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)

Etoposide is a topoisomerase II inhibitor that induces DNA cleavable complex and has been used as an antitumor drug. We isolated two genes that were transcriptionally suppressed at an early stage of incubation in etoposide-treated RVC lymphoma cells, using modified PCR-based subtractive hybridization. Sequencing revealed that one of these genes, which was approximately 1.7 kb and which encoded a protein of 320 amino acids, was identical to hnRNP A1. The other was a novel gene of about 2.2 kb encoding a protein of 469 amino acids. These genes were also down-regulated in the cells incubated with camptothecin, a topoisomerase I inhibitor that induces DNA single strand breaks, but not in those exposed to ICRF-154, a topoisomerase II inhibitor that does not induce DNA cleavable complex formation. These results suggest that the early down-regulation of these genes contributes to the cytotoxicity of the topoisomerase inhibitors that induce DNA cleavage.
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PMID:Molecular cloning of the genes suppressed in RVC lymphoma cells by topoisomerase inhibitors. 891 29

DNA topoisomerase II is a nuclear enzyme that modulates DNA topology during several metabolic processes and is the target of several antitumor drugs. The primary effect of anticancer agents is to induce apoptosis. The present study showed that etoposide, a topoisomerase II inhibitor which forms cleavable complexes, induced apoptosis in nonproliferative thymocytes and proliferative RVC cells, whereas ICRF-154, a bis(2,6-dioxopiperazine) derivative which does not form a cleavable complex, induced apoptosis only in thymocytes. Both etoposide and ICRF-154 inhibited topoisomerase II activity in thymocytes and RVC cells to a similar extent. Etoposide had no effect on the cell cycle of RVC cells, but ICRF-154 induced cell cycle arrest at the G2/M stage followed by cell death without forming a DNA ladder on an agarose gel. Incubation with ICRF-154 reduced the expression of topoisomerase IIa in thymocytes and IIb in RVC cells. These findings suggest that the catalytic inhibitor, ICRF-154, has a mechanism of cytotoxicity which differs from that of etoposide. In RVC cells exposed to etoposide, we identified two clones that were suppressed early in the incubation. One was highly homologous to hnRNP A1 which modulates splicing of selected transcripts or stabilizes mRNAs. The other was a novel gene of which the function remains unknown. These genes were also altered in RVC cells exposed to camptothecin, which underwent apoptosis, but not in those incubated with ICRF-154, indicating that the suppression of these genes is related to inhibitor-induced DNA breaks resulting in apoptosis. In thymocytes, however, a cleavable complex by topoisomerase II inhibitors is not essential for the induction of apoptosis, since it was induced by ICRF-154. This suggests that tissue-specific nuclear matrix proteins other than topoisomerase II, including SATP-1 in the thymus, should also be considered. The present findings also suggest that bis(2,6-dioxopiperazine) derivatives are useful agents with which to study the role of topoisomerase II in the regulation of gene expression as well as the role of the nuclear matrix.
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PMID:Topoisomerase II inhibitor-induced apoptosis in thymocytes and lymphoma cells. 938 84

Topoisomerase IIalpha plays essential roles in chromosome segregation. However, it is not well understood how topoisomerase IIalpha exerts its function during mitosis. In this report, we find that topoisomerase IIalpha forms a multisubunit complex, named toposome, containing two ATPase/helicase proteins (RNA helicase A and RHII/Gu), one serine/threonine protein kinase (SRPK1), one HMG protein (SSRP1), and two pre-mRNA splicing factors (PRP8 and hnRNP C). Toposome separates entangled circular chromatin DNA about fourfold more efficiently than topoisomerase IIalpha. Interestingly, this decatenation reaction yields knotted circles, which are not seen in reactions provided with monomeric circular DNA. Our results also show that interaction among toposome-associated proteins is highest in G2/M phase but drastically diminishes in G1/S phase. These results suggest that toposome is a dynamic complex whose assembly or activation is subject to cell cycle regulation.
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PMID:Identification of toposome, a novel multisubunit complex containing topoisomerase IIalpha. 1503

DNA-damaging agents cause a multifaceted cellular stress response. Cells set in motion either repair mechanisms or programmed cell death pathways, depending on the extent of the damage and on their ability to withstand it. The RNA-binding protein (RBP) Sam68, which is up-regulated in prostate carcinoma, promotes prostate cancer cell survival to genotoxic stress. Herein, we have investigated the function of Sam68 in this cellular response. Mitoxantrone (MTX), a topoisomerase II inhibitor, induced relocalization of Sam68 from the nucleoplasm to nuclear granules, together with several other RBPs involved in alternative splicing, such as TIA-1, hnRNP A1 and the SR proteins SC35 and ASF/SF2. Sam68 accumulation in nuclear stress granules was independent of signal transduction pathways activated by DNA damage. Using BrU labelling and immunofluorescence, we demonstrate that MTX-induced nuclear stress granules are transcriptionally active foci where Sam68 and the phosphorylated form of RNA polymerase II accumulate. Finally, we show that MTX-induced relocalization of Sam68 correlates with changes in alternative splicing of its mRNA target CD44, and that MTX-induced CD44 splicing depends on Sam68 expression. These results strongly suggest that Sam68 is part of a RNA-mediated stress response of the cell that modulates alternative splicing in response to DNA damage.
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PMID:Genotoxic stress causes the accumulation of the splicing regulator Sam68 in nuclear foci of transcriptionally active chromatin. 2011 Feb 58

Enterovirus 71 (EV71) causes life-threatening diseases with neurological manifestations in young children. However, the treatment of EV71 infections remains an unmet medical need. Idarubicin (IDR) is an anthracycline compound that is used therapeutically for certain types of tumour. In this study, we identified IDR as an EV71 inhibitor, which displayed antiviral potency in the submicromolar range and substantially protected cells from the cytopathic effects and cell death caused by EV71 infections. The antiviral effects extended to several other enterovirus (EV) species, and these effects were independent of cytotoxicity or topoisomerase inhibition. Structure-activity relationship studies indicated the importance of the anthracycline scaffold for anti-EV potency. IDR effectively blocked the synthesis of viral protein and RNA, but not the viral proteolysis processes. Moreover, anthracyclines were demonstrated to suppress EV internal ribosomal entry site (IRES)-mediated translation; conversely, the cellular p53 IRES activity was not sensitive to IDR action. Inhibition of IRES-mediated translation by IDR correlated with the affinity of binding between IDR and the particular IRES. Moreover, IDR impaired binding between the EV71 IRES RNA and hnRNP A1, a known host IRES trans-acting factor. In sum, we have identified a USA FDA-approved anticancer drug with the new indication as a selective EV IRES binder and inhibitor. The finding may also provide leads for the development of novel antiviral therapies directed at the EV IRES RNA.
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PMID:Idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site. 2687 94