Nek6 overexpression antagonizes p53-induced senescence in human cancer cells

Jee, Hye Jin; Kim, Ae Jeong; Song, Naree; Kim, Hyun-Ju; Kim, Minjee; Koh, Hyongjong; Yun, Jeanho

doi:10.4161/cc.9.23.14059

Cited by 65 publications

(64 citation statements)

References 26 publications

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“…Several kinases that had been previously shown to regulate telomerase were also among the hits, confirming the specificity of the functional read-out of the HTS (6)(7)(8). Moreover several of the identified kinases have been found overexpressed in different human cancers and are now being exploited as potential targets for cancer therapeutics (20)(21)(22)(25)(26)(27)(28)(29). Subsequent validation experiments showed that modulation of some of these proteins resulted in perturbation of telomerase function and elicited phenotypic changes characteristic of telomere dysfunctions, suggesting that the proteins identified in our screen are likely true modifiers of telomerase.…”

Section: Discussionmentioning

confidence: 73%

“…There is now substantial evidence that NEK2, NEK6, NEK7, and NEK9 regulate mitotic progression and mitotic spindle organization (24). Furthermore, high expression levels of NEK kinases have also been found in human cancers, such as breast and bladder cancers (25,26) and NEK kinases are now being pursued as potential therapeutic targets (27,28). Members of the MAPK superfamily were also selected given their diverse functions in a wide variety of biological processes (9,29).…”

Section: Resultsmentioning

confidence: 99%

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High-Throughput RNAi Screening Reveals Novel Regulators of Telomerase

Cerone

Burgess²,

Naceur-Lombardelli³

et al. 2011

Cancer Research

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Telomerase is considered an attractive anticancer target on the basis of its common and specific activation in most human cancers. While direct telomerase inhibition is being explored as a therapeutic strategy, alternative strategies to target regulators of telomerase that could disrupt telomere maintenance and cancer cell proliferation are not yet available. Here, we report the findings of a high-throughput functional RNA interference screen to globally profile the contribution of kinases to telomerase activity (TA). This analysis identified a number of novel telomerase modulators, including ERK8 kinase, whose inhibition reduces TA and elicited characteristics of telomere dysfunction. Given that kinases represent attractive drug targets, we addressed the therapeutic implications of our findings, such as demonstrating how limiting TA via kinase blockade could sensitize cells to inhibition of the telomere-associated protein tankyrase. Taken together, our findings suggest novel combinatorial approaches to targeting telomere maintenance as a strategy for cancer therapy. Cancer Res; 71(9); 3328-40. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

High-Throughput RNAi Screening Reveals Novel Regulators of Telomerase

Cerone

Burgess²,

Naceur-Lombardelli³

et al. 2011

Cancer Research

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“…NEK6 activity promotes anchorageindependent growth; depletion of NEK6 leads to death in cancer cell lines but is tolerated by normal fibroblasts (Nassirpour et al, 2010). Overexpression of NEK6 also inhibits p53-dependent cellular senescence (Jee et al, 2010). The molecular mechanisms that underlie these observations are unknown, and could reflect a nonmitotic function of NEK6.…”

Section: Box 2 Mitotic Kinases As Anti-cancer Targetsmentioning

confidence: 98%

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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“…NIMA (never in mitosis gene a)-related kinase 6 (NEK6; also called SID6-1512) is localized on chromosome 9q33-34 and is a serine/threonine kinase that belongs to the Neks (NIMArelated kinases) family, which has been implicated in mitosis control (30). Yin et al previously found that human Nek6 is required for metaphase-anaphase transition during cell cycle progression (31).…”

Section: Discussionmentioning

confidence: 99%

Aurora kinase A (AURKA) and never in mitosis gene A-related kinase 6 (NEK6) genes are upregulated in erosive esophagitis and esophageal adenocarcinoma

Kasap

Boyacioglu

Korkmaz

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. Gastroesophageal reflux disease is a risk factor for esophageal adenocarcinoma yet studies that have investigated the relationship between erosive esophagitis and esophageal adenocarcinoma have usually focused on symptom-related evidence or polymorphisms. There are no epigenetic gene expression studies on this topic. In this study, we aimed to evaluate the relationship between erosive esophagitis and esophageal adenocarcinoma to identify whether there is a genetic predisposition for esophageal adenocarcinoma. The Human Epigenetic Chromatin Modification Enzyme RT 2 Profiler TM PCR array (PAHS-085A) was used to detect the expression of 84 key genes encoding enzymes. This was carried out prospectively for samples from 60 patients (20 patients as a control group, 20 patients with erosive esophagitis and 20 patients with esophageal adenocarcinoma). AURKA, AURKB, NEK6 were expressed at significantly higher levels in esophageal adenocarcinoma compared to the control group. MBD2 was expressed at significantly lower levels in the esophageal adenocarcinoma group compared to the control group. AURKA, AURKC, HDAC9 and NEK6 were expressed at significantly higher levels in erosive esophagitis compared to the control group. There was no difference in upregulated gene expression between the erosive esophagitis and esophageal adenocarcinoma. MBD2 was significantly downregulated in esophageal adenocarcinoma compared to erosive esophagitis. NEK6 and AURKA were significantly upregulated in esophageal adenocarcinoma and erosive esophagitis compared to the control group. This is a novel study on the genetic predisposition for erosive esophagitis and esophageal adenocarcinoma. AURKA and NEK6 are two promising genetic markers for erosive esophagitis and esophageal adenocarcinoma.

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Nek6 overexpression antagonizes p53-induced senescence in human cancer cells

Cited by 65 publications

References 26 publications

High-Throughput RNAi Screening Reveals Novel Regulators of Telomerase

High-Throughput RNAi Screening Reveals Novel Regulators of Telomerase

Cell cycle regulation by the NEK family of protein kinases

Aurora kinase A (AURKA) and never in mitosis gene A-related kinase 6 (NEK6) genes are upregulated in erosive esophagitis and esophageal adenocarcinoma

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