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)

Non-radioactive in situ hybridization with mouse centromere specific (major) gamma satellite DNA probe was used to analyze the mechanism of induction of spermatid micronuclei (MN) caused by the alkylating agent mitomycin C (MMC), the spindle poison vinblastine sulfate (VBL) or the DNA topoisomerase II inhibitor etoposide (VP-16). Male mice were treated with a single i.p. injection of 25 mg/kg VP-16, 5 mg/kg MMC or 2 mg/kg VBL, respectively. After 24 h (VP-16, VBL) or 13 days (MMC) stage I spermatid slides were prepared and in situ hybridization was performed using a polymerase chain reaction amplified mouse (major) gamma satellite DNA probe. The observed MN frequencies for VP-16 and MMC, 6.2/1000 and 7.5/1000 round spermatids, respectively, show a strong mutagenic effect on mouse germ cells compared with controls (1.4/1000 spermatids). VBL, on the contrary, induced a much lower total frequency of MN (2.8/1000 spermatids) compared with previous results on mouse somatic cells. Of MN in controls, 24% carried a FISH signal. After correcting for background, MMC induced 38.6% signal-positive MN, consistent with a predominantly clastogenic mode of action, while VBL induced 67.9% signal-positive MN, consistent with a mainly aneugenic mechanism. VP-16 induced 65.5% signal-positive MN, indicating that its MN-inducing capacity is mainly due to whole chromosome lagging.
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PMID:Analysis of micronuclei induced in mouse early spermatids by mitomycin C, vinblastine sulfate or etoposide using fluorescence in situ hybridization. 813 86

The mixed lineage leukemia, MLL, gene is frequently rearranged in patients with secondary leukemia following treatment with DNA topoisomerase II inhibitors. By FISH and Southern blot analyses we identified a rearrangement in the MLL gene due to a novel t(3;11)(q28;q23) chromosomal translocation in a patient who developed AML-M5 3 years after treatment for a follicular lymphoma. Through inverse PCR, the LPP (lipoma preferred partner) gene on 3q28 was identified as the MLL fusion partner. LPP contains substantial identity to the focal adhesion protein, zyxin, and is frequently fused to HMGIC in lipomas. The breakpoint occurred in intron 8 of MLL and LPP. Two in-frame MLL-LPP transcripts, which fuse MLL exon 8 to LPP exon 9, were detected by RT-PCR, although the smaller of these contained a deletion of 120 bp from the MLL sequence. The predicted MLL-LPP fusion protein includes the A/T hook motifs and methyltransferase domain of MLL joined to the two last LIM domains of LPP. A reciprocal LPP-MLL transcript, predicted to include the proline-rich and leucine zipper motifs, and the first LIM domain of LPP were also detected by RT-PCR. In summary, LPP is a newly identified MLL fusion partner in secondary leukemia resulting from topoisomerase inhibitors. The MLL-LPP and LPP-MLL predicted proteins contain many of the features present in other MLL rearrangements.
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PMID:Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23). 1143 29

Translocation t(1;22)(p13;q13) is associated with a peculiar subtype of acute megakaryocytic leukemia (M7) occurring in infants. We have recently characterized a fusion gene, OTT-MAL, resulting from this translocation. We now report three additional cases and show that this gene fusion is present in all five t(1;22) cases studied to date. Nucleotide sequence analysis of two translocation breakpoints suggests a nonhomologous end joining mechanism in the genesis of this translocation and reveals a noncanonical topoisomerase II-like consensus sequence within the OTT gene. FISH and PCR techniques described in this work are useful for identifying t(1;22) associated with M7.
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PMID:Recurrence of OTT-MAL fusion in t(1;22) of infant AML-M7. 1174 84

We examined the MLL translocation in two cases of infant AML with X chromosome disruption. The G-banded karyotype in the first case suggested t(X;3)(q22;p21)ins(X;11)(q22;q13q25). Southern blot analysis showed one MLL rearrangement. Panhandle PCR approaches were used to identify the MLL fusion transcript and MLL genomic breakpoint junction. SEPTIN6 from chromosome band Xq24 was the partner gene of MLL. MLL exon 7 was joined in-frame to SEPTIN6 exon 2 in the fusion transcript. The MLL genomic breakpoint was in intron 7; the SEPTIN6 genomic breakpoint was in intron 1. Spectral karyotyping revealed a complex rearrangement disrupting band 11q23. FISH with a probe for MLL confirmed MLL involvement and showed that the MLL-SEPTIN6 junction was on the der(X). The MLL genomic breakpoint was a functional DNA topoisomerase II cleavage site in an in vitro assay. In the second case, the karyotype revealed t(X;11)(q22;q23). Southern blot analysis showed two MLL rearrangements. cDNA panhandle PCR detected a transcript fusing MLL exon 8 in-frame to SEPTIN6 exon 2. MLL and SEPTIN6 are vulnerable to damage to form recurrent translocations in infant AML. Identification of SEPTIN6 and the SEPTIN family members hCDCrel and MSF as partner genes of MLL suggests a common pathway to leukaemogenesis.
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PMID:MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia, and MLL genomic breakpoint in complex MLL-SEPTIN6 rearrangement is a DNA topoisomerase II cleavage site. 1209 48

In experiments involving different germ-cell stages, we had previously found meiotic prophase of the male mouse to be vulnerable to the induction of several types of genetic damage by the topoisomerase-II inhibitor etoposide. The present study of etoposide effects involved two end points of meiotic events known to occur in primary spermatocytes--chromosomal crossing-over and segregation. By following assortment of 13 microsatellite markers in two chromosomes (Ch 7 and Ch 15) it was shown that etoposide significantly affected crossing-over, but did not do so in a uniform fashion. Treatment generally changed the pattern for each chromosome, leading to local decreases in recombination, a distal shift in locations of crossing-over, and an overall decrease in double crossovers; at least some of these results might be interpreted as evidence for increased interference. Two methods were used to explore etoposide effects on chromosome segregation: a genetic experiment capable of detecting sex-chromosome nondisjunction in living progeny; and the use of FISH (fluorescence in situ hybridization) technology to score numbers of Chromosomes X, Y, and 8 in spermatozoa. Taken together these two approaches indicated that etoposide exposure of pachytene spermatocytes induces malsegregation, and that the findings of the genetic experiment probably yielded a marked underestimate of nondisjunction. As indicated by certain segregants, at least part of the etoposide effect could be due to disrupted pairing of achiasmatic homologs, followed by precocious sister-centromere separation. It has been shown for several organisms that absent or reduced levels of recombination, as well as suboptimally positioned recombination events, may be associated with abnormal segregation. Etoposide is the only chemical tested to date for which living progeny indicates an effect on both male meiotic crossing-over and chromosome segregation. Whether, however, etoposide-induced changes in recombination patterns are direct causes of the observed malsegregation requires additional investigation.
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PMID:Etoposide exposure during male mouse pachytene has complex effects on crossing-over and causes nondisjunction. 1557 40

Amplification or duplication of the AML1 gene at chromosome band 21q22 was detected by FISH using a locus-specific probe in three out of 171 unselected patients with therapy-related myelodysplasia (t-MDS) or t-AML (1.7%). In two patients AML1 signals were located tandemly on derivative chromosomes, in one patient on a dic(9;21) and in the the other patient on a derivative chromosome 18 made up of interchanging layers of material from chromosomes 9, 14, 18, and 21. In the third patient three single supernumerary copies of AML1 were located on derivatives of chromosomes 19 and 21. All three patients were older, had previously received therapy with alkylating agents without topoisomerase II inhibitors, had complex karyotypes including abnormalities of chromosomes 5 or 7, and presented acquired point mutations of the TP53 gene. No point mutations of the AML1 gene were observed. The results support a pivotal role of impaired TP53 function in the development of gene amplification or duplication in t-MDS and t-AML.
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PMID:Amplification or duplication of chromosome band 21q22 with multiple copies of the AML1 gene and mutation of the TP53 gene in therapy-related MDS and AML. 1561 58

In the wake of recent progress in understanding the genetic pathways involved in the development of brain tumors, a major goal is to correlate molecular data with clinical outcome, survival, and response to treatment modalities. This is of particular importance among the pediatric population. Reliable prognostic factors could potentially permit a tailoring of therapy in that only patients with the most aggressive tumors would receive the most intense treatments. A survey of publications about prognosis-related molecular features among pediatric brain tumors revealed 74 series, of which 46 presented statistically significant outcome-associated parameters as defined by a p value <0.05. Most investigations revealing significant prognosis-related features were performed on medulloblastomas (34 publications), followed by astrocytic tumors (6 publications) and ependymomas (5 publications). Promising approaches and molecular markers include gene expression profiles, DNA ploidy, loss of heterozygosity and chromosomal aberrations as detected by CGH and FISH (1q, 17p, 17q), as well as oncogenes/ tumor suppressor genes and their proteins (TP53, PTEN, c-erbB2, N-myc, c-myc), growth factor and hormonal receptors (PDGFRA, VEGF, EGFR, HER2, HER4, ErbB-2, hTERT, TrkC), cell cycle genes (p27) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (multi-drug resistance, DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the predictive potential of molecular markers for clinical outcome and their influence on therapeutic decision-making among children with brain tumors.
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PMID:Prognosis-related molecular markers in pediatric central nervous system tumors. 1562 58

Acute myeloid leukaemia (AML) is associated with exposure to benzene and treatment with chemotherapeutic agents. It is thought to arise from damage to specific regions of DNA, resulting in chromosome rearrangements or loss. For instance, a deletion on the long arm of chromosome 5 [e.g. del(5q31)] is common in AML patients previously treated with alkylating agents, such as melphalan, or exposed to benzene. Translocations of the MLL gene at 11q23 are frequently observed in AML arising from treatment with topoisomerase II inhibitors, such as etoposide. Our goal was to determine whether or not breakage at 5q31 and 11q23 is selectively induced by these chemical agents. To address this question, the comet assay combined with fluorescence in situ hybridization (comet-FISH) was used to detect DNA breakage in the specific chromosomal regions in an in vitro model. TK6 lymphoblastoid cells were exposed to melphalan, etoposide or the benzene metabolite, hydroquinone (HQ), at various concentrations. HQ, melphalan and etoposide induced DNA breaks at both 5q31 and 11q23 chromosome regions in a dose-dependant manner. However, HQ produced significantly more DNA damage at 5q31 than at 11q23. Etoposide produce slightly more DNA damage at 11q23 and melphalan had a somewhat greater effect at 5q31, but not significantly so. Thus, HQ and melphalan act similarly, perhaps explaining some similarities between benzene- and alkylating agent-induced AML. Comet-FISH also appears to be a useful approach for detecting and comparing damage to specific chromosome regions of significance in leukaemogenesis.
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PMID:Leukaemia-specific chromosome damage detected by comet with fluorescence in situ hybridization (comet-FISH). 1757 18

PICH (Plk1-interacting checkpoint helicase) was recently identified as an essential component of the spindle assembly checkpoint and shown to localize to kinetochores, inner centromeres, and thin threads connecting separating chromosomes even during anaphase. In this paper, we have used immuno-fiber fluorescence in situ hybridization and chromatin-immunoprecipitation to demonstrate that PICH associates with centromeric chromatin during anaphase. Furthermore, by careful analysis of PICH-positive anaphase threads through FISH as well as bromo-deoxyurdine and CREST labeling, we strengthen the evidence that these threads comprise mainly alphoid centromere deoxyribonucleic acid. Finally, by timing the addition of ICRF-193 (a specific inhibitor of topoisomerase-II alpha) to cells synchronized in anaphase, we demonstrate that topoisomerase activity is required specifically to resolve PICH-positive threads during anaphase (as opposed to being required to prevent the formation of such threads during earlier cell cycle stages). These data indicate that PICH associates with centromeres during anaphase and that most PICH-positive threads evolve from inner centromeres as these stretch in response to tension. Moreover, they show that topoisomerase activity is required during anaphase for the resolution of PICH-positive threads, implying that the complete separation of sister chromatids occurs later than previously assumed.
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PMID:Persistence of DNA threads in human anaphase cells suggests late completion of sister chromatid decatenation. 1798 90

A molecular analysis has three major roles in modern oncopathology--as an aid in the differential diagnosis, in molecular monitoring of diseases, and in estimation of the potential prognosis. In this report we review the application of the molecular analysis in a group of patients with mantle cell lymphoma (MCL). We demonstrate that detection of the cyclin D1 mRNA level is a molecular marker in 98% of patients with MCL. Cyclin D1 quantitative monitoring is specific and sensitive for the differential diagnosis and for the molecular monitoring of the disease in the bone marrow. Moreover, the dynamics of cyclin D1 in bone marrow reflects the disease development and it predicts the clinical course. We employed the molecular analysis for a precise quantitative detection of proliferation markers, Ki-67, topoisomerase IIalpha, and TPX2, that are described as effective prognostic factors. Using the molecular approach it is possible to measure the proliferation rate in a reproducible, standard way which is an essential prerequisite for using the proliferation activity as a routine clinical tool. Comparing with immunophenotyping we may conclude that the quantitative PCR-based analysis is a useful, reliable, rapid, reproducible, sensitive and specific method broadening our diagnostic tools in hematopathology. In comparison to interphase FISH in paraffin sections quantitative PCR is less technically demanding and less time-consuming and furthermore it is more sensitive in detecting small changes in the mRNA level. Moreover, quantitative PCR is the only technology which provides precise and reproducible quantitative information about the expression level. Therefore it may be used to demonstrate the decrease or increase of a tumor-specific marker in bone marrow in comparison with a previously aspirated specimen. Thus, it has a powerful potential to monitor the course of the disease in correlation with clinical data.
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PMID:Quantitative molecular analysis in mantle cell lymphoma. 2188 26


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