SAC‐ing mitotic errors: How the spindle assembly checkpoint (SAC) plays defense against chromosome mis‐segregation

Kadura, Sheila; Sazer, Shelley

doi:10.1002/cm.20072

Cited by 23 publications

(21 citation statements)

References 197 publications

(189 reference statements)

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“…The spindle assembly checkpoint (SAC) ensures that sister chromatid segregation in anaphase does not take place before all chromosomes are properly aligned at the metaphase plate and all kinetochores are under sufficient tension and occupancy by spindle microtubules. [2][3][4][5] As long as mitotic cells contain such unattached kinetochores or if the function of the mitotic spindle is perturbed (for instance by spindle poisons), the SAC remains active and prevents sister chromatid separation. 6,7 More than 60 different kinetochore proteins have been identified in budding yeast, many of which are conserved in animal cells.…”

Section: Sac Signaling At the Kinetochoresmentioning

confidence: 99%

“…2,13 To examine whether the SAC functions normally in cells lacking components of the Cul3 complex, we synchronized HeLa cells by the double thymidine block-release protocol as previously reported in ref. 45, and challenged the cells with the microtubule-depolymerizing drug nocodazole (Fig.…”

Section: Inactivation Of the Cul3/klhl9/klhl13 E3-ligase Leads To Prementioning

confidence: 99%

“…2,46 In the absence of a functional SAC, premature chromosome segregation often leads to cytokinesis failure, resulting in G 1 cells with ploidy errors including numerous micronuclei or 4N "restitution" nuclei. 10,47-49 SAC signaling prevents proteasomal degradation of substrates by inhibiting the APC Cdc20 ubiquitin ligase.…”

Section: How Does Cul3/klhl9/klhl13 E3-ligase Maintain Sac Signaling mentioning

confidence: 99%

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A Cul3-Based E3 Ligase Regulates Mitosis and is Required to Maintain the Spindle Assembly Checkpoint in Human Cells

Sumara

Peter

2007

Cell Cycle

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Section: Sac Signaling At the Kinetochoresmentioning

confidence: 99%

Section: Inactivation Of the Cul3/klhl9/klhl13 E3-ligase Leads To Prementioning

confidence: 99%

Section: How Does Cul3/klhl9/klhl13 E3-ligase Maintain Sac Signaling mentioning

confidence: 99%

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A Cul3-Based E3 Ligase Regulates Mitosis and is Required to Maintain the Spindle Assembly Checkpoint in Human Cells

Sumara

Peter

2007

Cell Cycle

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“…Mitotic stress evoked through spindle poisons such as paclitaxel (PTX) can impair proper chromosome capture by microtubules and arrest cell cycle progression through the activation of the spindle assembly checkpoint (Kadura and Sazer, 2005). This checkpoint monitors the occurrence of unattached kinetochores (Khodjakov and Rieder, 2009).…”

Section: Introductionmentioning

confidence: 99%

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

et al. 2010

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Microtubule-interfering cancer drugs such as paclitaxel (PTX) often cause chemoresistance and severe side effects, including neurotoxicity. To explore potentially novel antineoplastic molecular targets, we investigated the cellular response of breast carcinoma cells to short hairpin(sh)RNA-mediated depletion of the centrosomal protein transforming acidic coiled coil (TACC) 3, an Aurora A kinase target expressed during mitosis. Unlike PTX, knockdown of TACC3 did not trigger a cell death response, but instead resulted in a progressive loss of the pro-apoptotic Bcl-2 protein Bim that links microtubule integrity to spindle poison-induced cell death. Interestingly, TACC3-depleted cells arrested in G 1 through a cellular senescence program characterized by the upregulation of nuclear p21 WAF , downregulation of the retinoblastoma protein and extracellular signal-regulated kinase 1/2, formation of HP1c (phospho-Ser83)-positive senescence-associated heterochromatic foci and increased senescence-associated b-galactosidase activity. Remarkably, the onset of senescence following TACC3 knockdown was strongly accelerated in the presence of non-toxic PTX concentrations. Thus, we conclude that mitotic spindle stress is a major trigger of premature senescence and propose that the combined targeting of the centrosomal Aurora A-TACC3 axis together with drugs interfering with microtubule dynamics may efficiently improve the chemosensitivity of cancer cells.

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“…During mitosis, the non-attachment of even a single chromosome suffices to activate the mitotic spindle assembly checkpoint, which arrests cells in (pro)metaphase until all chromosomes are properly attached (Kadura and Sazer, 2005). The spindle assembly checkpoint, however, does not arrest cells permanently, and cells might escape from this block by a process called mitotic slippage.…”

Section: Introductionmentioning

confidence: 99%

TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest

et al. 2007

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Regulators of the mitotic spindle apparatus are attractive cellular targets for antitumor therapy. The centrosomal protein transforming acidic coiled coil (TACC) 3 is required for spindle assembly and proper chromosome segregation. In this study, we employed an inducible RNA interference approach to downregulate TACC3 expression. We show that TACC3 knock-down in NIH3T3 fibroblasts caused aneuploidy, but failed to overtly impair mitotic progression. TACC3 depletion rather triggered a postmitotic p53-p21 WAF pathway and led to a reversible cell cycle arrest. Similar effects were induced by low concentrations of paclitaxel, a spindle poison used in antitumor therapy. Interestingly, however, and unlike in TACC3-proficient cells, paclitaxel was able to induce strong polyploidy and subsequent apoptosis in TACC3-depleted cells. Even though paclitaxel treatment was associated with the activation of the survival kinase Akt and an antiapoptotic expression of cytoplasmic p21 WAF and cyclin D1, this inhibition of cell death was abrogated by depletion of TACC3. Thus, our data identify TACC3 as a potential target to overcome p21 WAF -associated protection of transformed cells against paclitaxel-induced cell death.

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SAC‐ing mitotic errors: How the spindle assembly checkpoint (SAC) plays defense against chromosome mis‐segregation

Cited by 23 publications

References 197 publications

A Cul3-Based E3 Ligase Regulates Mitosis and is Required to Maintain the Spindle Assembly Checkpoint in Human Cells

A Cul3-Based E3 Ligase Regulates Mitosis and is Required to Maintain the Spindle Assembly Checkpoint in Human Cells

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest

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