Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol

Kienitz, Anne; Vogel, Celia; Morales, Ivonne; Müller, Rolf; Bastians, Holger

doi:10.1038/sj.onc.1208589

Cited by 84 publications

(84 citation statements)

References 59 publications

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“…The active SAC when HDAC functions are disrupted [95][96][97]. In line with these findings, HDACIs (TSA, apicidin and sodium butyrate) induce premature sister chromatid separation [95], a phenotype consistently observed when the SAC is inhibited by RNA interference or genetic means [98][99][100]. Securin proteasome-dependent degradation is also observed in TSA treated mitotic cells and most likely accounts for premature sister chromatid separation [95].…”

Section: The Spindle Assembly Checkpointsupporting

confidence: 64%

Histone deacetylase inhibitors and genomic instability

Éot-Houllier¹,

Fulcrand²,

Magnaghi-Jaulin³

et al. 2009

Cancer Letters

114

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Abstract:Histone deacetylase inhibitors (HDACIs) are a promising new class of anticancer drugs.However, their mechanism of action has not been fully elucidated. Most studies have investigated the effect of HDACIs on the regulation of gene transcription. HDAC inhibition also leads to genomic instability by a variety of mechanisms. This phenomenon, which has been largely overlooked, may contribute to the cytotoxic effects of these drugs. Indeed, HDACIs sensitize DNA to exogenous genotoxic damage and induce the generation of reactive oxygen species. Moreover, HDACIs target mitosis resulting in chromosome segregation defects. Here, we review the effects of HDACI treatment on DNA damage and repair, and chromosome segregation control.

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Section: The Spindle Assembly Checkpointsupporting

confidence: 64%

Histone deacetylase inhibitors and genomic instability

Éot-Houllier¹,

Fulcrand²,

Magnaghi-Jaulin³

et al. 2009

Cancer Letters

114

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“…Controversial results have been reported on the effect of mitotic checkpoint inhibition on taxol-induced cell death. Incomplete functioning of the checkpoint has been suggested to induce resistance to high doses of taxol (17)(18)(19)(20), which is in line with the observation that CIN also correlated with taxol resistance (21). However, others have shown that inhibition of the mitotic checkpoint increases the effectiveness of taxol (22).…”

supporting

confidence: 68%

Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells

Janssen¹,

Kops

Medema³

2009

Proc. Natl. Acad. Sci. U.S.A.

280

249

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The mitotic checkpoint has evolved to prevent chromosome missegregations by delaying mitosis when unattached chromosomes are present. Inducing severe chromosome segregation errors by ablating the mitotic checkpoint causes cell death. Here we have analyzed the consequences of gradual increases in chromosome segregation errors on the viability of tumor cells and normal human fibroblasts. Partial reduction of essential mitotic checkpoint components in four tumor cell lines caused mild chromosome mis-segregations, but no lethality. These cells were, however, remarkably more sensitive to low doses of taxol, which enhanced the amount and severity of chromosome segregation errors. Sensitization to taxol was achieved by reducing levels of Mps1 or BubR1, proteins having dual roles in checkpoint activation and chromosome alignment, but not by reducing Mad2, functioning solely in the mitotic checkpoint. Moreover, we find that untransformed human fibroblasts with reduced Mps1 levels could not be sensitized to sublethal doses of taxol. Thus, targeting the mitotic checkpoint and chromosome alignment simultaneously may selectively kill tumor cells by enhancing chromosome mis-segregations.aneuploidy ͉ CIN ͉ mitosis ͉ paclitaxel

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“…13,25,27,29 Suppression of Mad2 or BubR1 in paclitaxeltreated breast cancer MCF-7 cells has been shown to abolish spindle checkpoint function, resulting in enhanced paclitaxel resistance. 29 The findings presented here strongly suggest that BRCA1 deficiency mediates paclitaxel resistance, at least in part, through downregulation of BubR1 expression resulting in premature inactivation of spindle checkpoint in MCF-7 cells.…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24] Surprisingly, spindle checkpoint deficiency has recently been associated with resistance to anti-microtubule agents. [25][26][27][28][29] Direct evidence that the induction of dysfunctional spindle checkpoint results in paclitaxel resistance has been demonstrated by knocking down Mad2 and/or BubR1 in MCF-7 breast carcinoma cells. 29 These cells harbor functional p53 but lack caspase-3 30 and undergo cell death following paclitaxel treatment by showing very weak apoptotic response but high micronuclei formation.…”

Section: Introductionmentioning

confidence: 99%

BRCA1 Downregulation Leads to Premature Inactivation of Spindle Checkpoint and Confers Paclitaxel Resistance

Chabalier¹,

Lamare²,

Racca³

et al. 2006

Cell Cycle

151

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BRCA1 germline mutations predispose women to early onset, familial breast and ovarian cancer. BRCA1 has been recently implicated in the cellular response to agents that disrupt the mitotic spindle. In this report, we studied BRCA1 contribution to paclitaxel response in MCF-7 breast cancer cells. We show that MCF-7 cells transfected with BRCA1 siRNA display a significant increase in resistance to paclitaxel compared with the control cells. We next demonstrate that downregulation of BRCA1 reduces the mitotic index and triggers premature cyclin B1 degradation and decrease in Cdk1 activity following paclitaxel treatment, suggesting that BRCA1 downregulation results in precocious inactivation of the spindle checkpoint. These findings were confirmed by showing that BRCA1 downregulation induces premature sister-chromatids separation in MCF-7 cells following spindle damage. Furthermore, we show that BRCA1 up-regulates the expression of the protein kinase BubR1, essential component of the functional spindle checkpoint, whose downregulation is known to result in paclitaxel resistance in MCF-7 cells. Altogether, our findings support the notion that downregulation of BRCA1 expression mediates paclitaxel resistance through premature inactivation of spindle checkpoint in MCF-7 breast cancer cells. They link BRCA1 to the mitotic checkpoint that plays an essential role in the maintenance of chromosomal stability.

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Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol

Cited by 84 publications

References 59 publications

Histone deacetylase inhibitors and genomic instability

Histone deacetylase inhibitors and genomic instability

Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells

BRCA1 Downregulation Leads to Premature Inactivation of Spindle Checkpoint and Confers Paclitaxel Resistance

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