APC/C is an essential regulator of centrosome clustering

Drosopoulos, Konstantinos; Tang, Chan; Chao, William Chong Hang; Linardopoulos, Spiros

doi:10.1038/ncomms4686

Cited by 75 publications

(82 citation statements)

References 42 publications

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“…40 Recently, it has been shown that Cdh1 is involved in centrosome clustering, which may be disturbed upon Cdh1 depletion and lead to more frequent multipolar mitoses because of stabilization of the motor protein Eg5. 41 However, we found no difference in centrosome clustering in Cdh1-kd cells compared with the control.…”

Section: Discussionmentioning

confidence: 80%

The role of APC/CCdh1 in replication stress and origin of genomic instability

et al. 2015

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It has been proposed that the APC/C(Cdh1) functions as a tumor suppressor by maintaining genomic stability. However, the exact nature of genomic instability following loss of Cdh1 is unclear. Using biochemistry and live cell imaging of single cells we found that Cdh1 knockdown (kd) leads to strong nuclear stabilization of the substrates cyclin A and B and deregulated kinetics of DNA replication. Restoration of the Cdh1-dependent G2 DNA damage checkpoint did not result in G2 arrest but blocked cells in prometaphase, suggesting that these cells enter mitosis despite incomplete replication. This results in DNA double-strand breaks, anaphase bridges, cytokinesis defects and tetraploidization. Tetraploid cells are the source of supernumerary centrosomes following Cdh1-kd, leading to multipolar mitosis or centrosome clustering, in turn resulting in merotelic attachment and lagging chromosomes. Whereas some of these events cause apoptosis during mitosis, surviving cells may accumulate chromosomal aberrations.

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Section: Discussionmentioning

confidence: 80%

The role of APC/CCdh1 in replication stress and origin of genomic instability

et al. 2015

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“…In non-transformed cells, levels of KIF11 fluctuate throughout the cell cycle and are regulated by targeted protein destruction by means of ubiquitination (28, 29). The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that is a central mediator of the ubiquitin-mediated degradation of mitotic proteins.…”

Section: Resultsmentioning

confidence: 99%

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

et al. 2015

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The proliferative and invasive nature of malignant cancers drives lethality. In glioblastoma, these two processes are presumed mutually exclusive and hence termed “go or grow”. Here, we identified a molecular target that shuttles between these disparate cellular processes—the molecular motor KIF11. Inhibition of KIF11 with a highly specific small molecule inhibitor stopped the growth of both the more treatment resistant glioblastoma tumor initiating cells (TICs, or cancer stem cells) as well as non-TICs and impeded tumor initiation and self-renewal of the TIC population. Targeting KIF11 also hit the other arm of the “go or grow” cell fate decision by reducing glioma cell invasion. Administration of a KIF11 inhibitor to mice bearing orthotopic glioblastoma prolonged their survival. In its role as a shared molecular regulator of cell growth and motility across intratumoral heterogeneity, KIF11 is a compelling target for glioblastoma.

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“…Since phospho-peptide analysis revealed that endogenous Eg5 is phosphorylated only at the T927 and S1040 sites in vivo (Rapley et al, 2008) , and since mutation of neither site abolish Eg5 ubiquitinylation, it is likely that Fbxo30-mediated Eg5 degradation occurs by a phosphorylation-independent pathway, which would be similar to the Fbxo1-CP110 and Fbx011-BCL6 interactions (D’Angiolella et al, 2010; Duan et al, 2012). Two recent studies demonstrated the APC/C-CDH1 complex also cause ubiquitinylation of EG5 (Drosopoulos et al, 2014; Eguren et al, 2014). Given the specific activation of the APC/C-CDH1 during mitosis, and given the relatively low expression and small effect of Fbxo30 deficiency on EG5 levels at M phase, we suggest that Fbxo30 and APC/C-CDH1 may function at different phases of cell cycle in regulating EG5 levels, although the possibility that these different E3 may function in different cell types cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

“…S6b). With recent identification of APC/C-CDH as an E3 ligase for EG5 (Drosopoulos et al, 2014; Eguren et al, 2014), it is possible that this or other E3 may serve to regulate EG5 depending on the cell types studied.…”

Section: Discussionmentioning

confidence: 99%

Fbxo30 Regulates Mammopoiesis by Targeting the Bipolar Mitotic Kinesin Eg5

Liu

Wang

et al. 2016

Cell Reports

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Fbxo30 is an orphan member of the F-box protein family with no known substrate or function. Here, we report that while Fbxo30−/− mice exhibit normal development, growth, life span, and fertility, the females fail to nurture their offspring due to defective mammopoiesis. Mass spectrometry analysis of Fbxo30-associated proteins revealed that Fbxo30 specifically interacts with the bipolar spindle kinesin EG5 (encoded by Kif11). As a result, Fbxo30 targets Eg5 for ubiquitinylation and controls its oscillation during the cell cycle. Correlated with EG5 dysregulation, Fbxo30−/− mammary epithelial cells exhibit multiple defects in centrosome homeostasis, mitotic spindle formation, and proliferation. Effects on proliferation, centrosome homeostasis, and mammopoiesis in the Fbxo30−/− mice were rescued through normalization of Eg5 activity using shRNA and/or an EG5 inhibitor. Our data reveal the Fbxo30-Eg5 interaction as a critical checkpoint in mammopoiesis and a critical role for ubiquitinylation-regulated Eg5 oscillation in the cell cycle.

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APC/C is an essential regulator of centrosome clustering

Cited by 75 publications

References 42 publications

The role of APC/CCdh1 in replication stress and origin of genomic instability

The role of APC/CCdh1 in replication stress and origin of genomic instability

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

Fbxo30 Regulates Mammopoiesis by Targeting the Bipolar Mitotic Kinesin Eg5

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