p55CDC/hCDC20 mutant induces mitotic catastrophe by inhibiting the MAD2-dependent spindle checkpoint activity in tumor cells

Sihn, Choong-Ryoul; Suh, Eun-Jung; Lee, Kee-Ho; Kim, Taeyoon; Kim, Sang Hoon

doi:10.1016/s0304-3835(03)00465-8

Cited by 28 publications

(16 citation statements)

References 21 publications

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“…Spindle damaging agents, such as paclitaxel (Taxol), stabilize microtubules, inducing a mitotic arrest and activating the spindle cell checkpoint before the subsequent sub-G 1 apoptosis (39). Recent work suggests that overexpression of MAD2 protein in checkpoint-defective cells enhances paclitaxel sensitivity (40,41). We plan further studies to test the spindle checkpoint response in dedifferentiated liposarcoma cell lines so as to develop a strategy for fostering enhanced apoptosis after treatment with microtubule inhibitors, such as paclitaxel.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Liposarcoma Identifies Distinct Biological Types/Subtypes and Potential Therapeutic Targets in Well-Differentiated and Dedifferentiated Liposarcoma

Singer

Socci²,

Ambrosini³

et al. 2007

Cancer Research

217

183

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Classification of liposarcoma into three biological types encompassing five subtypes, (a) well-differentiated/dedifferentiated, (b) myxoid/round cell, and (c) pleomorphic, based on morphologic features and cytogenetic aberrations, is widely accepted. However, diagnostic discordance remains even among expert sarcoma pathologists. We sought to develop a more systematic approach to liposarcoma classification based on gene expression analysis and to identify subtype-specific differentially expressed genes that may be involved in liposarcoma genesis/progression and serve as potential therapeutic targets. A classifier based on gene expression profiling was able to distinguish between liposarcoma subtypes, lipoma, and normal fat samples. A 142-gene predictor of tissue class was derived to automatically determine the class of an independent validation set of lipomatous samples and shows the feasibility of liposarcoma classification based entirely on gene expression monitoring. Differentially expressed genes for each liposarcoma subtype compared with normal fat were used to identify histology-specific candidate genes with an indepth analysis of signaling pathways important to liposarcoma pathogenesis and progression in the well-differentiated/ dedifferentiated subset. The activation of cell cycle and checkpoint pathways in well-differentiated/dedifferentiated liposarcoma provides several possible novel therapeutic strategies with MDM2 serving as a particularly promising target. We show that Nutlin-3a, an antagonist of MDM2, preferentially induces apoptosis and growth arrest in dedifferentiated liposarcoma cells compared with normal adipocytes. These results support the development of a clinical trial with MDM2 antagonists for liposarcoma subtypes which overexpress MDM2 and show the promise of using this expression dataset for new drug discovery in liposarcoma. [Cancer Res 2007;67(14):6626-36]

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Liposarcoma Identifies Distinct Biological Types/Subtypes and Potential Therapeutic Targets in Well-Differentiated and Dedifferentiated Liposarcoma

Singer

Socci²,

Ambrosini³

et al. 2007

Cancer Research

217

183

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“…Sihn et al (29) showed that a truncated form of hCDC20, the anaphase-promoting complex target of BubR1 and Mad2, could bypass microtubule drug-induced mitotic arrest and induce an increase in apoptosis when compared with similarly treated control cells. Another study has shown that depletion of BubR1 protein in HeLa cells by RNA interference increased HeLa cell sensitivity to both paclitaxel and nocodazole (28).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that impairment of spindle checkpoint function leads to a reduction in the level of mitotic arrest and apoptosis normally induced by antimicrotubule drugs (25 -27). Other studies, however, have concluded that inactivation of the spindle checkpoint sensitizes cells to apoptosis induced by antimicrotubule drugs (28,29).…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by monastrol, an inhibitor of the mitotic kinesin Eg5, is independent of the spindle checkpoint

Chin

Herbst²

2006

Molecular Cancer Therapeutics

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Spindle poisons such as paclitaxel are widely used as cancer therapeutics. By interfering with microtubule dynamics, paclitaxel induces mitotic arrest and apoptosis. Targeting the kinesin Eg5, which is required for the formation of a bipolar spindle, is a promising therapeutic alternative to drugs that interfere with microtubule dynamics. Recent data suggest that the spindle checkpoint can determine the response of tumor cells to microtubule poisons. The relationship between checkpoint function and Eg5 inhibition, however, has not yet been fully investigated. Here, we used time-lapse video microscopy and biochemical analysis to study the effect of spindle checkpoint abrogation on the response of HeLa cells to monastrol, a selective Eg5 inhibitor. In HeLa cells, monastrol activated the spindle checkpoint, leading to mitotic arrest and apoptosis. Small interfering RNAmediated depletion of the spindle checkpoint proteins BubR1 or Mad2 significantly shortened drug-induced arrest, causing premature mitotic exit without cell division. Time-lapse microscopy as well as analysis of caspase activation shows that these checkpoint-deficient cells initiate apoptosis after mitotic exit in response to monastrol. Checkpoint-deficient cells treated with paclitaxel, on the other hand, yielded a higher frequency of cells with >4N DNA content and a decreased incidence of apoptotic events, particularly in Mad2-depleted cells. These results indicate that the immediate fate of postmitotic cells is influenced by both the nature of the checkpoint defect and the type of drug used. Furthermore, these results show that inactivation of the kinesin Eg5 can induce apoptosis in tumor cells in the absence of critical spindle checkpoint components. [Mol Cancer Ther 2006;5(10):2580 -91]

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“…Multiple groups have reported that a functional mitotic checkpoint is required for sensitivity to microtubule poisons and that a weakened mitotic checkpoint confers resistance (68)(69)(70)(71). However, numerous other groups have found that cells with a weakened mitotic checkpoint are more sensitive to microtubule poisons (72)(73)(74) or that there is no difference (66,75,76). One recent hypothesis is that mitotic checkpoint impairment causes re- (75).…”

Section: Cells Expressing High Levels Of Mad1 Are Resistant To Microtmentioning

confidence: 99%

Up-regulation of the mitotic checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons

Ryan

Britigan

Zasadil

et al. 2012

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

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The mitotic checkpoint is the major cell cycle checkpoint acting during mitosis to prevent aneuploidy and chromosomal instability, which are hallmarks of tumor cells. Reduced expression of the mitotic checkpoint component Mad1 causes aneuploidy and promotes tumors in mice [Iwanaga Y, et al. (2007) Cancer Res 67:160–166]. However, the prevalence and consequences of Mad1 overexpression are currently unclear. Here we show that Mad1 is frequently overexpressed in human cancers and that Mad1 up-regulation is a marker of poor prognosis. Overexpression of Mad1 causes aneuploidy and chromosomal instability through weakening mitotic checkpoint signaling caused by mislocalization of the Mad1 binding partner Mad2. Cells overexpressing Mad1 are resistant to microtubule poisons, including currently used chemotherapeutic agents. These results suggest that levels of Mad1 must be tightly regulated to prevent aneuploidy and transformation and that Mad1 up-regulation may promote tumors and cause resistance to current therapies.

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p55CDC/hCDC20 mutant induces mitotic catastrophe by inhibiting the MAD2-dependent spindle checkpoint activity in tumor cells

Cited by 28 publications

References 21 publications

Gene Expression Profiling of Liposarcoma Identifies Distinct Biological Types/Subtypes and Potential Therapeutic Targets in Well-Differentiated and Dedifferentiated Liposarcoma

Gene Expression Profiling of Liposarcoma Identifies Distinct Biological Types/Subtypes and Potential Therapeutic Targets in Well-Differentiated and Dedifferentiated Liposarcoma

Induction of apoptosis by monastrol, an inhibitor of the mitotic kinesin Eg5, is independent of the spindle checkpoint

Up-regulation of the mitotic checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons

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