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)

Sympathetic neurons depend on nerve growth factor (NGF) for their survival and die by apoptosis when NGF is withdrawn, despite their post-mitotic state. Martin et al. (1990, J. Neurosci. 10, 184-193) showed that cytosine arabinoside, but no other arabinofuranosyl nucleoside, could induce cell death in the presence of NGF and they suggested that it may block a critical step in the NGF-signalling pathway. We show that cytosine arabinoside is not the only nucleoside capable of inducing apoptosis in sympathetic neurons in the presence of NGF. In newly isolated neurons from P0 rat pups cultured in the presence of NGF, all the arabinose nucleosides (adenine, cytosine, guanine and thymine) induce apoptosis at 10 microM when combined with 5-fluorodeoxyuridine treatment. Because 1-beta-arabinofuranosylcytosine is associated with double-strand breaks and chromosomal abberrations, we examined whether topoisomerase II inhibitors, which also cause double-strand breaks by stabilising the enzyme-DNA 'cleavable complex', were capable of promoting apoptosis in these neurons. Although P0 rat neurons are strictly postmitotic, topoisomerase II inhibitors teniposide and mitoxantrone induced them to die by apoptosis in the presence of NGF with the same apparent time-course as arabinose treatment or NGF withdrawal. By contrast, ICRF 193, a catalytic inhibitor of topoisomerase II, reduced the extent of apoptosis induced by mitoxantrone or teniposide by 80% if added simultaneously with the latter but by 2 hours it had no rescue effect, suggesting that topoisomerase II is highly active in these neurons. ICRF 193 also partially reduced the induction of fluorodeoxyuridine-dependent apoptosis by the arabinose nucleosides.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Apoptosis is induced in post-mitotic rat sympathetic neurons by arabinosides and topoisomerase II inhibitors in the presence of NGF. 796 92

Previous studies have demonstrated that G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases (CDKs) prevent the death of nerve growth factor (NGF)-deprived PC12 cells and sympathetic neurons, suggesting that proteins normally involved in the cell cycle may also serve to regulate neuronal apoptosis. Past findings additionally demonstrate that DNA-damaging agents, such as the DNA topoisomerase (topo-I) inhibitor camptothecin, also induce neuronal apoptosis. In the present study, we show that camptothecin-induced apoptosis of PC12 cells, sympathetic neurons, and cerebral cortical neurons is suppressed by the G1/S blockers deferoxamine and mimosine, as well as by the CDK-inhibitors flavopiridol and olomoucine. In each case, the IC50 values were similar to those reported for inhibition of death induced by NGF-deprivation. In contrast, other agents that arrest DNA synthesis, such as aphidicolin and N-acetylcysteine, failed to block death. This suggests that the inhibition of DNA synthesis per se is insufficient to provide protection from camptothecin. We find additionally that the cysteine aspartase family protease inhibitor zVAD-fmk inhibits apoptosis evoked by NGF-deprivation but not camptothecin treatment. Thus, despite their shared sensitivity to G1/S blockers and CDK inhibitors, the apoptotic pathways triggered by these two causes of death diverge at the level of the cysteine aspartase. In summary, neuronal apoptosis induced by the DNA-damaging agent camptothecin appears to involve signaling pathways that normally control the cell cycle. The consequent death signals of such deregulation, however, are different from those that result from trophic factor deprivation.
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PMID:G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis. 900 70