Cep63 Recruits Cdk1 to the Centrosome: Implications for Regulation of Mitotic Entry, Centrosome Amplification, and Genome Maintenance

Löffler, Harald; Fechter, Anne; Matuszewska, Marc; Saffrich, Rainer; Mistrík, Martin; Marhold, J.; Hornung, Christin; Westermann, Frank; Bártek, Jiří; Krämer, Alwin

doi:10.1158/0008-5472.can-10-2684

Cited by 49 publications

(50 citation statements)

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“…EP300 and MAP3K3 are, respectively, involved in the TP53 and RAS singnal pathway, which plays an important role in the pathogenesis of lung cancer. CEP63 binds to and recruits Cdk1 to centrosomes, and thus regulates mitotic entry (14). Although the function of CADM2 remained elusive, it has been reported that CADM2 was recurrently disrupted in prostate cancer (15).…”

Section: Molecular Modeling Of Tp53mentioning

confidence: 99%

Whole-exome sequencing to identify novel somatic mutations in squamous cell lung cancers

Zheng¹,

Gu²,

Han³

et al. 2013

International Journal of Oncology

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Abstract. Squamous cell lung cancer is a major histotype of non-small cell lung cancer (NSCLC) that is distinct from lung adenocarcinoma. We used whole-exome sequencing to identify novel non-synonymous somatic mutations in squamous cell lung cancer. We identified 101 single-nucleotide variants (SNVs) including 77 non-synonymous SNVs (67 missense and 10 nonsense mutations) and 11 INDELs causing frameshifts. We also found four SNVs located within splicing sites. We verified 62 of the SNVs (51 missense, 10 nonsense and 1 splicing-site mutation) and 10 of the INDELs as somatic mutations in lung cancer tissue. Sixteen of the mutated genes were also mutated in at least one patient with a different type of lung cancer in the Catalogue of Somatic Mutation in Cancer (COSMIC) database. Four genes (LPHN2, TP53, MYH2 and TGM2) were mutated in approximately 10% of the samples in the COSMIC database. We identified two missense mutations in C10orf137 and MS4A3 that also occurred in other solid-tumor tissues in the COSMIC database. We found another somatic mutation in EP300 that was mutated in 4.2% of the 2,020 solid-tumor samples in the COSMIC database. Taken together, our results implicate TP53, EP300, LPHN2, C10orf137, MYH2, TGM2 and MS4A3 as potential driver genes of squamous cell lung cancer. IntroductionLung cancer is the leading cause of cancer-related death worldwide and accounts for one quarter of all cancer mortalities in the US (1). Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases and can be classified by histotypes as adenocarcinoma (AC), squamous cell carcinoma (SCC), and large-cell lung cancer (LCLC). The high mortality rate of lung cancer is mainly attributed to the disease not being diagnosed until it is in advanced stages. Chemotherapy with platinum-based drugs in combination with taxanes, camptothecins, or vinca alkaloids, the first-line treatment for patients with NSCLC, has made little progress in improving prognoses in recent decades (1).Similar to other malignancies, tumorigenesis in NSCLC depends on the clustering of gene dysfunction as a result of genetic susceptibility and/or the accumulation of noxious environmental factors. The discoveries of recurrent mutations in the epidermal growth-factor receptor (EGFR) kinase and fusions, such as EML4-ALK, involving anaplastic lymphoma kinase (ALK) led to a dramatic change in the treatment of lung AC (2,3). Recent data suggest that substance CI1040 can bind to MEK and mutated BRAF, resulting in the shrinkage of lung ACs that harbor mutated KRAS and BRAF, respectively (4). Other recent data show that targeting mutations in AKT1, ERBB2 and PIK3CA and fusions involving ROS1 and RET may also be successful (5). Unfortunately, activating mutations in EGFR, EML4-ALK fusions, and mutations in KRAS are only detected in lung AC, and are not present in the second most-common type of lung cancer, SCC (6). Thus, targeted agents developed for lung AC are largely ineffective against lung SCC (7).Lung SCC accounts for 45% of NSCLC, and ...

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Section: Molecular Modeling Of Tp53mentioning

confidence: 99%

Whole-exome sequencing to identify novel somatic mutations in squamous cell lung cancers

Zheng¹,

Gu²,

Han³

et al. 2013

International Journal of Oncology

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“…In prophase, Cdk1 is recruited to centrosomes by Cep63 and activated by forming a complex with phosphorylated Cyclin B1 (15,16). The most intriguing process in prometaphase is the appropriately timed search and capture of chromosomes by spindles (17).…”

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confidence: 99%

Phosphorylation of Astrin Regulates Its Kinetochore Function

Chung

Park

Lee

et al. 2016

Journal of Biological Chemistry

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The error-free segregation of chromosomes, which requires the precisely timed search and capture of chromosomes by spindles during early mitotic and meiotic cell division, is responsible for genomic stability and is achieved by the spindle assembly checkpoint in the metaphase-anaphase transition. Mitotic kinases orchestrate M phase events, such as the reorganization of cell architecture and kinetochore (KT) composition with the exquisite phosphorylation of mitotic regulators, to ensure timely and temporal progression. However, the molecular mechanisms underlying the changes of KT composition for stable spindle attachment during mitosis are poorly understood. Here, we show that the sequential action of the kinase Cdk1 and the phosphatase Cdc14A control spindle attachment to KTs. During prophase, the mitotic spindle protein Spag5/Astrin is transported into centrosomes by Kinastrin and phosphorylated at Ser-135 and Ser-249 by Cdk1, which, in prometaphase, is loaded onto the spindle and targeted to KTs. We also demonstrate that Cdc14A dephosphorylates Astrin, and therefore the overexpression of Cdc14A sequesters Astrin in the centrosome and results in aberrant chromosome alignment. Mechanistically, Plk1 acts as an upstream kinase for Astrin phosphorylation by Cdk1 and targeting phospho-Astrin to KTs, leading to the recruitment of outer KT components, such as Cenp-E, and the stable attachment of spindles to KTs. These comprehensive findings reveal a regulatory circuit for protein targeting to KTs that controls the KT composition change of stable spindle attachment and chromosome integrity.The maintenance of genome integrity during mitosis is crucial for cell survival and organismal development. To generate two daughter cells with identical genetic information, each sister chromatid must be captured by spindle microtubules (MTs), 4 aligned at the mitotic equator, and segregated toward the spindle poles. Cells build a proteinaceous structure, known as the KT, at the centromere and form a bipolar spindle with an amphitelic spindle attachment to achieve accurate chromosome segregation (1). The KT is made up of protein complexes that control its localization on the chromosome, assembly, attachment to spindle MTs, and chromosome movements, such as congression and segregation (2). KTs lacking essential proteins for KT-MT attachment, such as Knl1, Mis12, and Ndc80 protein subcomplexes, are unable to attach to spindle MTs (3), which in turn results in chromosome loss and concurrent cell death (4).Entry into mitosis is controlled by the concerted action of several mitotic kinases, such as Cyclin-dependent kinase 1 (Cdk1), Polo-like kinase 1 (Plk1), and Aurora A, whose activities are regulated indirectly in a positive feedback loop (5). Plk1 activates Cdk1 by phosphorylating and activating Cdc25, which then removes inhibitory phosphorylation at the Thr-14 and Tyr-15 sites of Cdk1. Aurora A phosphorylates Thr-210 in the active loop of Plk1 with the aid of Bora (6). Cdk1 also activates Plk1 via Bora phosphorylation to promote mit...

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“…In 2011, we published a characterization of the phenotypes of Cep63 downregulation and overexpression in human cells in Cancer Research (1). Recently, it was shown that several antibodies commonly used to detect Cdk1 cross-react with Cep152 (2).…”

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confidence: 99%

“…Significances were determined using the heteroscedastic, twotailed Student t test. A, U2OS cells were transfected with siRNA to luciferase (Luc) or Cep63, respectively, fixed after 72 hours, and immunostained for g-tubulin and Cdk1 as described earlier (1). For Cdk1 immunostaining, the antibodies indicated in parentheses were used.…”

mentioning

confidence: 99%

“…D, U2OS cells were treated, immunostained, and selected for analysis as described in C, with the ab8040 (Abcam) antibody used for Cdk1 detection. Using a Zeiss LSM 780 laser scanning microscope (Zeiss Application Center, Heidelberg), three-dimensional confocal datasets from 50 centrosomes per data bar were collected under standardized settings, and the indicated centrosomal proteins were quantified as described earlier (1).…”

mentioning

confidence: 99%

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