Mitotic Checkpoint Slippage in Humans Occurs via Cyclin B Destruction in the Presence of an Active Checkpoint

Brito, Daniela A.; Rieder, Conly L.

doi:10.1016/j.cub.2006.04.043

Cited by 476 publications

(533 citation statements)

References 29 publications

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“…Some proteins involved in overriding the mitotic checkpoint have been described. In addition, cyclin B destruction was demonstrated to occur in the presence of an active checkpoint to enable mitotic checkpoint slippage (Brito and Rieder, 2006 and Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

et al. 2008

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Fbw7 is a tumor suppressor that is mutated in numerous cancers. It encodes an E3 ubiquitin ligase, whose ability to decrease the levels of pivotal regulators of cell growth and proliferation underlies its tumor suppressor function. Here, we explore the consequences of Fbw7 inactivation on the outcome of chemotherapeutic treatments. When exposed to spindle toxins such as vinblastine and taxol, Fbw7-deficient cells undergo extensive mitotic slippage and endoreduplication, rendering them polyploid. A combined deregulation of several Fbw7 target proteins is required for this phenotype. Specifically, elevated expression of cyclin E and Aurora A in Fbw7-deficient cells is required for drug-induced polyploidy. However, overexpression of either cyclin E or Aurora A alone is not sufficient for drug-induced polyploidy. In addition, we demonstrate that Fbw7 deficiency limits the ability of p53 to respond to mitotic toxins but not to DNA damage. Furthermore, Fbw7 expression regulates the p53-dependent induction of genes such as Lats2 and p21 in response to vinblastine. Hence, we suggest that Fbw7 serves as a master regulator of the mitotic and tetraploidy checkpoints.

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Section: Discussionmentioning

confidence: 99%

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

et al. 2008

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“…Prolonged mitotic arrest can lead cells (i) to apoptosis or (ii) to escape mitosis via mitotic slippage through the ubiquitination and proteolysis of Cyclin B [36]. Mitotic slippage leads to the accumulation of postmitotic G1 cells, which are subsequently arrested in their cell cycle progression by activating a p53-dependent G1 checkpoint [37,38,39].…”

Section: Bis-demethoxycurcumin Triggers a Concurrent G1/s And Mitoticmentioning

confidence: 99%

Curcumin derivatives: Molecular basis of their anti-cancer activity

Basile

Ferrari

Lazzari

et al. 2009

Biochemical Pharmacology

164

129

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Curcumin, a phenolic compound from the plant Curcuma longa L., has shown a wide-spectrum of chemopreventive, anti-oxidant and anti-tumor properties. Although its promising chemotherapeutic activity, preclinical and clinical studies highlight Curcumin limited therapeutic application due to its instability in physiological conditions. To improve its stability and activity, many derivatives have been synthesized and studied, among which bis-DemethoxyCurcumin (bDMC) and diAcetylCurcumin (DAC). In this report, we show that both bDMC and DAC are more stable than Curcumin in physiological medium. To explore the mechanism of their chemotherapeutic effect, we studied their role in proliferation in the HCT116 human colon cancer cells. We correlated kinetic stability and cellular uptake data to their biological effects. Both bDMC and DAC impair correct spindles formation and induce a p53-and p21 CIP1/WAF1 -independent mitotic arrest, which is more stable and long-lasting for bDMC. A subsequent p53/p21 CIP1/WAF1 -dependent inhibition of G1 to S transition is triggered by Curcumin and DAC as a consequence of the mitotic slippage, preventing postmitotic cells from re-entering the cell cycle. Conversely, the G1/S arrest induced by bDMC is a direct effect of the drug and concomitant to the mitotic block. Finally, we demonstrate that bDMC induces rapid DNA double-strand breaks, moving for its possible development in anti-cancer clinical applications.

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“…Our experiments and those involving checkpoint adaptation involve processes, which are different from checkpoint recovery in which the checkpoint is inactivated due to repair of the initial damage. The mitotic arrest induced by spindle disruptive agents also can be released by the gradual loss of the checkpoint effector, cyclin B, despite the continued presence of spindle damage and the activation of upstream checkpoint proteins (29,30).…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 99%

Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit

Bekier

Fischbach

Lee

et al. 2009

Molecular Cancer Therapeutics

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Cell death induced by agents that disrupt microtubules can kill cells by inducing a prolonged mitotic block. This mitotic block is dependent on the spindle assembly checkpoint, a surveillance system that ensures the bipolar attachment of chromosomes to the mitotic spindle before the onset of anaphase. Under some conditions, the spindle assembly checkpoint can become weakened, allowing cells to exit mitosis despite the presence of chromosomes that are not properly attached to the mitotic spindle. Here, we use an Aurora kinase inhibitor to drive mitotic exit and test the effect of mitotic arrest length on death in the subsequent interphase. Cells that are blocked in mitosis for >15 h die shortly after exiting from mitosis, whereas cells that exit after being blocked for <15 h show variable fates, with some living for days after exiting mitosis. Cells blocked in mitosis by either Taxol or epothilone B are acutely sensitive to the death ligand tumor necrosis factor-related apoptosisinducing ligand, suggesting that prolonged mitosis allows the gradual accumulation of internal death signals, rendering cells hypersensitive to additional prodeath cues. Death under these conditions is initiated while cyclin B1 is still present, indicating that cells are in mitosis. Our experiments suggest that there is a point of no return during prolonged mitotic block after which mitotic exit can no longer block death.

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Mitotic Checkpoint Slippage in Humans Occurs via Cyclin B Destruction in the Presence of an Active Checkpoint

Cited by 476 publications

References 29 publications

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

Curcumin derivatives: Molecular basis of their anti-cancer activity

Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit

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