Nek6 is involved in G<sub>2</sub>/M phase cell cycle arrest through DNA damage-induced phosphorylation

Lee, Min Young; Kim, Hyun-Ju; Myoung-Ae, Kim; Jee, Hye Jin; Kim, Ae Jeong; Bae, Yoe‐Sik; Park, Joo-In; Chung, Jay H.; Yun, Jeanho

doi:10.4161/cc.7.17.6551

Cited by 57 publications

(60 citation statements)

References 19 publications

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“…The sequence of the Nek7 kinase targeting leads to polyploidy H Salem et al short N-terminal tail of the proteins is quite variable and can contribute to interactions with different substrates. Indeed, it has been recently demonstrated that a functional Chk kinase-dependent phosphorylation site exists in the N-terminal region of Nek6, but not of Nek7 (Lee et al, 2008). The different spatio-temporal subcellular localization of the proteins could also contribute to their divergent roles.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2010

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“…Whereas some NEKs, such as NEK2 and NEK6, are checkpoint targets that are inhibited by DNA damage (Fletcher et al, 2004;Lee et al, 2008), others have more integral roles in DNA-damageresponse (DDR) signalling. NEK1 is involved in both the sensing and the repair of DNA strand breaks at the G1-S and G2-M transitions (Chen et al, 2011;Chen et al, 2008;Pelegrini et al, 2010;Polci et al, 2004).…”

Section: The Role Of Neks In Cell Cycle Checkpointsmentioning

confidence: 99%

Cell cycle regulation by the NEK family of protein kinases

Fry

O’Regan

Sabir

et al. 2012

Journal of Cell Science

308

322

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SummaryGenetic screens for cell division cycle mutants in the filamentous fungus Aspergillus nidulans led to the discovery of never-in-mitosis A (NIMA), a serine/threonine kinase that is required for mitotic entry. Since that discovery, NIMA-related kinases, or NEKs, have been identified in most eukaryotes, including humans where eleven genetically distinct proteins named NEK1 to NEK11 are expressed. Although there is no evidence that human NEKs are essential for mitotic entry, it is clear that several NEK family members have important roles in cell cycle control. In particular, NEK2, NEK6, NEK7 and NEK9 contribute to the establishment of the microtubulebased mitotic spindle, whereas NEK1, NEK10 and NEK11 have been implicated in the DNA damage response. Roles for NEKs in other aspects of mitotic progression, such as chromatin condensation, nuclear envelope breakdown, spindle assembly checkpoint signalling and cytokinesis have also been proposed. Interestingly, NEK1 and NEK8 also function within cilia, the microtubule-based structures that are nucleated from basal bodies. This has led to the current hypothesis that NEKs have evolved to coordinate microtubule-dependent processes in both dividing and non-dividing cells. Here, we review the functions of the human NEKs, with particular emphasis on those family members that are involved in cell cycle control, and consider their potential as therapeutic targets in cancer.

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“…Several of the human NEK kinases have been implicated in mitotic progression and DNA damage responses, however, their mechanistic role in checkpoint control was not wellunderstood. [23][24][25][26] Interestingly, previous results had demonstrated that several types of genotoxic stress lead to an increase in NEK11 activity, which can be blocked by caffeine, an inhibitor of ATM and ATR kinases. Moreover, NEK11 was suggested to participate in the S-phase checkpoint, however, the mechanism of NEK11 action was not demonstrated.…”

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confidence: 99%

NEK11−Linking CHK1 and CDC25A in DNA damage checkpoint signaling

Sørensen

Melixetian

Klein³

et al. 2010

Cell Cycle

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Nek6 is involved in G₂/M phase cell cycle arrest through DNA damage-induced phosphorylation

Cited by 57 publications

References 19 publications

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

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

Cell cycle regulation by the NEK family of protein kinases

NEK11−Linking CHK1 and CDC25A in DNA damage checkpoint signaling

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Nek6 is involved in G2/M phase cell cycle arrest through DNA damage-induced phosphorylation

Cited by 57 publications

References 19 publications

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

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

Cell cycle regulation by the NEK family of protein kinases

NEK11−Linking CHK1 and CDC25A in DNA damage checkpoint signaling

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Nek6 is involved in G₂/M phase cell cycle arrest through DNA damage-induced phosphorylation