Cep57 Protein Is Required for Cytokinesis by Facilitating Central Spindle Microtubule Organization

He, Runsheng; Wu, Qixi; Zhou, Huanbin; Chen, Jianguo; Jiang, Teng

doi:10.1074/jbc.m112.441501

Cited by 12 publications

(12 citation statements)

References 32 publications

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“…We previously reported that Cep57 is a component of the spindle pole and midzone, and functions in spindle pole architecture and central spindle microtubule organization 34 35 . Previous findings have revealed that x Cep57 is a kinetochore component 31 .…”

Section: Discussionmentioning

confidence: 99%

“… 33 ). The localization and function of Cep57R remains unknown, while Cep57 is an ubiquitously-expressed protein that functions in spindle assembly, spindle pole integrity and central spindle organization as a microtubule- and centrosome-associated protein 33 34 35 36 . Also, Cep57 is required for centriole duplication, and is highly expressed in prostate cancer cells 37 .…”

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confidence: 99%

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Cep57 is a Mis12-interacting kinetochore protein involved in kinetochore targeting of Mad1–Mad2

et al. 2016

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The spindle assembly checkpoint (SAC) arrests cells in mitosis by sensing unattached kinetochores, until all chromosomes are bi-oriented by spindle microtubules. Kinetochore accumulation of the SAC component Mad1–Mad2 is crucial for SAC activation. However, the mechanism by which Mad1–Mad2 accumulation at kinetochores is regulated is not clear. Here we find that Cep57 is localized to kinetochores in human cells, and binds to Mis12, a KMN (KNL1/Mis12 complex/Ndc80 complex) network component. Cep57 also interacts with Mad1, and depletion of Cep57 results in decreased kinetochore localization of Mad1–Mad2, reduced SAC signalling and increased chromosome segregation errors. We also show that the microtubule-binding activity of Cep57 is involved in the timely removal of Mad1 from kinetochores. Thus, these findings reveal that the KMN network-binding protein Cep57 is a mitotic kinetochore component, and demonstrate the functional connection between the KMN network and the SAC.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Cep57 is a Mis12-interacting kinetochore protein involved in kinetochore targeting of Mad1–Mad2

et al. 2016

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“…Mosaic variegated aneuploidy (MVA) syndrome is a rare disorder characterized by mosaic aneuploidies of many chromosomes . The inheritance is autosomal recessive and caused by biallelic mutations in TRIP13 , BUB1B, or CEP57 , which establish the spindle assembly checkpoint, stabilize mitotic spindle attachment, and stabilize mitotic microtubule attachment, respectively . The phenotype of MVA is nonspecific and includes growth retardation, intrauterine growth restriction (IUGR), microcephaly, facial dysmorphia, and intellectual disability (ID) .…”

Section: Introductionmentioning

confidence: 99%

Mosaic variegated aneuploidy syndrome caused by a CEP57 mutation diagnosed by whole exome sequencing

Brightman

Ejaz

Dauber

2018

Clinical Case Reports

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“…Biallelic mutations of CEP57 have been detected in a subset of patients with mosaic variegated aneuploidy syndrome [31] , but how exactly loss of CEP57 leads to aneuploidy and cancer predisposition in these patients remains to be determined. Our finding that all metastatic lesions analyzed showed a loss of CEP57 expression together with the poor outcome of a patient with absence of CEP57 expression in TMA II ( Figure 1 ), however, underscores that CEP57 loss of function can promote malignant progression, potentially through a number of mechanisms [17] , [25] , [26] , [32] .…”

Section: Discussionmentioning

confidence: 84%

“…It is important to mention in this context that CEP57 is not only a centrosomal protein but also a component of the central spindle and the midbody [25] . Depletion of CEP57 has previously been reported to negatively impact on cytokinesis through disruption of these structures, leading to an increase of binucleated cells [25] . Results shown here indicate that overexpression of CEP57 likewise affects proper cell division.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance and Functional Role of CEP57 in Prostate Cancer

Mang

Korzeniewski

Dietrich

et al. 2015

Translational Oncology

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We have recently shown that centrosomal protein 57 (CEP57) is overexpressed in a subset of human prostate cancers. CEP57 is involved in intracellular transport processes, and its overexpression causes mitotic defects as well as abnormal microtubule nucleation and bundling. In the present study, we further characterized the prognostic and functional role of CEP57 in prostate cancer. Unexpectedly, we found that high CEP57 expression is an independent prognostic factor for a more favorable biochemical recurrence-free survival in two large patient cohorts. To reconcile this finding with the ability of CEP57 to cause cell division errors and thus potentially promote malignant progression, we hypothesized that alterations of microtubule-associated transport processes, in particular nuclear translocation of the androgen receptor (AR), may play a role in our finding. However, CEP57 overexpression and microtubule bundling had, surprisingly, no effect on the nuclear translocation of the AR. Instead, we found a significant increase of cells with disarranged microtubules and a cellular morphology suggestive of a cytokinesis defect. Because mitotic dysfunction leads to a reduced daughter cell formation, it can explain the survival benefit of patients with increased CEP57 expression. In contrast, we show that a reduced expression of CEP57 is associated with malignant growth and metastasis. Taken together, our findings underscore that high CEP57 expression is associated with mitotic impairment and less aggressive tumor behavior. Because the CEP57-induced microtubule stabilization had no detectable effect on AR nuclear translocation, our results furthermore suggest that microtubule-targeting therapeutics used in advanced prostate cancer such as docetaxel may have modes of action that are at least in part independent of AR transport inhibition.

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Cep57 Protein Is Required for Cytokinesis by Facilitating Central Spindle Microtubule Organization

Cited by 12 publications

References 32 publications

Cep57 is a Mis12-interacting kinetochore protein involved in kinetochore targeting of Mad1–Mad2

Cep57 is a Mis12-interacting kinetochore protein involved in kinetochore targeting of Mad1–Mad2

Mosaic variegated aneuploidy syndrome caused by a CEP57 mutation diagnosed by whole exome sequencing

Prognostic Significance and Functional Role of CEP57 in Prostate Cancer

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