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)

The Fas receptor mediates a signalling cascade resulting in programmed cell death (apoptosis) within hours of receptor cross-linking. In this study Fas activated the stress-responsive mitogen-activated protein kinases, p38 and JNK, within 2 h in Jurkat T lymphocytes but not the mitogen-responsive kinase ERK1 or pp70S6k. Fas activation of p38 correlated temporally with the onset of apoptosis, and transfection of constitutively active MKK3 (glu), an upstream regulator of p38, potentiated Fas-induced cell death, suggesting a potential involvement of the MKK3/p38 activation pathway in Fas-mediated apoptosis. Fas has been shown to require ICE (interleukin-1 beta-converting enzyme) family proteases to induce apoptosis from studies utilizing the cowpox ICE inhibitor protein CrmA, the synthetic tetrapeptide ICE inhibitor YVAD-CMK, and the tripeptide pan-ICE inhibitor Z-VAD-FMK. In this study, crmA antagonized, and YVAD-CMK and Z-VAD-FMK completely inhibited, Fas activation of p38 kinase activity, demonstrating that Fas-dependent activation of p38 requires ICE/CED-3 family members and conversely that the MKK3/p38 activation cascade represents a downstream target for the ICE/CED-3 family proteases. Intriguingly, p38 activation by sorbitol and etoposide was resistant to YVAD-CMK and Z-VAD-FMK, suggesting the existence of an additional mechanism(s) of p38 regulation. The ICE/CED-3 family-p38 regulatory relationship described in the current work indicates that in addition to the previously described destructive cleavage of substrates such as poly(ADP ribose) polymerase, lamins, and topoisomerase, the apoptotic cysteine proteases also function to regulate stress kinase signalling cascades.
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PMID:Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases. 897 82

The mitogen-activated protein (MAP) kinases, extracellular signal-related kinase 1 (ERK1) and ERK2, regulate cellular responses by mediating extracellular growth signals toward cytoplasmic and nuclear targets. A potential target for ERK is topoisomerase IIalpha, which becomes highly phosphorylated during mitosis and is required for several aspects of nucleic acid metabolism, including chromosome condensation and daughter chromosome separation. In this study, we demonstrated interactions between ERK2 and topoisomerase IIalpha proteins by coimmunoprecipitation from mixtures of purified enzymes and from nuclear extracts. In vitro, diphosphorylated active ERK2 phosphorylated topoisomerase IIalpha and enhanced its specific activity by sevenfold, as measured by DNA relaxation assays, whereas unphosphorylated ERK2 had no effect. However, activation of topoisomerase II was also observed with diphosphorylated inactive mutant ERK2, suggesting a mechanism of activation that depends on the phosphorylation state of ERK2 but not on its kinase activity. Nevertheless, activation of ERK by transient transfection of constitutively active mutant MAP kinase kinase 1 (MKK1) enhanced endogenous topoisomerase II activity by fourfold. Our findings indicate that ERK regulates topoisomerase IIalpha in vitro and in vivo, suggesting a potential target for the MKK/ERK pathway in the modulation of chromatin reorganization events during mitosis and in other phases of the cell cycle.
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PMID:Extracellular signal-regulated kinase activates topoisomerase IIalpha through a mechanism independent of phosphorylation. 1020 78

We recently demonstrated that physiological induction of apoptosis by cytotoxic sphingolipid messengers proceeds via activating protein-1 (AP1)-dependent and AP1-independent mechanisms in U937 human monoblastic leukemia cells. Here we examine involvement of the stress-activated protein kinase (SAPK) cascade and AP1 in the initiation of apoptosis in U937 cells by podophyllotoxin-derived inhibitors of topoisomerase II. Induction of apoptotic cell death and DNA damage by treatment of U937 cells with etoposide (100 microM) was associated with phosphorylation and activation of the c-Jun NH(2)-terminal kinase (JNK1) SAPK enzymes p46 and p54-JNK2 and transient increases in expression of the transcription factor c-Jun, a primary JNK substrate. These responses were accompanied by a modest, but sustained, recruitment of the mitogen-activated protein kinases p42-extracellular signal receptor-activated kinase (ERK)1 and p44-extracellular signal receptor-activated kinase 2. The capacity of etoposide to promote double-stranded DNA degradation and cell death was unaffected by manipulations that interfere with SAPK signaling outflow through c-Jun/AP1, including: 1) pharmacological inhibition of AP1 activity by diferuloylmethane and 2) molecular ablation of normal c-Jun function by the Jun dominant-negative mutant TAM-67. Cytotoxicity of the structurally related compound teniposide was similarly unaffected. In parallel trials, the lethal actions of ceramide (but not of sphingosine) were markedly diminished by pretreatment with diferuloylmethane or expression of TAM-67, confirming the effectiveness of these interventions in suppression of SAPK/AP1-dependent apoptosis. The involvement of AP1 in the proapoptotic actions of other inhibitors of topoisomerase II activity was also evaluated. Induction of cell death by the anthracyclines daunorubicin, daunorubicin, and idarubicin was found to be insensitive to pretreatment with diferuloylmethane or expression of TAM-67. Collectively, the present data indicate that induction of apoptosis by etoposide and related inhibitors of topoisomerase II is mediated through a cell death pathway that does not require SAPK-dependent recruitment of AP1. These findings additionally suggest that activation of the SAPK represents a consequence, rather than an underlying cause, of etoposide-induced apoptosis in myeloid leukemia cells.
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PMID:Evidence that the apoptotic actions of etoposide are independent of c-Jun/activating protein-1-mediated transregulation. 1045 18

Etoposide, an inhibitor of topoisomerase II that induces DNA damage and can trigger cell death, is used as a chemotherapeutic agent. Because chemotherapies can result in neurological complications and because DNA damage in neurons is implicated in the pathogenesis of several neurodegenerative disorders, we studied the effects of etoposide on cultured hippocampal neurons. We found that etoposide induces neuronal apoptosis and that, prior to the cell death commitment point, there is an increase in whole-cell alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-induced current but no change in N-methyl-D-aspartate (NMDA)-induced current. Associated with the increase in AMPA-induced current was an increase in the amounts of AMPA receptor subunits GluR1 and GluR4, whereas levels of the NMDA receptor subunit NR1 were unaffected by etoposide. AMPA receptor activation can result in excitotoxic cell death but can also activate signaling pathways that promote synaptic plasticity and cell survival. We found that etoposide increases the activation of p42 and p44 mitogen-activated protein (MAP) kinases, and that activation of the MAP kinases by etoposide requires AMPA receptor activation. Pharmacological blockade of AMPA receptors and p42/p44 MAP kinases, but not of NMDA receptors, exacerbated etoposide-induced cell death. These findings suggest that, although etoposide is neurotoxic, it also activates a cell survival pathway involving AMPA receptor-mediated activation of p42/p44 MAP kinases. Agents that selectively inhibit the cell life or death pathways triggered by DNA damage may prove useful in the settings of cancer and neurodegenerative disorders, respectively.
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PMID:The DNA damaging agent etoposide activates a cell survival pathway involving alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors and mitogen-activated protein kinases in hippocampal neurons. 1242 35

Previously, 7-hydroxycoumarin (7-OHC) and 6-nitro-7-hydroxycoumarin (6-NO2-7-OHC) have been shown to be potent and selective anti-proliferative agents to the human renal cell carcinoma (RCC) cell line, A-498. Their effect on mitogen-activated protein kinases (MAPK's) was investigated. 6-NO2-7-OHC was shown to alter the phosphorylation status of ERK1/ERK2, p38 and SAPK, while 7-OHC activated ERK1/ERK2 but had no effect on p38 and SAPK. Also, 7-OHC inhibited topoisomerase II mediated relaxation of DNA, while neither compound was a substrate for P-glycoprotein (P-gp) mediated multi-drug resistance (MDR). Therefore, 6-NO2-7-OHC, rather than 7-OHC, modulated signalling events associated with cellular differentiation and apoptosis, suggesting its mechanism of action may be the promotion of cellular maturation and/or death. Consequently, 6-NO2-7-OHC may represent a novel therapeutic agent for the treatment of RCC's.
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PMID:Investigation of intracellular signalling events mediating the mechanism of action of 7-hydroxycoumarin and 6-nitro-7-hdroxycoumarin in human renal cells. 1503 63

Hypoxia-inducible factor-1 (HIF-1) is the central mediator of cellular responses to low oxygen and vital to many aspects of cancer biology. In a search for HIF-1 inhibitors, we identified a quassinoid 6alpha-tigloyloxychaparrinone (TCN) as an inhibitor of HIF-1 activation from Ailantus altissima. We here demonstrated the effect of TCN on HIF-1 activation induced by hypoxia or CoCl2. TCN showed the potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1alpha protein dose-dependently, whereas it did not affect the expressions of HIF-1beta and topoisomerase-I. Furthermore, TCN prevented hypoxia-induced expression of HIF-1 target genes for vascular endothelial growth factor (VEGF) and erythropoietin. Further analysis revealed that TCN strongly inhibited HIF-1alpha protein synthesis, without affecting the expression level of HIF-1alpha mRNA or degradation of HIF-1alpha protein. Moreover, the levels of phosphorylation of extracellular signal-regulated kinase-1/2 (ERK1/2), mitogen-activated protein (MAP) kinase-interacting protein kinase-1 (MNK1) and eukaryotic initiation factor 4E (eIF4E) were significantly suppressed by the treatment of TCN, without changing the total levels of these proteins. Our data suggested that TCN may exhibit anticancer activity by inhibiting HIF-1alpha translation through the inhibition of eIF4E phosphorylation pathway and thus provide a novel mechanism for the anticancer activity of quassinoids. TCN could be a new HIF-1-targeted anticancer agent and be effective on mammalian target of rapamycin (mTOR)-targeted cancer therapy, in which mTOR inhibition increases eIF4E phosphorylation.
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PMID:A quassinoid 6alpha-tigloyloxychaparrinone inhibits hypoxia-inducible factor-1 pathway by inhibition of eukaryotic translation initiation factor 4E phosphorylation. 1863 43

The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1 (ERK1) and ERK2 play well-characterized roles in the regulation of key cellular processes, such as proliferation, differentiation, and survival, by acting as serine and threonine kinases in the phosphorylation of ~200 substrates that are distributed in different subcellular localizations. However, over the past few years, evidence has mounted that indicates that the mechanism of action of ERK1 and ERK2 may extend beyond their role as canonical kinases. For example, proteins such as poly(ADP-ribose) polymerase 1, topoisomerase II, and MAPK phosphatase 3 (MKP-3) are activated by a direct interaction with ERK2 that does not involve any phosphotransfer activity. In addition, ERK2 binds to DNA and acts as a transcriptional regulator independently of its function as a kinase. Moreover, other studies demonstrate that ERK1 and ERK2 can regulate cell cycle entry by disrupting the interaction between the retinoblastoma pocket protein and lamin A in a kinase-independent fashion. These findings strongly support the notion that ERK1 and ERK2 can play functionally important roles independently of their regular catalytic activities and provide the basis for a new perspective from which to view these hitherto archetypical signaling kinases.
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PMID:Working without kinase activity: phosphotransfer-independent functions of extracellular signal-regulated kinases. 2202 68