Chfr defines a mitotic stress checkpoint that delays entry into metaphase

Scolnick, Daniel M.; Halazonetis, Thanos D.

doi:10.1038/35019108

Cited by 363 publications

(470 citation statements)

References 24 publications

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“…Higher tendency for teraploidization and for micronuclear formation is commonly reported in cells deficient in mitotic checkpoint elements, such as MAD2, Chfr and SNM1 (Scolnick and Halazonetis, 2000;Michel et al, 2001;Akhter et al, 2004) …”

Section: Nek7-negative Mefs Do Not Exhibit Metaphase Arrestmentioning

confidence: 94%

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

et al. 2010

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The mammalian NIMA-related kinases (Neks) are commonly referred to as mitotic kinases, although a definitive in vivo verification of this definition is largely missing. Reduction in the activity of Nek7 or its close paralog, Nek6, has previously been shown to arrest cells in mitosis, mainly at metaphase. In this study, we investigate the developmental and cellular roles of Nek7 kinase through the generation and analysis of Nek7-deficient mice. We show that absence of Nek7 leads to lethality in late embryogenesis or at early post-natal stages and to severe growth retardation. Mouse embryonic fibroblasts (MEFs) derived from Nek7 À/À embryos show increase tendency for chromosomal lagging, micronuclei formation and cytokinesis failure. Tetraploidy and aneuploidy were commonly observed and their prevalence arises with MEFs passages. The frequency of multicentrosomal cells in the mutant's MEF cells was higher, and it commonly occurred concurrently with a binuclear phenotype, suggesting cytokinesis failure etiology. Lastly, the percentage of mutant MEF cells bearing primary cilia (PC) was low, whereas a cell population having two cilia appeared in the mutant MEFs. Taken together, these results confirm Nek7 as a regulator of cell division, and reveal it as an essential component for mammalian growth and survival. The intimate connection between tetraploidy, aneuploidy and cancer development suggests that Nek7 deregulation can induce oncogenesis.

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Section: Nek7-negative Mefs Do Not Exhibit Metaphase Arrestmentioning

confidence: 94%

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

et al. 2010

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“…A second difference is observed in the checkpoint duration. The CHFR-mediated checkpoint has been reported to be transient, even with protracted MIA treatment (Scolnick and Halazonetis, 2000). In contrast, UBE2Q2-inhibited cells appear to have a nearly permanent prophase arrest.…”

Section: Ube2q2 Inactivation Increases the Cytotoxicity Of Miasmentioning

confidence: 99%

“…Ubiquitinmediated protein degradation is known to play a pivotal role in regulation of diverse cellular processes including both normal cell cycle regulation (reviewed in Pray et al, 2002;Vodermaier, 2004) and cell cycle checkpoint function (Scolnick and Halazonetis, 2000;Lew and Burke, 2003;Matsusaka and Pines, 2004;Zhang et al, 2005). Ubiquitin conjugating enzymes (or E2s) perform an intermediate step in the enzymatic cascade and provide some of the specificity for the process of target protein ubiquitination through their interactions with specific ubiquitin ligases (or E3s) (reviewed in Weissman, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…The mitotic arrest induced by MIAs is mediated by at least two distinct checkpoints. The checkpoint with forkhead and ring (CHFR) checkpoint (also referred to as the mitotic stress checkpoint and the antephase checkpoint) causes a prophase arrest with transient chromatin decondensation (Rieder and Cole, 2000;Scolnick and Halazonetis, 2000;Matsusaka and Pines, 2004). This checkpoint is inactivated in many human tumors and cell lines by loss of expression of the ubiquitin ligase CHFR (Mizuno et al, 2002;Corn et al, 2003;Toyota et al, 2003;Matsusaka and Pines, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Inactivation of the ubiquitin conjugating enzyme UBE2Q2 causes a prophase arrest and enhanced apoptosis in response to microtubule inhibiting agents

2007

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A putative ubiquitin conjugating enzyme known as UBE2Q2 was previously identified in a microarray screen for mitotic regulatory proteins. UBE2Q2 is very similar to another human protein, UBE2Q1 and orthologs from other higher eukaryotic species. In these studies, we demonstrate that UBE2Q2 can covalently bind ubiquitin on the active site cysteine in vitro and show that inhibition of this protein in vivo causes an early mitotic arrest and increased cytotoxicity when cells are treated with microtubule inhibiting agents (MIAs). Changes in cell cycle progression and viability are not observed in the absence of MIA treatment, indicating that UBE2Q2 is involved in the response to MIAs rather than performing a more general function in mitosis. Inhibition of the UBE2Q2 protein causes cells to undergo a prolonged prophase arrest suggesting that UBE2Q2 normally functions to antagonize an early mitotic checkpoint. Furthermore, UBE2Q2 inhibition sensitizes cells to the cytotoxic effects of MIAs through caspase-mediated apoptosis that is correlated with PARP-1 cleavage. These data provide insights into the cellular response to MIAs and demonstrate that inhibition of UBE2Q2 protein function may be useful in the treatment of malignancies.

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“…The CHFR protein contains two conserved domains (that is, the forkhead-associated (FHA) domain and the RING finger domain) that have been identified in many different species. Originally, CHFR was believed to mediate a delay in early prophase in response to microtubule stress (Scolnick and Halazonetis, 2000). The RING finger domain is commonly found in E3 ligase proteins and is thought to influence substrate specificity during ubiquitination reactions (Jackson et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

et al. 2009

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The mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger domains) is silenced in various human cancers by promoter hypermethylation, suggesting that CHFR is a tumor suppressor. Here, we show that CHFR functions as a negative regulator of the nuclear factor-jB (NF-jB) pathway. Expression of CHFR inhibited NF-jB reporter activity, whereas knockdown of CHFR activated reporter activity. These activities are independent of its RING finger domain. Furthermore, we found that CHFR physically interacts with p65 in cells. Electrophoretic mobility shift assays (EMSAs) and ELISA-based NF-jB-binding assays showed that CHFR negatively regulated transcriptional activity of p65. In addition, our data show that interleukin (IL)-8 is significantly downregulated by CHFR, and that the migration of human endothelial cells is suppressed in culture medium conditioned from CHFR-expressing cancer cells. Using a xenograft model, we show that neovascularization is suppressed by adenovirus-mediated transfer of CHFR. These results indicate that expression of CHFR markedly reduces the expression of IL-8 through the inhibition of NF-jB. As the NF-jB signaling pathway plays a critical role in the development and progression of cancer, our findings show the functional relationship between epigenetic alteration and inflammation/angiogenesis in human cancer cells, thereby showing several potential targets for therapeutic intervention.

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Chfr defines a mitotic stress checkpoint that delays entry into metaphase

Cited by 363 publications

References 24 publications

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

Inactivation of the ubiquitin conjugating enzyme UBE2Q2 causes a prophase arrest and enhanced apoptosis in response to microtubule inhibiting agents

CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

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