Okadaic Acid Overrides the S-Phase Check Point and Accelerates Progression of G2-Phase to Induce Premature Mitosis in HeLa Cells

Ghosh, Sibdas; Schroeter, D.; Paweletz, Neidhard

doi:10.1006/excr.1996.0262

Cited by 36 publications

(26 citation statements)

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“…Treatment of some cell types with ca eine, okadaic acid or staurosporine can override the S phase completion checkpoint, causing premature chromatin condensation, DNA fragmentation and cell death (Ghosh et al, 1996;Schlegel and Pardee, 1986;Steinmann et al, 1991;Yoshida et al, 1997). We observed that p53-null MDAH041 ®broblasts, derived from Li-Fraumeni cells, continued to attempt mitosis when DNA synthesis was inhibited with hydroxyurea, leading to fragmentation of chromatin and cell death.…”

Section: Role Of P53 In the S Phase Completion Checkpointmentioning

confidence: 81%

Regulation of the G2/M transition by p53

Taylor¹,

Stark²

2001

Oncogene

1,392

1,110

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Section: Role Of P53 In the S Phase Completion Checkpointmentioning

confidence: 81%

Regulation of the G2/M transition by p53

Taylor¹,

Stark²

2001

Oncogene

1,392

1,110

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“…1 ± 7 There is evidence that multiple pathways activated by PP inhibition may converge to elicit the apoptotic response. In various instances, apoptosis induced by okadaic acid (OA), a potent inhibitor of PP type 2A and PP type 1,8 has been shown to associate with cell cycle deregulation leading to abortive mitosis, 2,7,9 a view consistent with the notion that PPs can modulate the expression and/or the activity of various proteins that ensure proper progression through the replicative cycle. 8,10 PP inhibition, on the other hand, has also been shown to modulate the expression of proteins involved in apoptosis control.…”

Section: Introductionmentioning

confidence: 76%

Ceramide accumulation precedes caspase-dependent apoptosis in CHP-100 neuroepithelioma cells exposed to the protein phosphatase inhibitor okadaic acid

et al. 1999

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The protein phosphatase inhibitor okadaic acid (OA) dosedependently induced apoptosis in CHP-100 neuroepithelioma cells when administered for 24 h at concentrations ranging from 10 ± 100 nM. Apoptosis was largely, albeit not completely, dependent on cystein protease (caspase) activation. CPP32 processing and poly(ADP-ribose) polymerase (PARP) cleavage started to be observed only at 20 nM OA; moreover, the caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone (Z-VAD.fmk) (100 mM) had negligible effect on apoptosis induced by 10 nM OA, but rescued from death an increasing cell fraction as OA concentration was raised from 20 ± 100 nM. Cell treatment for 24 h with OA induced ceramide accumulation; the phenomenon started to be evident at 20 nM OA and reached its maximum at 50 ± 100 nM OA. In cells exposed to 50 nM OA, ceramide was already elevated by 5 h; at this time, however, PARP cleavage and apoptosis were not yet observed. Z-VAD.fmk (100 mM) had no effect on ceramide elevation induced by 50 nM OA within 5 h, but markedly reduced ceramide accumulation as the incubation was prolonged to 24 h. The latter phenomenon was accompanied by elevation of glucosylceramide levels, thus suggesting that a caspase-dependent reduction of glucosylceramide synthesis might contribute to late ceramide accumulation. Shortchain ceramide (30 mM) induced apoptosis in CHP-100 cells and its effect was additive with that evoked by OA (10 ± 20 nM). These results suggest that ceramide generation might be an important mechanism through which sustained protein phosphatase inhibition induces caspase activation and apoptosis in CHP-100 cells.

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“…In plants, caffeine is able to override the G2 DNA damage checkpoint (Hartley-Asp et al, 1980;González-Fernández et al, 1985) but it is unable to cancel replication checkpoints in S phase (Amino and Nagata, 1996;Pelayo et al, 2001). Okadaic acid, a protein phosphatase 2A inhibitor, induces premature mitosis in animal cells in a similar way to caffeine (Ghosh et al, 1996). Correspondingly, endothal, another PP2A-specific phosphatase inhibitor, was found to prematurely activate a plant mitotic CDK resulting in microtubule and chromosome condensation abnormalities (Ayaydin et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

A plant cyclin B2 is degraded early in mitosis and its ectopic expression shortens G2-phase and alleviates the DNA-damage checkpoint

Weingartner

Pelayo

Binarová

et al. 2003

Journal of Cell Science

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Mitotic progression is timely regulated by the accumulation and degradation of A- and B-type cyclins. In plants, there are three classes of A-, and two classes of B-type cyclins, but their specific roles are not known. We have generated transgenic tobacco plants in which the ectopic expression of a plant cyclin B2 gene is under the control of a tetracycline-inducible promoter. We show that the induction of cyclin B2 expression in cultured cells during G2 phase accelerates the entry into mitosis and allows cells to override the replication checkpoint induced by hydroxyurea in the simultaneous presence of caffeine or okadaic acid, drugs that are known to alleviate checkpoint control. These results indicate that in plants, a B2-type cyclin is a rate-limiting regulator for the entry into mitosis and a cyclin B2-CDK complex might be a target for checkpoint control pathways. The cyclin B2 localization and the timing of its degradation during mitosis corroborate these conclusions: cyclin B2 protein is confined to the nucleus and during mitosis it is only present during a short time window until mid prophase, but it is effectively degraded from this timepoint onwards. Although cyclin B2 is not present in cells arrested by the spindle checkpoint in metaphase, cyclin B1 is accumulating in these cells. Ectopic expression of cyclin B2 in developing plants interferes with differentiation events and specifically blocks root regeneration, indicating the importance of control mechanisms at the G2- to M-phase transition during plant developmental processes.

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Okadaic Acid Overrides the S-Phase Check Point and Accelerates Progression of G2-Phase to Induce Premature Mitosis in HeLa Cells

Cited by 36 publications

References 0 publications

Regulation of the G2/M transition by p53

Regulation of the G2/M transition by p53

Ceramide accumulation precedes caspase-dependent apoptosis in CHP-100 neuroepithelioma cells exposed to the protein phosphatase inhibitor okadaic acid

A plant cyclin B2 is degraded early in mitosis and its ectopic expression shortens G2-phase and alleviates the DNA-damage checkpoint

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