Cdk1 promotes kinetochore bi-orientation and regulates Cdc20 expression during recovery from spindle checkpoint arrest

Liang, Hongqing; Lim, Hong Hwa; Venkitaraman, Ashok R.; Surana, Uttam

doi:10.1038/emboj.2011.385

Cited by 14 publications

(26 citation statements)

References 46 publications

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“…This is balanced by continuous synthesis of the protein hence ensuring constant steady state levels of Cdc20 during prometaphase 133 . APC15, a subunit of the platform sub-complex of APC/C is required for Cdc20 ubiquitylation and degradation 20, 127, 128 .…”

Section: Regulation Of the Apc/c In Early Mitosismentioning

confidence: 99%

Spatiotemporal regulation of the anaphase-promoting complex in mitosis

Sivakumar

Gorbsky

2015

Nat Rev Mol Cell Biol

237

266

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The appropriate timing of events that lead to chromosome segregation during mitosis and cytokinesis is essential to prevent aneuploidy, and defects in these processes can contribute to tumorigenesis. Key mitotic regulators are controlled through ubiquitylation and proteasome-mediated degradation. The Anaphase-Promoting Complex or Cyclosome (APC/C) is an E3 ubiquitin ligase that has a crucial function in the regulation of the mitotic cell cycle, particularly at the onset of anaphase and during mitotic exit. Co-activator proteins, inhibitor proteins, protein kinases and phosphatases interact with the APC/C to temporally and spatially control its activity and thus ensure accurate timing of mitotic events.

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Section: Regulation Of the Apc/c In Early Mitosismentioning

confidence: 99%

Spatiotemporal regulation of the anaphase-promoting complex in mitosis

Sivakumar

Gorbsky

2015

Nat Rev Mol Cell Biol

237

266

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“…To enrich for metaphase cells, the cdc20Δ GAL-CDC20 strain US1375 (Liang et al, 2012) was incubated in YEP supplemented with 2% raffinose and 2% galactose in a 24°C water bath overnight. On the next day, the cells were synchronized in G1 with α-factor (final concentration, 5 μg/ml).…”

Section: S Cerevisiae Cell Culturementioning

confidence: 99%

Budding yeast chromatin is dispersed in a crowded nucleoplasmin vivo

Chen

Shi

Lim

et al. 2016

Preprint

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Chromatin organization has an important role in the regulation of eukaryotic systems. Although recent studies have refined the three-dimensional models of chromatin organization with high resolution at the genome sequence level, little is known about how the most fundamental units of chromatin-nucleosomes-are positioned in three dimensions in vivo. Here we use electron cryotomography to study chromatin organization in the budding yeast Saccharomyces cerevisiae. Direct visualization of yeast nuclear densities shows no evidence of 30-nm fibers. Aside from preribosomes and spindle microtubules, few nuclear structures are larger than a tetranucleosome. Yeast chromatin does not form compact structures in interphase or mitosis and is consistent with being in an "open" configuration that is conducive to high levels of transcription. From our study and those of others, we propose that yeast can regulate its transcription using local nucleosome-nucleosome associations.

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“…Furthermore, Mps1 has been reported to be implicated in an error correction mechanism that resolves erroneous KT-MT attachments, which are frequently formed in early mitosis, by phosphorylation of the chromosome passenger complex subunit borealin (13,14). Accordingly, the inhibition of Mps1 abrogates the SAC, thereby leading to shortened mitosis, chromosome missegregation, aneuploidy or polyploidy, and cell death (13,(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Novel Mps1 Kinase Inhibitors with Potent Antitumor Activity

Wengner

Siemeister

Koppitz

et al. 2016

Molecular Cancer Therapeutics

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Monopolar spindle 1 (Mps1) has been shown to function as the key kinase that activates the spindle assembly checkpoint (SAC) to secure proper distribution of chromosomes to daughter cells. Here, we report the structure and functional characterization of two novel selective Mps1 inhibitors, BAY 1161909 and BAY 1217389, derived from structurally distinct chemical classes. BAY 1161909 and BAY 1217389 inhibited Mps1 kinase activity with IC 50 values below 10 nmol/L while showing an excellent selectivity profile. In cellular mechanistic assays, both Mps1 inhibitors abrogated nocodazole-induced SAC activity and induced premature exit from mitosis ("mitotic breakthrough"), resulting in multinuclearity and tumor cell death. Both compounds efficiently inhibited tumor cell proliferation in vitro (IC 50 nmol/L range). In vivo, BAY 1161909 and BAY 1217389 achieved moderate efficacy in monotherapy in tumor xenograft studies. However, in line with its unique mode of action, when combined with paclitaxel, low doses of Mps1 inhibitor reduced paclitaxel-induced mitotic arrest by the weakening of SAC activity. As a result, combination therapy strongly improved efficacy over paclitaxel or Mps1 inhibitor monotreatment at the respective MTDs in a broad range of xenograft models, including those showing acquired or intrinsic paclitaxel resistance. Both Mps1 inhibitors showed good tolerability without adding toxicity to paclitaxel monotherapy. These preclinical findings validate the innovative concept of SAC abrogation for cancer therapy and justify clinical proof-ofconcept studies evaluating the Mps1 inhibitors BAY 1161909 and BAY 1217389 in combination with antimitotic cancer drugs to enhance their efficacy and potentially overcome resistance. Mol Cancer Ther; 15(4); 583-92. Ó2016 AACR.

show abstract

Cdk1 promotes kinetochore bi-orientation and regulates Cdc20 expression during recovery from spindle checkpoint arrest

Cited by 14 publications

References 46 publications

Spatiotemporal regulation of the anaphase-promoting complex in mitosis

Spatiotemporal regulation of the anaphase-promoting complex in mitosis

Budding yeast chromatin is dispersed in a crowded nucleoplasmin vivo

Novel Mps1 Kinase Inhibitors with Potent Antitumor Activity

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