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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA chip technology was used in an attempt to identify target genes responsible for apoptosis induced by etoposide, a p53 activating topoisomerase II inhibitor used clinically as an antitumor agent. 62 Individual mRNAs whose mass changed significantly were identified after screening oligonucleotide arrays capable of detecting 6591 unique human mRNA species. 12 (Nine induced and three repressed) of the etoposide-responsive genes were further studied by Northern analysis and an agreement rate of 92%, was reached. Among the 12 genes studied, two (WAF1/p21 and PCNA) are known p53 regulatory genes, two (glutathione peroxidase and S100A2 calcium-binding protein) appear to be the novel p53 target genes and the others appear to be p53-independent. Based upon these findings, the signalling pathways that possibly mediate etoposide-induced apoptosis are proposed.
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PMID:Identification of the genes responsive to etoposide-induced apoptosis: application of DNA chip technology. 1009 70

Somatic changes in CpG dinucleotide methylation occur quite commonly in human cancer cell DNA. Relative to DNA from normal human colonic cells, DNA from human colorectal cancer cells typically displays regional CpG dinucleotide hypermethylation amid global CpG dinucleotide hypomethylation. The role of the maintenance DNA methyltransferase (DNMT1) in the acquisition of such abnormal CpG dinucleotide methylation changes in colorectal cancer cells remains controversial; in one study, 60-200-fold increases in DNMT1 mRNA expression were detected in colorectal polyps and cancers relative to normal colonic tissue [W. S. El-Deiry et al., Proc. Natl. Acad. Sci. USA, 88: 3470-3474, 1991], whereas in another study, only small increases in DNMT1 mRNA expression, commensurate with differences in cell proliferation accompanying colonic tumorigenesis, were observed [P. J. Lee et al., Proc. Natl. Acad. Sci. USA, 93: 10366-10370, 1996]. To definitively ascertain whether abnormal DNMT1 expression might accompany human colorectal carcinogenesis, we subjected a series of normal and neoplastic colonic tissues to immunohistochemical staining using a polyclonal antiserum raised against a DNMT1 polypeptide. A concordance of DNMT1 expression with the expression of PCNA and other cell proliferation markers, such as Ki-67 and DNA topoisomerase IIalpha, was observed in normal colonic epithelial cells and in cells comprising other normal epithelia and lymphoid tissues. The polypeptide p21, which has been reported to undermine DNMT1 binding to proliferating cell nuclear antigen at DNA replication sites, was not expressed by normal colonic cells containing DNMT1 and other cell proliferation markers. In adenomatous polyps, although DNMT1 expression coincided with the expression of other cell proliferation markers, many DNMT1-expressing cells also expressed p21. The fidelity of DNMT1 expression was further undermined in colorectal carcinomas, in which a striking heterogeneity in DNMT1 expression, with some carcinoma cells containing very high DNMT1 levels and others containing very low DNMT1 levels, was observed. These results indicate that human colorectal carcinogenesis is accompanied by a progressive dysregulation of DNMT1 expression and suggest that abnormalities in DNMT1 expression may contribute to the abnormal CpG dinucleotide methylation changes characteristic of human colorectal carcinoma cell DNA.
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PMID:Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. 1046 69

The transcription factor YB-1 is expressed in a wide range of cell types and has been implicated in the regulation of various genes involved in cell proliferation. Nuclear expression of YB-1 is correlated with MDR-1 gene expression in breast cancer and osteosarcoma. In this study, we asked whether YB-1 expression is enhanced in human colorectral carcinoma and if it is associated with the expression of target genes such as MDR-1, DNA topoisomerase II alpha and PCNA. YB-1, DNA topoisomerase II alpha, PCNA and MDR-1 expression were assessed by Western blotting, Northern blotting and immunohistochemistry in 26 human colorectal carcinomas. The involvement of YB-1 in DNA topoisomerase II alpha gene expression was examined by transient DNA transfection assays. YB-1 was overexpressed in almost all cancerous lesions in comparison with normal mucosa in surgically resected colorectal carcinomas of 26 patients. YB-1 expression correlated well with both DNA topoisomerase II alpha and PCNA expression. In contrast, no correlation was observed between YB-1 and MDR-1 expression. We also found that a transient co-transfection with a DNA topoisomerase II alpha promoter-luciferase plasmid and an antisense YB-1 expression construct resulted in a significant reduction of the promoter activity in KM12C human colon cancer cells. YB-1 may be an excellent proliferation-associated marker and may be a transcription factor regulating DNA topoisomerase II alpha gene expression in human colorectal carcinoma.
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PMID:Enhanced coexpression of YB-1 and DNA topoisomerase II alpha genes in human colorectal carcinomas. 1059 87

Most of meningiomas belong to benign tumor. But inspite of Simpson grade I surgical resection, it had been reported that a part of these cases recurred after initial operation. In discussing tumor recurrence in meningioma, it is important to evaluate not only the extent of surgical resection and malignancy but also cell proliferative potential, which had been studied immunohistochemically by using BudR, PCNA and MIB-1. Recently, it is known that topoisomerase (Topo) II alpha expression becomes remarkable in tumorigenesis. The correlation with cell proliferative potential has been reported. In this paper we evaluated the relationship of cell proliferative potential and tumor recurrence immunohistochemically by using Topo II alpha and MIB-1 monoclonal antibody in the 21 recurrent cases of meningiomas and hemangiopericytomas. As a result, mean Topo II alpha staining index (SI) and MIB-1 SI initial surgical resection were 2.29% and 3.41%, respectively, at recurrence these SIs had risen at 4.3% and 6.25%, respectively. As to the interval from initial surgical resection to recurrence, in the cases which recurred under 3 years Topo II alpha SI and MIB-1 SI were 3.13% and 5.00%, on the other hand, in the cases which recurred later than 3 years were 1.16% and 1.30%, respectively. Topo II alpha SI and MIB-1 SI 1 of former cases were higher than latter cases. Furthermore good correlation between the Topo II alpha SI and MIB-1 SI was found. It is concluded that Topo II alpha expression was as well available for the marker of cell proliferative potential and for one of the predicting factors for tumor recurrence in meningioma and hemangiopericytoma as MIB-1 SI.
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PMID:[Immunohistochemical evaluation of intracranial recurrent meningiomas: correlation of topoisomerase II alpha expression and cell proliferative potential]. 1065 98

On a series of thirty trephine bone marrow biopsies from patients with multiple myeloma, the authors evaluated expression of markers of cell proliferation or of its blockade (Ki-67, PCNA, topoisomerase IIa, cyclin D-1, AgNOR, and p27kip1) and markers indicating multidrug resistance (P-170 and Bcl-2). Expression of Ki-67 and of topoisomerase IIa was unfrequent. Marked positivity of PCNA was expressed in about one third of cases, negative staining was exceptional. No expression of cyclin D-1 was noted. Positivity of p27kip1 was frequent. P-170 was demonstrated in a small number of cases, Bcl-2 was strongly positive in most cases. The results characterise multiple myeloma as a tumour with low proliferation rate and, simultaneously, with high resistance to apoptosis.
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PMID:[Biological characteristics of multiple myeloma]. 1097 46

The main objective of this study to analyze which of 31 cellular factors (resistance proteins, proliferative factors, apoptotic factors, angiogenic factors, proto-oncogenes) most accurately predict the resistance of non-small cell lung carcinomas. To this purpose, we used a short-term in vitro test that measures changes in the rate at which radioactive nucleic acid precursors are incorporated into tumor cells after the addition of doxorubicin to determine the response to doxorubicin in 94 non-small cell lung carcinomas. The results obtained by the short-term test were related to the various cellular factors which were in turn determined by immunohistochemistry and flow cytometry. A significant correlation was found between the data obtained by the short-term test and the expression of P-glycoprotein 170 (P = 0.00004), glutathione-S-transferase-pi (P = 0.0002), metallothionein (P = 0.0008), thymidylate synthase (P = 0.002), O6-methylguanine-DNA-methyltransferase (P = 0.008) and lung resistance-related protein (LRP, P = 0.03). There was only a weak correlation between heat shock proteins (HSP70) and no correlation between the expression of topoisomerase II or catalase and the short-term test results. To measure the proliferative activity, the following were determined: PCNA, cyclin A, cyclin D and cdk2. Only a weak relationship was found between the expression of cdk2 (P = 0.04) and PCNA (P = 0.05) and the doxorubicin response in vitro. Of the investigated pro-apoptotic factors (Fas/CD95, Fas ligand, caspase-3), only Fas/CD95 is significantly associated with the drug response (P = 0.007). The apoptotic index also reveals a significant correlation (P = 0.03). Angiogenesis, as measured by the microvessel density and the angiogenic factors, is inversely correlated to the resistance of non-small cell lung cancer. Platelet-derived endothelial cell growth factor (PD-ECGF) and vascular endothelial growth factor (VEGF) exhibit a significant relationship to the drug resistance (P = 0.0006 and P = 0.004, respectively). Of the investigated proto-oncogenes (Fos, Jun, ErbB-1, ErbB-2, Myc, Ras), only ErbB-2 is weakly associated with the in vitro short term test. In order to determine whether combining factors can result in improved predictive information, combinations of the factors (pairs, triplets) were analyzed. The systematic investigation of these combinations yields an improvement in the predictive information. With one factor up to 76.6% of the tumors, with two factors up to 85.4% and with three factors up to 89.5% of the tumors could be correctly diagnosed.
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PMID:Cellular predictive factors for the drug response of lung cancer. 1113 47

In eukaryotic cells DNA replication occurs in specific nuclear compartments, called replication factories, that undergo complex rearrangements during S-phase. The molecular mechanisms underlying the dynamics of replication factories are still poorly defined. Here we show that etoposide, an anticancer drug that induces double-strand breaks, triggers the redistribution of DNA ligase I and proliferating cell nuclear antigen from replicative patterns and the ensuing dephosphorylation of DNA ligase I. Moreover, etoposide triggers the formation of RPA foci, distinct from replication factories. The effect of etoposide on DNA ligase I localization is prevented by aphidicolin, an inhibitor of DNA replication, and by staurosporine, a protein kinase inhibitor and checkpoints' abrogator. We suggest that dispersal of DNA ligase I is triggered by an intra-S-phase checkpoint activated when replicative forks meet topoisomerase II-DNA--cleavable complexes. However, etoposide treatment of ataxia telangiectasia cells demonstrated that ataxia-telangiectasia-mutated activity is not required for the disassembly of replication factories and the formation of replication protein A foci.
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PMID:Etoposide induces the dispersal of DNA ligase I from replication factories. 1145 7

Clones for DNA topoisomerase IIalpha and beta (topo-IIalpha and beta) were isolated from a cDNA expression library of chicken MSB-1 cells by immunoscreening. The deduced sequences of chicken topo-IIalpha and beta were about 80% identical for the N-terminal ATPase domain and the central core domain but only 37% for the C-terminal domain. Polyclonal antibodies were raised against C-terminal polypeptides specific to topo-IIalpha and beta. Indirect immunofluorescence with these antibodies to chicken embryonic fibroblasts demonstrated that topo-IIalpha was distributed in discrete intranuclear spots, which coincided with sites of DNA replication as indicated by incorporation of 5-bromo-2'-deoxyuridine, whereas topo-IIbeta was distributed rather uniformly within a nucleus. Examination of intranuclear distribution patterns of chimeric constructs between topo-IIalpha and beta suggested that a sequence region (residues 1280-1294) in the C-terminal domain of topo-IIalpha was effective in co-localization with sites of DNA replication. This region consists of a QTxhxF motif (x, any residue; h, hydrophobic residue) followed by a KR-rich sequence, which resembles those found in several proteins known to associate with proliferating cell nuclear antigen (PCNA) or targeted to the replication factory. An in vitro pull-down assay with glutathione-S-transferase-PCNA and (His)6-tagged truncated forms of topo-IIalpha demonstrated that polypeptides containing the above region (residues 1158-1553 or 1158-1294) bound to PCNA in vitro.
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PMID:Co-localization of chicken DNA topoisomerase IIalpha, but not beta, with sites of DNA replication and possible involvement of a C-terminal region of alpha through its binding to PCNA. 1145 53

The expression of two novel proliferation-associated markers, mitosin and topoisomerase IIalpha (Topo IIalpha), was evaluated immunohistochemically in consecutive paraffin sections from 60 diffuse astrocytomas (grades 2 to 4) in relation to clinicopathologic parameters, proliferating cell nuclear antigen (PCNA) and Ki-67 (MIB-1) expression and survival. The percentage of mitosin and Topo IIalpha-positive cells (LI) increased with grade and Ki-67 LI, but could not discriminate between grade 3 on the one hand and grades 2 or 4 on the other hand. In 51% of cases, Ki-67 LI exceeded Topo IIalpha LI, especially within grade 4. Topo IIalpha and mitosin expression was adversely related to overall and disease-free survival in the entire cohort and in grades 2/3. However, only Topo IIalpha LI affected disease-free survival in grade 4 tumors. Multivariate analysis selected only mitosin LI along with the age of the patient, as the independent parameters predicting overall survival, whereas Topo IIalpha emerged as the single independent predictor of disease-free survival. It is concluded that the proliferative potential of astrocytomas, as measured by mitosin and Topo IIalpha immunostaining, conveys useful prognostic information, in addition to that obtained by standard clinicopathologic parameters.
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PMID:Mitosin and DNA topoisomerase IIalpha: two novel proliferation markers in the prognostication of diffuse astrocytoma patient survival. 1155 47

Y box-binding protein-1 (YB-1), a member of the DNA binding protein family, interacts with inverted CCAAT boxes (Y-boxes). Y-boxes are located on the promoter of numerous genes, such as DNA topoisomerase IIalpha (Topo IIalpha), proliferating cell nuclear antigen (PCNA) and multidrug resistance 1 (MDR1). In this study, we used immunohistochemical (IHC) staining to detect YB-1 expression in 59 lung cancer tissues and to evaluate whether YB-1 expression was associated with the expression of YB-1 target genes such as Topo IIalpha, PCNA and MDR1 in human lung carcinoma. Twenty-eight out of 59 cases (47.5%) were stained positive for YB-1 in the cytoplasm, while 30 out of 59 cases (50.8%) were positive for PCNA in the nuclei. Topo IIalpha-positive cells were detected in 16 out of 59 cases (27.1%). Eight out of 59 cases (13.6%) had greater than 5% P-gp positive cells expression. There was a significant correlation between the YB-1 and Topo IIalpha expression in small cell lung cancer (SCLC) (p=0.0242). YB-1 expression also correlated with PCNA expression in non-small cell lung cancer (NSCLC) (p=0.0001). Higher levels of YB-1 expression were associated with T3-4 and Stage III-IV tumors in adenocarcinomas (p=0.0072; p=0.0168). In contrast, no relationship was found between YB-1 expression and P-gp expression. Our study suggests that YB-1 expression correlates with Topo IIalpha and PCNA expression in lung cancer.
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PMID:Expression of Y box-binding protein-1 correlates with DNA topoisomerase IIalpha and proliferating cell nuclear antigen expression in lung cancer. 1172 93


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