclin B1, cyclin D1, Cdk1 and Cdk4 were examined separately in p53 wild-type and p53 mutant cell subsets. We suggest that the theranostic relationships we have detected in vitro may have potential relevance in vivo and should prompt clinical theranostic studies which take account of p53 mutational status.
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PMID:Theranostic proteomic profiling of cyclins, cyclin dependent kinases and Ras in human cancer cell lines is dependent on p53 mutational status. 1836 Jul 17

Chk1 is the major mediator of cell-cycle checkpoints in response to various forms of genotoxic stress. Although it was previously speculated that checkpoint abrogation due to Chk1 inhibition may potentiate the efficacy of DNA-damaging agents through induction of mitotic catastrophe, there has not been direct evidence proving this process. Here, through both molecular marker and morphological analysis, we directly demonstrate that specific downregulation of Chk1 expression by Chk1 siRNA potentiates the cytotoxicities of topoisomerase inhibitors through the induction of premature chromosomal condensation and mitotic catastrophe. More importantly, we discovered that the cellular cyclin B1 level is the major determinant of the potentiation. We show that downregulation of cyclin B1 leads to impairment of the induction of mitotic catastrophe and correspondingly a reduction of the potentiation ability of either Chk1 siRNA or a small molecule Chk1 inhibitor. More significantly, we have extended the study by examining a panel of 10 cancer cell-lines with different tissue origins for their endogenous levels of cyclin B1 and the ability of a Chk1 inhibitor to sensitize the cells to DNA-damaging agents. The cellular levels of cyclin B1 positively correlate with the degrees of potentiation achieved. Of additional interest, we observed that the various colon cancer cell lines in general appear to express higher levels of cyclin B1 and also display higher sensitivity to Chk1 inhibitors, implying that Chk1 inhibitor may be more efficacious in treating colon cancers. In summary, we propose that cyclin B1 is a biomarker predictive of the efficacy of Chk1 inhibitors across different types of cancers. Unlike previously established efficacy-predictive biomarkers that are usually the direct targets of the therapeutic agents, cyclin B1 represents a non-drug-target biomarker that is based on the mechanism of action of the target inhibitor. This finding may be potentially very useful for the stratification of patients for Chk1 inhibitor clinical trials and hence, maximize its chance of success.
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PMID:Cyclin B1 is an efficacy-predicting biomarker for Chk1 inhibitors. 1867 Nov 43

The authors have made an immunohistochemical determination of Ki-67, topoisomerase IIalpha, cyclins D1, A, and B1, and calculated their indices in 145 acinar adenocarcinomas of the prostate. This tumor is characterized by a wide range of Ki-67 index (from 3 to 90% or more) although 90% of cases are in the range of 5-35%. Other study proliferative markers are distributed in the following descending order: cyclin D1 (1.32 to 63.27%), topoisomerase IIalpha (0.47 to 53.17%), cyclin A (0.46 to 28.09%), and cyclin B1 (0.29 to 9.34%). The indices of the study markers are increased as the Gleason grade is higher. The exception is cyclin D1 that shows high expression in intact and tumor tissues, which is frequently greater than that of Ki-67, and its stable expression independent of the Gleason score.
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PMID:[The proliferative properties and regulators of the mitotic cell cycle of prostate adenocarcinoma]. 2013 1


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