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)

Aminoflavone (5-amino-2,3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one) (NSC 686288) is a candidate for possible advancement to phase I clinical trial. Aminoflavone has a unique activity profile in the NCI 60 cell lines (COMPARE analysis; http://www.dtp.nci.nih.gov/docs/dtp_search.html), and exhibits potent cellular and animal antitumor activity. To elucidate the mechanism of action of aminoflavone, we studied DNA damage in MCF-7 cells. Aminoflavone induced DNA-protein cross-links (DPC) and DNA single-strand breaks (SSB). Aminoflavone induced high levels of DPC and much lower level of SSB than camptothecin, which induces equal levels of DPC and SSB due to the trapping topoisomerase I-DNA complexes. Accordingly, neither topoisomerase I nor topoisomerase II were detectable in the aminoflavone-induced DPC. Aminoflavone also induced dose- and time-dependent histone H2AX phosphorylation (gamma-H2AX). Gamma-H2AX foci occurred with DPC formation, and like DPC, persisted after aminoflavone removal. Aphidicolin prevented gamma-H2AX formation, suggesting that gamma-H2AX foci correspond to replication-associated DNA double-strand breaks. Accordingly, no gamma-H2AX foci were found in proliferating cell nuclear antigen-negative or in mitotic cells. Bromodeoxyuridine incorporation and fluorescence-activated cell sorting analyses showed DNA synthesis inhibition uniformly throughout the S phase after exposure to aminoflavone. Aminoflavone also induced RPA2 and p53 phosphorylation, and induced p21(Waf1/Cip1) and MDM2, demonstrating S-phase checkpoint activation. These studies suggest that aminoflavone produces replication-dependent DNA lesions and S-phase checkpoint activation following DPC formation. Gamma-H2AX may be a useful clinical marker for monitoring the efficacy of aminoflavone in tumor therapies.
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PMID:DNA-protein cross-links and replication-dependent histone H2AX phosphorylation induced by aminoflavone (NSC 686288), a novel anticancer agent active against human breast cancer cells. 1595 81

In the last few decades, proliferative markers have been broadly evaluated as prognostic and predictive factors for early stage breast cancer patients. Several papers evaluating one or more markers have been published, often with contradictory results. As a consequence, there is still uncertainty about the role of these proliferative markers. The present paper critically reviews the current knowledge about the following markers: thymidine labeling index, S phase fraction/flow cytometry, Ki 67, thymidine kinase (TK), cyclins E, cyclin D, the cyclin inhibitors p27 and p21, and topoisomerase IIalpha. For each marker, the prognostic and predictive role was separately analyzed. Only papers published in English in peer-reviewed journals before June 2004 that include at least 100 evaluable patients were selected. In addition, the prognostic and predictive role of the proliferative markers had to be assessed through multivariate analyses. One hundred and thirty-two papers fulfilled these criteria and 159 516 patients were analyzed. Unfortunately, several methodological problems in the research to date prevent us from including any one of these proliferative markers among the standard prognostic and predictive factors. Early incorporation of translational research and new technologies with clinical trials are needed to prospectively validate biological markers and allow their use in clinical practice.
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PMID:Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? 1598 Jan 58

The tumor suppressor protein p53 promotes apoptosis in response to death stimuli by transactivation of target genes and by transcription-independent mechanisms. Recently, it was shown that during apoptosis p53 can specifically translocate to mitochondria, where it physically interacts with and inactivates prosurvival Bcl-2 proteins. In the present study, we therefore investigated the role of mitochondrial translocation of p53 for the stress response of tumor cells. In various cell lines, DNA damage induced by either ionizing irradiation or topoisomerase inhibitors triggered a robust translocation of a fraction of p53 to mitochondria to a similar extent. Nevertheless, the cells succumbed to apoptosis only in response to topoisomerase inhibitors, but remained resistant to apoptosis induced by ionizing radiation. Irradiated cells became senescent, although irradiation triggered a functional p53 response and induced expression of p21, Bax, and Puma. Interestingly, even the targeted expression of p53 to mitochondria was insufficient to launch apoptosis, whereas overexpression of wild-type p53 induced Bax activation and apoptotic alterations. Together, these results suggest that, in contrast to previous reports, mitochondrial translocation of p53 does not per se lead to cell death and that this might constitute a mechanism that contributes to the resistance of tumor cells to ionizing radiation-induced apoptosis.
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PMID:Irradiation-induced translocation of p53 to mitochondria in the absence of apoptosis. 1614 12

The vaccinia-related kinase (VRK) proteins are a new family with three members in the human kinome. The VRK1 protein phosphorylates several transcription factors and has been postulated to be involved in regulation of cell proliferation. In normal squamous epithelium, VRK1 is expressed in the proliferation area. Because VRK1 can stabilize p53, the expression of the VRK1 protein was analyzed in the context of the p53 pathway and the proliferation phenotype in a series of 73 head and neck squamous cell carcinomas. VRK1 protein level positively correlated with p53 response proteins, particularly hdm2 and p21. The VRK1 protein also correlated positively with several proteins associated with proliferation, such as cyclin-dependent kinase 2 (CDK2), CDK6, cdc2, cyclins B1 and A, topoisomerase II, survivin, and Ki67. The level of VRK1 protein behaves like a proliferation marker in this series of head and neck squamous cell carcinomas. To identify a possible regulatory role for VRK1 and because it regulates gene transcription, the promoters of two genes were studied, CDK2 and SURVIVIN, whose proteins correlated positively with VRK1. VRK1 increases the activity of both the CDK2 and SURVIVIN gene promoters. The expression of VRK1 was analyzed in the context of regulators of the G1-S transition. VRK1 protein levels increase in response to E2F1 and are reduced by retinoblastoma and p16. These data suggest that VRK1 might play a role in cell cycle regulation and is likely to represent the beginning of a new control mechanism of cell cycle, particularly late in the G1-S phase.
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PMID:VRK1 signaling pathway in the context of the proliferation phenotype in head and neck squamous cell carcinoma. 1654 55

The loss of p53 function is a key event in tumorigenesis. Inactivation of p53 in primary tumors and cell lines is mediated by several molecular mechanisms, including deletions and rearrangements. However, generation of a p53 fusion gene has not yet been reported. Here we report a novel p53/an autosomal homolog of the fragile X mental retardation (FXR2) chimeric gene generated by an interstitial deletion. Western blot analyses have shown that the p53/FXR2 protein is indeed expressed in a Down syndrome-related acute megakaryoblastic leukemia cell line, CMK11-5 cells. To investigate the properties of the p53/FXR2 protein, we observed its subcellular localization. Flag-tagged expression vectors were transfected into COS-7 cells and the proteins were stained with an anti-Flag antibody. The p53/FXR2 protein was expressed at high levels in the cytoplasm, whereas wild-type p53 and FXR2 were localized primarily in the nucleus and in the periphery of the nucleus, respectively. Treatment with a topoisomerase II inhibitor, VP16, failed to induce expression of a p53 target gene, the cyclin-dependent kinase inhibitor p21(WAF-1/CIP1), in CMK11-5 cells, and transient transfection analysis showed that the p53/FXR2 protein failed to transactivate the p21(WAF-1/CIP1) promoter. These results suggest that the p53/FXR2 fusion protein lacks the ability of wild-type p53 to function as a transcription factor. The p53/FXR2 gene is the first reported p53 fusion gene.
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PMID:Cloning and characterization of the novel chimeric gene p53/FXR2 in the acute megakaryoblastic leukemia cell line CMK11-5. 1677 63

The 14-3-3 protein family consists of seven isoforms, most of which are expressed abundantly in neurons and glial cells, although the sigma isoform, a p53 target gene originally identified as an epithelium-specific marker, has not been identified in the human central nervous system. Here, we show that human astrocytes in culture expressed 14-3-3sigma under stress conditions. By Western blot, the expression of 14-3-3sigma, p53 and p21 was coordinately upregulated in astrocytes following exposure to hydrogen peroxide, 4-hydroxy-2-nonenal (4-HNE) or etoposide, a topoisomerase II inhibitor. 14-3-3sigma was induced by treatment with 5-aza-2'-deoxycytidine, suggesting a hypermethylated status of the gene promoter in astrocytes. In vivo, a small subset of hypertrophic reactive astrocytes, often showing a multinucleated morphology, expressed 14-3-3sigma in active demyelinating lesions of multiple sclerosis (MS) and ischemic lesions of cerebral infarction, where the expression of 4-HNE and 8-hydroxy-2'-deoxyguanosine was enhanced in reactive astrocytes. Microarray analysis of etoposide-treated astrocytes verified upregulation of p53-responsive genes and concurrent downregulation of mitotic checkpoint-regulatory genes. These observations suggest that 14-3-3sigma might serve as a marker of oxidative and DNA-damaging stresses inducing the mitotic checkpoint dysfunction in reactive astrocytes under pathological conditions.
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PMID:Human astrocytes express 14-3-3 sigma in response to oxidative and DNA-damaging stresses. 1679 59

We clarified that etoposide (VP-16), a topoisomerase II inhibitor, induced apoptosis in the mouse fetal brain. Apoptotic mechanisms and cell cycle arrest in this system were investigated. Four mg/kg of VP-16 was injected into pregnant mice on day 12 of gestation (GD12). The cell cycle and expression of protein and mRNA of p53 and its transcriptional target genes were examined in the fetal brain. The number of p53- and p21-protein-positive cells peaked at 4 h after treatment (HAT). The expression of p21 mRNA was significantly increased at 4 HAT and 8 HAT. The expression of fas mRNA was significantly increased from 2 to 12 HAT. Significant expression of puma mRNA was observed from 1 HAT to 48 HAT. Flow cytometric analysis revealed that VP-16 induced S-phase accumulation and G2 arrest at 4 and 8 HAT, and VP-16-induced apoptosis was significantly increased from 4 to 24 HAT. In an experiment using BrdU treatment of pregnant mice, the migration of neuroepithelial cells in the fetuses was delayed as compared to the migration of controls, and BrdU-positive signals were observed in some pyknotic cells from 8 to 12 HAT. The present results suggest that VP-16 might induce cell cycle arrest at G2/M phase and apoptosis in a p53-related manner.
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PMID:Etoposide induces apoptosis and cell cycle arrest of neuroepithelial cells in a p53-related manner. 1709 87

Epithelial ovarian carcinoma is worldwide the sixth most common female cancer, and this malignancy carries the highest mortality among all gynecological cancers. The high mortality is due mostly to the fact that the tumor is frequently diagnosed late, in advanced stage, as the early disease is often asymptomatic and no effective screening methods are available. The most important prognostic factors in ovarian carcinoma are the stage, size of residual tumor following surgery, presence of ascites, age and the general condition of the patient, tumor histology, and, in patients with early disease, also the grade of the tumor. Large number of studies on prognostic and predictive factors in epithelial ovarian carcinoma has been published, often with contradictory results. The most intensely studied prognostic factors are those for expression of hormonal receptors, for tumor proliferation activity (mainly by antigen Ki-67 and topoisomerase IIalpha), the markers of apoptosis (p53, p21, mdm2, bcl-2 and other proteins), or other oncoproteins (particularly HER-2/neu).
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PMID:Contribution of immunohistochemistry in prognostic assessment of epithelial ovarian carcinoma --review of the literature I. 1711 4

D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is herein identified as a novel antineoplastic agent with a broad spectrum of antitumoral activity against several human cancer cells and an IC(50) value in the nanomolar range. The IC(50) values for D-501036 in the renal proximal tubule, normal bronchial epithelial, and fibroblast cells were >10 mumol/L. D-501036 exhibited no cross-resistance with vincristine- and paclitaxel-resistant cell lines, whereas a low level of resistance toward the etoposide-resistant KB variant was observed. Cell cycle analysis established that D-501036 treatment resulted in a dose-dependent accumulation in S phase with concomitant loss of both the G(0)-G(1) and G(2)-M phase in both Hep 3B and A-498 cells. Pulsed-field gel electrophoresis showed D-501036-induced, concentration-dependent DNA breaks in both Hep 3B and A-498 cells. These breaks did not involve interference with either topoisomerase-I and topoisomerase-II function or DNA binding. Rapid reactive oxygen species production and formation of Se-DNA adducts were evident following exposure of cells to D-501036, indicating that D-501036-mediated DNA breaks were attributable to the induction of reactive oxygen species and DNA adduct formation. Moreover, D-501036-induced DNA damage activated ataxia telangiectasia-mutated nuclear protein kinase, leading to hyperphosphorylation of Chk1, Chk2, and p53, decreased expression of CDC25A, and up-regulation of p21(WAF1) in both p53-proficient and p53-deficient cells. Collectively, the results indicate that D-501036-induced cell death was associated with DNA damage-mediated induction of ataxia telangiectasia-mutated activation, and p53-dependent and -independent apoptosis pathways. Notably, D-501036 shows potent activity against the growth of xenograft tumors of human renal carcinoma A-498 cells. Thus, D-501036 is a promising anticancer compound that has strong potential for the management of human cancers.
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PMID:D-501036, a novel selenophene-based triheterocycle derivative, exhibits potent in vitro and in vivo antitumoral activity which involves DNA damage and ataxia telangiectasia-mutated nuclear protein kinase activation. 1723 79

Scatter factor (SF) (hepatocyte growth factor) is a pleiotrophic cytokine that accumulates within tumors in vivo and protects tumor cells against cytotoxicity and apoptosis due to DNA damaging agents in vitro. Previous studies have established that SF-mediated cell protection involves antiapoptotic signaling from its receptor (c-Met) to PI3 kinase --> c-Akt --> Pak1 (p21-activated kinase -1) --> NF-kappaB (nuclear factor-kappa B). Here, we found that Ras proteins (H-Ras and R-Ras) enhance SF-mediated activation of NF-kappaB and protection of DU-145 and MDCK (Madin-Darby canine kidney) cells against the topoisomerase IIalpha inhibitor adriamycin. Studies of Ras effector loop mutants and their downstream effectors suggest that Ras/PI3 kinase and Ras/Raf1 pathways contribute to SF stimulation of NF-kappaB signaling and cell protection. Further studies revealed that Raf1 positively regulates the ability of SF to stimulate NF-kappaB activity and cell protection. The ability of Raf1 to stimulate NF-kappaB activity was not due to the classical Raf1 --> MEK1/2 --> ERK1/2 pathway. However, we found that a MEK3/6 --> p38 pathway contributes to SF-mediated activation of NF-kappaB. In contrast, RalA, a target of the Ras/RalGDS pathway negatively regulated the ability of SF to stimulate NF-kappaB activity and cell protection. Ras, Raf1 and RalA modulate SF stimulation of NF-kappaB activity, in part, by regulating IkappaB kinase (IKK)-beta kinase activity. These findings suggest that Ras/Raf1/RalA pathways may converge to modulate NF-kappaB activation and SF-mediated survival signaling at the IKK complex and/or a kinase upstream of this complex.
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PMID:Ras effector pathways modulate scatter factor-stimulated NF-kappaB signaling and protection against DNA damage. 1729 51


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