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

Ryan, Sean D.; Britigan, Eric M. C.; Zasadil, Lauren M.; Witte, K. H.; Audhya, Anjon; Roopra, Avtar; Weaver, Beth A.

doi:10.1073/pnas.1201911109

Cited by 88 publications

(104 citation statements)

References 85 publications

(119 reference statements)

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“…It has been reported that the weakening of the checkpoint due to individual unattached kinetochores does not block anaphase onset but lead to increased frequency of aneuploidy. 36 In our research, the levels of Mad2 and BubR1 were reduced in EWSR1-depleted cells, but not eliminated, due to the presence of some unaligned chromosomes. We also observed a high ratio of multipolar spindles in EWSR1-depleted cells, which might be the result of weak signal generation at individual unattached kinetochores.…”

Section: Discussionmentioning

confidence: 45%

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

et al. 2016

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EWSR1, participating in transcription and splicing, has been identified as a translocation partner for various transcription factors, resulting in translocation, which in turn plays crucial roles in tumorigenesis. Recent studies have investigated the role of EWSR1 in mitosis. However, the effect of EWSR1 on mitosis is poorly understood. Here, we observed that depletion of EWSR1 resulted in cell cycle arrest in the mitotic phase, mainly due to an increase in the time from nuclear envelope breakdown to metaphase, resulting in a high percentage of unaligned chromosomes and multipolar spindles. We also demonstrated that EWSR1 is a spindle-associated protein that interacts with a-tubulin during mitosis. EWSR1 depletion increased the cold-sensitivity of spindle microtubules, and decreased the rate of spindle assembly. EWSR1 regulated the level of microtubule acetylation in the mitotic spindle; microtubule acetylation was rescued in EWSR1-depleted mitotic cells following suppression of HDAC6 activity by its specific inhibitor or siRNA treatment. In summary, these results suggest that EWSR1 regulates the acetylation of microtubules in a cell cycledependent manner through its dynamic location on spindle MTs, and may be a novel regulator for mitosis progress independent of its translocation.

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Section: Discussionmentioning

confidence: 45%

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

et al. 2016

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“…This leads to rapid mitotic exit and SAC abolishment. 15,16 Through our study, we hypothesize that reduced Mad1 levels, due to excess miR-125b, increases free-Mad2 pool, which can bind more Cdc20 molecules, as a result of which APC/C remains inactive and cells are halted at metaphase. In summary, (1) the SAC gene MAD1 is a novel target of miR-125b, (2) Mad1 downregulation brings about transient SAC activation and mitotic delay and (3) this delay gives rise to chromosomal abnormalities, presumable accumulation of which leads to apoptosis.…”

Section: Discussionmentioning

confidence: 78%

“…This is reminiscent of a recent report that Mad1 upregulation might promote tumour miR-125b represses MAD1 expression S Bhattacharjya et al formation and manifest resistance to therapies. 16 It is wellknown that accelerated mitotic progression can induce CIN. 29,16 Our data also reveal a higher incidence of chromosomal defects in presence of ectopic miR-125b, mostly in metaphase-to-anaphase transition.…”

Section: Discussionmentioning

confidence: 99%

“…16 It is wellknown that accelerated mitotic progression can induce CIN. 29,16 Our data also reveal a higher incidence of chromosomal defects in presence of ectopic miR-125b, mostly in metaphase-to-anaphase transition. Cell viability too was considerably reduced by increased apoptotic death.…”

Section: Discussionmentioning

confidence: 99%

“…12 The importance of Mad1 in regulating SAC is accentuated by the observation that excess Mad1 reduces free-Mad2 level in Xenopus extracts, 15 and weakens SAC by disrupting mitotictiming. 16 Conversely, excess Mad2 can arrest cells in metaphase, in spite of all chromosomes being bi-oriented successfully. 15 This underlines the need for a proper Mad1/ Mad2 ratio to maintain the integrity of SAC.…”

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confidence: 99%

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miR-125b promotes cell death by targeting spindle assembly checkpoint gene MAD1 and modulating mitotic progression

et al. 2012

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The spindle assembly checkpoint (SAC) is a 'wait-anaphase' mechanism that has evolved in eukaryotic cells in response to the stochastic nature of chromosome-spindle attachments. In the recent past, different aspects of the SAC regulation have been described. However, the role of microRNAs in the SAC is vaguely understood. We report here that Mad1, a core SAC protein, is repressed by human miR-125b. Mad1 serves as an adaptor protein for Mad2 -which functions to inhibit anaphase entry till the chromosomal defects in metaphase are corrected. We show that exogenous expression of miR-125b, through downregulation of Mad1, delays cells at metaphase. As a result of this delay, cells proceed towards apoptotic death, which follows from elevated chromosomal abnormalities upon ectopic expression of miR-125b. Moreover, expressions of Mad1 and miR-125b are inversely correlated in a variety of cancer cell lines, as well as in primary head and neck tumour tissues. We conclude that increased expression of miR-125b inhibits cell proliferation by suppressing Mad1 and activating the SAC transiently. We hypothesize an optimum Mad1 level and thus, a properly scheduled SAC is maintained partly by miR-125b.

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Molecular characterization of an MLL1 fusion and its role in chromosomal instability

et al. 2018

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Chromosomal rearrangements involving the mixed‐lineage leukemia (MLL1) gene are common in a unique group of acute leukemias, with more than 100 fusion partners in this malignancy alone. However, do these fusions occur or have a role in solid tumors? We performed extensive network analyses of MLL1‐fusion partners in patient datasets, revealing that multiple MLL1‐fusion partners exhibited significant interactions with the androgen‐receptor signaling pathway. Further exploration of tumor sequence data from TCGA predicts the presence of MLL1 fusions with truncated SET domain in prostate tumors. To investigate the physiological relevance of MLL1 fusions in solid tumors, we engineered a truncated version of MLL1 by fusing it with one of its known fusion partners, ZC3H13, to use as a model system. Functional characterization with cell‐based assays revealed that MLL1‐ZC3H13 fusion induced chromosomal instability, affected mitotic progression, and enhanced tumorsphere formation. The MLL1‐ZC3H13 chimera consistently increased the expression of a cancer stem cell marker (CD44); in addition, we detected potential collateral lethality between DOT1L and MLL1 fusions. Our work reveals that MLL1 fusions are likely prevalent in solid tumors and exhibit a potential pro‐tumorigenic role.

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

Cited by 88 publications

References 85 publications

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

miR-125b promotes cell death by targeting spindle assembly checkpoint gene MAD1 and modulating mitotic progression

Molecular characterization of an MLL1 fusion and its role in chromosomal instability

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