NEK2

Gene Summary

Gene:NEK2; NIMA-related kinase 2
Aliases: NLK1, RP67, NEK2A, HsPK21, PPP1R111
Location:1q32.3
Summary:This gene encodes a serine/threonine-protein kinase that is involved in mitotic regulation. This protein is localized to the centrosome, and undetectable during G1 phase, but accumulates progressively throughout the S phase, reaching maximal levels in late G2 phase. Alternatively spliced transcript variants encoding different isoforms with distinct C-termini have been noted for this gene. [provided by RefSeq, Feb 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:serine/threonine-protein kinase Nek2
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
Show (31)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Gene Expression Profiling
  • Mitosis
  • Neoplastic Cell Transformation
  • Sweden
  • Chromosome 1
  • Aneuploidy
  • Thiazoles
  • Centrosome
  • Cancer Gene Expression Regulation
  • Cluster Analysis
  • Cell Cycle Proteins
  • Cell Cycle
  • Apoptosis
  • Receptor, erbB-2
  • Staging
  • Cell Proliferation
  • Breast Cancer
  • RTPCR
  • Disease Progression
  • siRNA
  • Vaccination
  • Chromosomal Instability
  • RNA-Binding Proteins
  • Signal Transduction
  • Risk Factors
  • Spindle Apparatus
  • ROC Curve
  • Oligonucleotide Array Sequence Analysis
  • Western Blotting
  • Tumor Markers
  • Single Nucleotide Polymorphism
  • Antineoplastic Agents
  • Prostate Cancer
  • Transcription Factors
  • Ribonucleoside Diphosphate Reductase
  • Genetic Markers
  • Tamoxifen
  • Protein-Serine-Threonine Kinases
  • Lung Cancer
  • Immunohistochemistry
  • Messenger RNA
  • RNA Interference
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NEK2 (cancer-related)

Huang LY, Chang CC, Lee YS, et al.
Inhibition of Hec1 as a novel approach for treatment of primary liver cancer.
Cancer Chemother Pharmacol. 2014; 74(3):511-20 [PubMed] Related Publications
PURPOSE: Highly expressed in cancer protein 1 (Hec1) is an oncogene and a promising molecular target for novel anticancer drugs. The purpose of this study was to evaluate the potential of a Hec1 inhibitor, TAI-95, as a treatment for primary liver cancer.
METHODS: In vitro and in vivo methods were used to test the activity of TAI-95. Gene expression analysis was used to evaluate clinical correlation of the target.
RESULTS: In vitro growth inhibition results showed that TAI-95 has excellent potency on a wide range of primary liver cancer cell lines (hepatoblastoma or hepatocellular carcinoma) (GI(50) 30-70 nM), which was superior to sorafenib and other cytotoxic agents. TAI-95 was relatively inactive in non-cancerous cell lines (GI(50) > 10 μM). TAI-95 disrupts the interaction between Hec1 and Nek2 and leads to degradation of Nek2, chromosomal misalignment, and apoptotic cell death. TAI-95 showed synergistic activity in selected cancer cell lines with doxorubicin, paclitaxel, and topotecan, but not with sorafenib. TAI-95 shows excellent potency in a Huh-7 xenograft mouse model when administered orally. Gene expression analysis of clinical samples demonstrated increased expression of Hec1/NDC80 and associated genes (Nek2, SMC1A, and SMC2) in 27 % of patients, highlighting the potential for using this therapeutic approach to target patients with high Hec1 expression.
CONCLUSION: Inhibition of Hec1 using small molecule approach may represent a promising novel approach for the treatment of primary liver cancers.

Ning Z, Wang A, Liang J, et al.
Abnormal expression of Nek2 in pancreatic ductal adenocarcinoma: a novel marker for prognosis.
Int J Clin Exp Pathol. 2014; 7(5):2462-9 [PubMed] Free Access to Full Article Related Publications
Nek2 is a serine/threonine kinase that has a critical role in mitosis during the cell division process. Despite its importance in centrosome regulation and spindle formation, no direct binders are reported between human pancreatic cancer and Nek2 protein. Our aim in studying Nek2 expression and survival in PDA patients is to determine whether Nek2 is a valuable prognostic factor in PDA tumorigenesis. We found that Nek2 mRNA was elevated in PDA tissues. A high level of expression of Nek2 was significantly correlated with histological differentiation (P=0.042), lymph node metastasis (P=0.003) and tumor stage (P=0.001). Patients with a high Nek2 expression had a significantly worse overall survival (OS) than those patients with low Nek2 expression (P=0.002). Univariate and multivariate analysis revealed that high expression of Nek2 could serve as an independent predictor of poor prognosis. These results indicate that Nek2 could be a promising prognostic molecular marker and an attractive therapeutic target for PDA.

Lee MY, Moreno CS, Saavedra HI
E2F activators signal and maintain centrosome amplification in breast cancer cells.
Mol Cell Biol. 2014; 34(14):2581-99 [PubMed] Free Access to Full Article Related Publications
Centrosomes ensure accurate chromosome segregation by directing spindle bipolarity. Loss of centrosome regulation results in centrosome amplification, multipolar mitosis and aneuploidy. Since centrosome amplification is common in premalignant lesions and breast tumors, it is proposed to play a central role in breast tumorigenesis, a hypothesis that remains to be tested. The coordination between the cell and centrosome cycles is of paramount importance to maintain normal centrosome numbers, and the E2Fs may be responsible for regulating these cycles. However, the role of E2F activators in centrosome amplification is unclear. Because E2Fs are deregulated in Her2(+) cells displaying centrosome amplification, we addressed whether they signal this abnormal process. Knockdown of E2F1 or E2F3 in Her2(+) cells decreased centrosome amplification without significantly affecting cell cycle progression, whereas the overexpression of E2F1, E2F2, or E2F3 increased centrosome amplification in MCF10A mammary epithelial cells. Our results revealed that E2Fs affect the expression of proteins, including Nek2 and Plk4, known to influence the cell/centrosome cycles and mitosis. Downregulation of E2F3 resulted in cell death and delays/blocks in cytokinesis, which was reversed by Nek2 overexpression. Nek2 overexpression enhanced centrosome amplification in Her2(+) breast cancer cells silenced for E2F3, revealing a role for the E2F activators in maintaining centrosome amplification in part through Nek2.

Cheng Y, Hong M, Cheng B
Identified differently expressed genes in renal cell carcinoma by using multiple microarray datasets running head: differently expressed genes in renal cell carcinoma.
Eur Rev Med Pharmacol Sci. 2014; 18(7):1033-40 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to identify differentially expressed genes and analysis biological processes related to renal cell carcinoma.
METHODS: A meta-analysis was performed using the Rank Product package of Gene Expression Omnibus datasets of renal cell carcinoma. Then Gene Ontology enrichment analyses and pathway analysis were performed based on Gene Ontology website and Kyoto Encyclopedia of Genes and Genomes. Protein-protein interaction network was constructed used Cytoscape software.
RESULTS: We identified a total of 1992 differentially expressed genes Rank Product package of renal cell carcinoma, 840 of them were not involved in individual DEGs. Gene Ontology enrichment analyses showed that those 840 genes enriched in terms such as response to hormone stimulus, endogenous stimulus, biological adhesion, and cell proliferation. Pathway analysis showed that significant pathways included pyruvate metabolism, glycerolipid metabolism, complement and coagulation cascades and so on. Protein-protein interaction network indicated that MT2A, MYC, CENPF and NEK2 has high degree which participated many interactions.
CONCLUSIONS: Our study displayed genes that were consistently differentially expressed in renal cell carcinoma, and the biological pathways, protein-protein interaction network associated with those genes.

Zhong X, Guan X, Dong Q, et al.
Examining Nek2 as a better proliferation marker in non-small cell lung cancer prognosis.
Tumour Biol. 2014; 35(7):7155-62 [PubMed] Related Publications
The purpose of this study is to identify a better potential biomarker for the prognosis of patients with non-small cell lung cancer (NSCLC). The expressions of Nek2, MCM7, and Ki-67 were evaluated in 270 NSCLC tissues using immunohistochemical and immunofluorescence techniques. Associations between protein expression and clinical pathologic characters were assessed, and the impact on overall survival was analyzed. We detected high levels of Nek2, MCM7, and Ki-67 expression in 25.9, 35.2, and 24.4 % of NSCLC tissues, respectively. Overexpressions of Nek2 were detected more frequently in high T-stage and N-stage cases (P = 0.000, 0.011). The expressions of Nek2, MCM7, and Ki-67 were correlated with each other. Kaplan-Meier curves indicated that patients with overexpression of Nek2, MCM7, and Ki-67 had a poorer overall survival rate compared to those with low expression for all stages (P = 0.000). In particular, the patients with Nek2 overexpression had the most negative prognosis. Multivariate Cox regression analysis showed that Nek2, MCM7, and Ki-67 are independent prognostic indicators for NSCLC. Our data suggest that among Nek2 kinase, MCM7, and Ki-67, it is Nek2 kinase that is the more effective tumor proliferation marker of poor prognosis for NSCLC patients. Thus, Nek2 may represent a new potential target for NSCLC therapeutic intervention.

Huang LY, Chang CC, Lee YS, et al.
Activity of a novel Hec1-targeted anticancer compound against breast cancer cell lines in vitro and in vivo.
Mol Cancer Ther. 2014; 13(6):1419-30 [PubMed] Related Publications
Current cytotoxic chemotherapy produces clinical benefit in patients with breast cancer but the survival impact is modest. To explore novel cytotoxic agents for the treatment of advanced disease, we have characterized a new and pharmacokinetically improved Hec1-targeted compound, TAI-95. Nine of 11 breast cancer cell lines tested were sensitive to nanomolar levels of TAI-95 (GI(50) = 14.29-73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI(50) > 10 μmol/L) to other established cytotoxic agents. TAI-95 demonstrates strong inhibition of in vivo tumor growth of breast cancer model when administered orally, without inducing weight loss or other obvious toxicity. Mechanistically, TAI-95 acts by disrupting the interaction between Hec1 and Nek2, leading to apoptotic cell death in breast cancer cells. Furthermore, TAI-95 is active on multidrug-resistant (MDR) cell lines and led to downregulation of the expression of P-glycoprotein (Pgp), an MDR gene. In addition, TAI-95 increased the potency of cytotoxic Pgp substrates, including doxorubicin and topotecan. Certain clinical subtypes of breast cancer more likely to respond to Hec1-targeted therapy were identified and these subtypes are the ones associated with poor prognosis. This study highlights the potential of the novel anticancer compound TAI-95 in difficult-to-treat breast cancers.

Hu CM, Zhu J, Guo XE, et al.
Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism.
Oncogene. 2015; 34(10):1220-30 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
Hec1 (highly expressed in cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators, and phosphorylation of Hec1 S165 by Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here we showed that new derivatives of INH (inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394-408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408-422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application.

Frett B, Brown RV, Ma M, et al.
Therapeutic melting pot of never in mitosis gene a related kinase 2 (Nek2): a perspective on Nek2 as an oncology target and recent advancements in Nek2 small molecule inhibition.
J Med Chem. 2014; 57(14):5835-44 [PubMed] Related Publications
The global incidence of cancer is on the rise, and within the next decade, the disease is expected to become the leading cause of death worldwide. Forthcoming strategies used to treat cancers focus on the design and implementation of multidrug therapies to target complementary cancer specific pathways. A more direct means by which this multitargeted approach can be achieved is by identifying and targeting interpathway regulatory factors. Recent advances in understanding Nek2 (NIMA related kinase 2) biology suggest that the kinase potentially represents a multifaceted therapeutic target. In this regard, pharmacologic modulation of Nek2 with a single agent may effect several mechanisms important for tumor growth, survival, progression, and metastasis. We herein review the development of Nek2 as an oncology target and provide a succinct chronology of drug discovery campaigns focused on targeting Nek2.

Salhia B, Kiefer J, Ross JT, et al.
Integrated genomic and epigenomic analysis of breast cancer brain metastasis.
PLoS One. 2014; 9(1):e85448 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.

Naro C, Barbagallo F, Chieffi P, et al.
The centrosomal kinase NEK2 is a novel splicing factor kinase involved in cell survival.
Nucleic Acids Res. 2014; 42(5):3218-27 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
NEK2 is a serine/threonine kinase that promotes centrosome splitting and ensures correct chromosome segregation during the G2/M phase of the cell cycle, through phosphorylation of specific substrates. Aberrant expression and activity of NEK2 in cancer cells lead to dysregulation of the centrosome cycle and aneuploidy. Thus, a tight regulation of NEK2 function is needed during cell cycle progression. In this study, we found that NEK2 localizes in the nucleus of cancer cells derived from several tissues. In particular, NEK2 co-localizes in splicing speckles with SRSF1 and SRSF2. Moreover, NEK2 interacts with several splicing factors and phosphorylates some of them, including the oncogenic SRSF1 protein. Overexpression of NEK2 induces phosphorylation of endogenous SR proteins and affects the splicing activity of SRSF1 toward reporter minigenes and endogenous targets, independently of SRPK1. Conversely, knockdown of NEK2, like that of SRSF1, induces expression of pro-apoptotic variants from SRSF1-target genes and sensitizes cells to apoptosis. Our results identify NEK2 as a novel splicing factor kinase and suggest that part of its oncogenic activity may be ascribed to its ability to modulate alternative splicing, a key step in gene expression regulation that is frequently altered in cancer cells.

Liu X, Gao Y, Lu Y, et al.
Upregulation of NEK2 is associated with drug resistance in ovarian cancer.
Oncol Rep. 2014; 31(2):745-54 [PubMed] Related Publications
NEK2 [NIMA (never in mitosis gene A)-related expressed kinase 2] is associated with various biological behaviors in the development of cancer, while research concerning its association with drug resistance is limited. The association of NEK2 with drug resistance in ovarian cancer has not yet been reported. In the present study, on the basis of microarray results from Oncomine and the GEO Profiles online database, we revealed that NEK2 mRNA expression in ovarian cancer tissues is upregulated. In addition, its expression in drug-resistant ovarian cancer cells was upregulated when compared with expression with their sensitive or parental counterparts. Finally, we performed a comprehensive bioinformatic analysis consisting of protein/gene-protein/gene interaction network, annotation of biological processes and microRNA-mRNA interaction analysis. We observed that NEK2 directly or indirectly interacts with a number of genes, proteins, microRNAs and biological processes associated with drug resistance in ovarian and other types of cancer. These results indicate that NEK2 contributes to drug resistance in ovarian cancer and it may be an important therapeutic target.

Bidkhori G, Narimani Z, Hosseini Ashtiani S, et al.
Reconstruction of an integrated genome-scale co-expression network reveals key modules involved in lung adenocarcinoma.
PLoS One. 2013; 8(7):e67552 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
Our goal of this study was to reconstruct a "genome-scale co-expression network" and find important modules in lung adenocarcinoma so that we could identify the genes involved in lung adenocarcinoma. We integrated gene mutation, GWAS, CGH, array-CGH and SNP array data in order to identify important genes and loci in genome-scale. Afterwards, on the basis of the identified genes a co-expression network was reconstructed from the co-expression data. The reconstructed network was named "genome-scale co-expression network". As the next step, 23 key modules were disclosed through clustering. In this study a number of genes have been identified for the first time to be implicated in lung adenocarcinoma by analyzing the modules. The genes EGFR, PIK3CA, TAF15, XIAP, VAPB, Appl1, Rab5a, ARF4, CLPTM1L, SP4, ZNF124, LPP, FOXP1, SOX18, MSX2, NFE2L2, SMARCC1, TRA2B, CBX3, PRPF6, ATP6V1C1, MYBBP1A, MACF1, GRM2, TBXA2R, PRKAR2A, PTK2, PGF and MYO10 are among the genes that belong to modules 1 and 22. All these genes, being implicated in at least one of the phenomena, namely cell survival, proliferation and metastasis, have an over-expression pattern similar to that of EGFR. In few modules, the genes such as CCNA2 (Cyclin A2), CCNB2 (Cyclin B2), CDK1, CDK5, CDC27, CDCA5, CDCA8, ASPM, BUB1, KIF15, KIF2C, NEK2, NUSAP1, PRC1, SMC4, SYCE2, TFDP1, CDC42 and ARHGEF9 are present that play a crucial role in cell cycle progression. In addition to the mentioned genes, there are some other genes (i.e. DLGAP5, BIRC5, PSMD2, Src, TTK, SENP2, PSMD2, DOK2, FUS and etc.) in the modules.

Velimezi G, Liontos M, Vougas K, et al.
Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer.
Nat Cell Biol. 2013; 15(8):967-77 [PubMed] Related Publications
The DNA damage response (DDR) pathway and ARF function as barriers to cancer development. Although commonly regarded as operating independently of each other, some studies proposed that ARF is positively regulated by the DDR. Contrary to either scenario, we found that in human oncogene-transformed and cancer cells, ATM suppressed ARF protein levels and activity in a transcription-independent manner. Mechanistically, ATM activated protein phosphatase 1, which antagonized Nek2-dependent phosphorylation of nucleophosmin (NPM), thereby liberating ARF from NPM and rendering it susceptible to degradation by the ULF E3-ubiquitin ligase. In human clinical samples, loss of ATM expression correlated with increased ARF levels and in xenograft and tissue culture models, inhibition of ATM stimulated the tumour-suppressive effects of ARF. These results provide insights into the functional interplay between the DDR and ARF anti-cancer barriers, with implications for tumorigenesis and treatment of advanced tumours.

Cappello P, Blaser H, Gorrini C, et al.
Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells.
Oncogene. 2014; 33(18):2375-84 [PubMed] Related Publications
Breast cancer is the most common solid tumor and the second most common cause of death in women. Despite a large body of literature and progress in breast cancer research, many molecular aspects of this complex disease are still poorly understood, hindering the design of specific and effective therapeutic strategies. To identify the molecules important in breast cancer progression and metastasis, we tested the in vivo effects of inhibiting the functions of various kinases and genes involved in the regulation/modulation of the cytoskeleton by downregulating them in mouse PyMT mammary tumor cells and human breast cancer cell lines. These kinases and cytoskeletal regulators were selected based on their prognostic values for breast cancer patient survival. PyMT tumor cells, in which a selected gene was stably knocked down were injected into the tail veins of mice, and the formation of tumors in the lungs was monitored. One of the several genes found to be important for tumor growth in the lungs was NIMA-related kinases 2 (Nek2), a cell cycle-related protein kinase. Furthermore, Nek2 was also important for tumor growth in the mammary fat pad. In various human breast cancer cell lines, Nek2 knockdown induced aneuploidy and cell cycle arrest that led to cell death. Significantly, the breast cancer cell line most sensitive to Nek2 depletion was of the triple negative breast cancer subtype. Our data indicate that Nek2 has a pivotal role in breast cancer growth at primary and secondary sites, and thus may be an attractive and novel therapeutic target for this disease.

Hawkins SM, Loomans HA, Wan YW, et al.
Expression and functional pathway analysis of nuclear receptor NR2F2 in ovarian cancer.
J Clin Endocrinol Metab. 2013; 98(7):E1152-62 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
CONTEXT: Recent evidence implicates the orphan nuclear receptor, nuclear receptor subfamily 2, group F, member 2 (NR2F2; chicken ovalbumin upstream promoter-transcription factor II) as both a master regulator of angiogenesis and an oncogene in prostate and other human cancers.
OBJECTIVE: The objective of the study was to determine whether NR2F2 plays a role in ovarian cancer and dissect its potential mechanisms of action.
DESIGN, SETTING, AND PATIENTS: We examined NR2F2 expression in healthy ovary and ovarian cancers using quantitative PCR and immunohistochemistry. NR2F2 expression was targeted in established ovarian cancer cell lines to assess the impact of dysregulated NR2F2 expression in the epithelial compartment of ovarian cancers.
RESULTS: Our results indicate that NR2F2 is robustly expressed in the stroma of healthy ovary with little or no expression in epithelia lining the ovarian surface, clefts, or crypts. This pattern of NR2F2 expression was markedly disrupted in ovarian cancers, in which decreased levels of stromal expression and ectopic epithelial expression were frequently observed. Ovarian cancers with the most disrupted patterns of NR2F2 were associated with significantly shorter disease-free interval by Kaplan-Meier analysis. Targeting NR2F2 expression in established ovarian cancer cell lines enhanced apoptosis and increased proliferation. In addition, we found that NR2F2 regulates the expression of NEK2, RAI14, and multiple other genes involved in the cell cycle, suggesting potential pathways by which dysregulated expression of NR2F2 impacts ovarian cancer.
CONCLUSIONS: These results uncover novel roles for NR2F2 in ovarian cancer and point to a unique scenario in which a single nuclear receptor plays potentially distinct roles in the stromal and epithelial compartments of the same tissue.

Habel LA, Sakoda LC, Achacoso N, et al.
HOXB13:IL17BR and molecular grade index and risk of breast cancer death among patients with lymph node-negative invasive disease.
Breast Cancer Res. 2013; 15(2):R24 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
INTRODUCTION: Studies have shown that a two-gene ratio (HOXB13:IL17BR) and a five-gene (BUB1B, CENPA, NEK2, RACGAP1, RRM2) molecular grade index (MGI) are predictive of clinical outcomes among early-stage breast cancer patients. In an independent population of lymph node-negative breast cancer patients from a community hospital setting, we evaluated the performance of two risk classifiers that have been derived from these gene signatures combined, MGI+HOXB13:IL17BR and the Breast Cancer Index (BCI).
METHODS: A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 who did not receive adjuvant chemotherapy. For 191 cases (breast cancer deaths) and 417 matched controls, archived tumor tissues were available and analyzed for expression levels of the seven genes of interest and four normalization genes by RT-PCR. Logistic regression methods were used to estimate the relative risk (RR) and 10-year absolute risk of breast cancer death associated with prespecified risk categories for MGI+HOXB13:IL17BR and BCI.
RESULTS: Both MGI+HOXB13:IL17BR and BCI classified over half of all ER-positive patients as low risk. The 10-year absolute risks of breast cancer death for ER-positive, tamoxifen-treated patients classified in the low-, intermediate-, and high-risk groups were 3.7% (95% confidence interval (CI) 1.9% to 5.4%), 5.9% (95% CI 3.0% to 8.6%), and 12.9% (95% CI 7.9% to 17.6%) by MGI+HOXB13:IL17BR and 3.5% (95% CI 1.9% to 5.1%), 7.0% (95% CI 3.8% to 10.1%), and 12.9% (95% CI 7.1% to 18.3%) by BCI. Those for ER-positive, tamoxifen-untreated patients were 5.7% (95% CI 4.0% to 7.4%), 13.8% (95% CI 8.4% to 18.9%), and 15.2% (95% CI 9.4% to 20.5%) by MGI+HOXB13:IL17BR and 5.1% (95% CI 3.6% to 6.6%), 18.6% (95% CI 10.8% to 25.7%), and 17.5% (95% CI 11.1% to 23.5%) by BCI. After adjusting for tumor size and grade, the RRs of breast cancer death comparing high- versus low-risk categories of both classifiers remained elevated but were attenuated for tamoxifen-treated and tamoxifen-untreated patients.
CONCLUSION: Among ER-positive, lymph node-negative patients not treated with adjuvant chemotherapy, MGI+HOXB13:IL17BR and BCI were associated with risk of breast cancer death. Both risk classifiers appeared to provide risk information beyond standard prognostic factors.

Stricker TP, Henriksen KJ, Tonsgard JH, et al.
Expression profiling of 519 kinase genes in matched malignant peripheral nerve sheath tumor/plexiform neurofibroma samples is discriminatory and identifies mitotic regulators BUB1B, PBK and NEK2 as overexpressed with transformation.
Mod Pathol. 2013; 26(7):930-43 [PubMed] Related Publications
About 50% of all malignant peripheral nerve sheath tumors (MPNSTs) arise as neurofibromatosis type 1 associated lesions. In those patients malignant peripheral nerve sheath tumors are thought to arise through malignant transformation of a preexisting plexiform neurofibroma. The molecular changes associated with this transformation are still poorly understood. We sought to test the hypothesis that dysregulation of expression of kinases contributes to this malignant transformation. We analyzed expression of all 519 kinase genes in the human genome using the nanostring nCounter system. Twelve cases of malignant peripheral nerve sheath tumor arising in a background of preexisting plexiform neurofibroma were included. Both components were separately sampled. Statistical analysis compared global changes in expression levels as well as changes observed in the pairwise comparison of samples taken from the same surgical specimen. Immunohistochemical studies were performed on tissue array slides to confirm expression of selected proteins. The expression pattern of kinase genes can separate malignant peripheral nerve sheath tumors and preexisting plexiform neurofibromas. The majority of kinase genes is downregulated rather than overexpressed with malignant transformation. The patterns of expression changes are complex without simple recurring alteration. Pathway analysis demonstrates that differentially expressed kinases are enriched for kinases involved in the direct regulation of mitosis, and several of these show increased expression in malignant peripheral nerve sheath tumors. Immunohistochemical studies for the mitotic regulators BUB1B, PBK and NEK2 confirm higher expression levels at the protein level. These results suggest that the malignant transformation of plexiform neurofibroma is associated with distinct changes in the expression of kinase genes. The patterns of these changes are complex and heterogeneous. There is no single unifying alteration. Kinases involved in mitotic regulation are particularly enriched in the pool of differentially expressed kinases. Some of these are overexpressed and are therefore possible targets for kinase inhibitors.

Zhou W, Yang Y, Xia J, et al.
NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers.
Cancer Cell. 2013; 23(1):48-62 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
Using sequential gene expression profiling (GEP) samples, we defined a major functional group related to drug resistance that contains chromosomal instability (CIN) genes. One CIN gene in particular, NEK2, was highly correlated with drug resistance, rapid relapse, and poor outcome in multiple cancers. Overexpressing NEK2 in cancer cells resulted in enhanced CIN, cell proliferation and drug resistance, while targeting NEK2 by NEK2 shRNA overcame cancer cell drug resistance and induced apoptosis in vitro and in a xenograft myeloma mouse model. High expression of NEK2 induced drug resistance mainly through activation of the efflux pumps. Thus, NEK2 represents a strong predictor for drug resistance and poor prognosis in cancer and could be an important target for cancer therapy.

Komatsu M, Yoshimaru T, Matsuo T, et al.
Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis.
Int J Oncol. 2013; 42(2):478-506 [PubMed] Related Publications
Triple negative breast cancer (TNBC) has a poor outcome due to the lack of beneficial therapeutic targets. To clarify the molecular mechanisms involved in the carcinogenesis of TNBC and to identify target molecules for novel anticancer drugs, we analyzed the gene expression profiles of 30 TNBCs as well as 13 normal epithelial ductal cells that were purified by laser-microbeam microdissection. We identified 301 and 321 transcripts that were significantly upregulated and downregulated in TNBC, respectively. In particular, gene expression profile analyses of normal human vital organs allowed us to identify 104 cancer-specific genes, including those involved in breast carcinogenesis such as NEK2, PBK and MELK. Moreover, gene annotation enrichment analysis revealed prominent gene subsets involved in the cell cycle, especially mitosis. Therefore, we focused on cell cycle regulators, asp (abnormal spindle) homolog, microcephaly-associated (Drosophila) (ASPM) and centromere protein K (CENPK) as novel therapeutic targets for TNBC. Small-interfering RNA-mediated knockdown of their expression significantly attenuated TNBC cell viability due to G1 and G2/M cell cycle arrest. Our data will provide a better understanding of the carcinogenesis of TNBC and could contribute to the development of molecular targets as a treatment for TNBC patients.

Koch M, Wiese M
Gene expression signatures of angiocidin and darapladib treatment connect to therapy options in cervical cancer.
J Cancer Res Clin Oncol. 2013; 139(2):259-67 [PubMed] Related Publications
PURPOSE: To assign functional properties to gene expression profiles of cervical cancer stages and identify clinically relevant biomarker genes.
EXPERIMENTAL DESIGN: Microarray samples of 24 normal and 102 cervical cancer biopsies from four publicly available studies were pooled and evaluated. High-quality microarrays were normalized using the CONOR package from the Bioconductor project. Gene expression profiling was performed using variance-component analysis for accessing most reliable probes, which were subsequently processed by gene set enrichment analysis.
RESULTS: Of 22.277 probes that were subject to variance-component analysis, eleven probes had low heterogeneity, that is, a W/T ratio between 0.18 and 0.38. Seven of these probes are induced in all cervical cancer stages: they are GINS1, PAK2, DTL, AURKA, PRKDC, NEK2 and CEP55. The other four probes are induced in normal cervix: P11, EMP1, UPK1A and HSPC159. We performed GSEA of 9.873 probes exhibiting less variability, that is, having a W/T ratio of <0.75. Repeatedly, significant gene expression signatures were found that are related to treatment using angiocidin and darapladib. Additionally, expression signatures from immunological disease signatures were found, for example graft versus host disease and acute kidney rejection. Another finding comprises a gene expression signature in stage IB2 that refers to MT1-MMP-dependent migration and invasion. This gene signature is accompanied by gene expression signatures which refer to ECM receptor-mediated interactions.
CONCLUSION: Analysis of cervical cancer patient gene expression data reveals a novel perspective on HPV-mediated transcription processes. This novel point of view contains a better understanding and even might provide improvements to cancer therapy.

Wang H, Xie YT, Han JY, et al.
Genetic polymorphisms in centrobin and Nek2 are associated with breast cancer susceptibility in a Chinese Han population.
Breast Cancer Res Treat. 2012; 136(1):241-51 [PubMed] Related Publications
Centrosome aberrations have been suggested to cause chromosomal instability and aneuploidy, and eventually promote cancer development. The Centrobin and Nek2 proteins interact with each other and both are involved in centrosome duplication and chromosome segregation. This study aimed to investigate whether genetic polymorphisms in these two genes may affect breast cancer susceptibility in Chinese Han population using a haplotype-based analysis. Five single nucleotide polymorphisms (SNPs) in centrobin and four SNPs in Nek2 were genotyped in 1,215 cases of infiltrating ductal breast cancer and 1,215 age-matched cancer-free controls from Chinese Han population. The results showed that CATCG haplotype of centrobin was strongly associated with decreased breast cancer risk (adjusted OR = 0.14, 95 % CI = 0.09-0.22), which was mainly driven by the C allele of SNP rs11650083 (A>C, located in exon 12, resulting in Pro578Gln). None of the individual SNPs in Nek2 was associated with breast cancer risk. However, haplotype GTAT of Nek2 was associated with increased risk of breast cancer (adjusted OR = 1.56, 95 % CI = 1.18-2.06) and its risk was significantly elevated among women with both family history of cancer and a longer menarche-first full-term pregnancy (FFTP) interval (>11 years) (adjusted OR = 5.31, 95 % CI = 1.97-14.32). Furthermore, women harboring both at-risk haplotype GTAT of Nek2 and protective haplotype CATCG of centrobin were linked with decreased breast cancer risk, suggesting that the association between genetic variants of Nek2 and increased breast cancer risk was modified by genetic variants of centrobin. Our results indicate that genetic polymorphisms of centrobin and Nek2 are related to breast cancer susceptibility in Chinese Han women.

Nischalke HD, Schmitz V, Luda C, et al.
Detection of IGF2BP3, HOXB7, and NEK2 mRNA expression in brush cytology specimens as a new diagnostic tool in patients with biliary strictures.
PLoS One. 2012; 7(8):e42141 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
INTRODUCTION: It is a challenging task to distinguish between benign and malignant lesions in patients with biliary strictures. Here we analyze whether determination of target gene mRNA levels in intraductal brush cytology specimens may be used to improve the diagnosis of bile duct carcinoma.
MATERIALS AND METHODS: Brush cytology specimens from 119 patients with biliary strictures (malignant: n = 72; benign: n = 47) were analyzed in a retrospective cohort study. mRNA of IGF-II mRNA-binding protein 3 (IGF2BP3), homeobox B7 (HOXB7), Forkhead box M1 (FOXM1), kinesin family member 2C (KIF2C) and serine/threonine kinase NEK2 was determined by semi-quantitative RT-PCR using the ΔCt method.
RESULTS: IGF2BP3 (p<0.0001), HOXB7 (p<0.0001), and NEK2 (p<0.0001) mRNA expression levels were significantly increased in patients with cholangiocarcinoma or pancreatic cancer. Median ΔCt values differed by 3.5 cycles (IGF2BP3), 2.8 cycles (HOXB7) and 1.3 cycles (NEK2) corresponding to 11-fold, 7-fold and 2.5-fold increased mRNA levels in malignant versus benign samples. Sensitivity to detect biliary cancer was 76.4% for IGF2BP3 (80.9% specificity); 72.2% for HOXB7 (78.7% specificity) and 65.3% for NEK2 (72.3% specificity), whereas routine cytology reached only 43.1% sensitivity (85.4% specificity). Diagnostic precision was further improved, when all three molecular markers were assessed in combination (77.8% sensitivity, 87.2% specificity) and achieved 87.5% sensitivity and 87.2% specificity when molecular markers were combined with routine cytology.
CONCLUSIONS: Our data suggest that measuring IGF2BP3, HOXB7 and NEK2 mRNA levels by RT-PCR in addition to cytology has the potential to improve detection of malignant biliary disorders from brush cytology specimens.

Liu Z, Wang Y, Wang S, et al.
Nek2C functions as a tumor promoter in human breast tumorigenesis.
Int J Mol Med. 2012; 30(4):775-82 [PubMed] Related Publications
The serine⁄threonine kinase Nek2 has been proposed as a requirement for the progression of breast cancer. The aim of this study was to investigate the expression of Nek2C, which is a splice variant of Nek2, and the role it plays in the different stages of breast cancer. We investigated the role of Nek2C in the MCF10 breast cancer cell lines, MCF10A, MCF10AT, MCF10DCIS.com and MCF10CA1a, using RNA interference and plasmid transfection, as well as breast tissue samples of normal breast tissue (NBT), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). We detected the mRNA Nek2C expression levels in the MCF10 cell lines and in human breast samples. Our results revealed that the mRNA expression of Nek2C was significantly upregulated in the MCF10DCIS.com and MCF10CA1a cell lines as well as in human primary breast cancer tissue (DCIS and IDC). As expected, the Nek2C downregulation, using RNA interference, decreased the survival, invasion and migration of MCF10DCIS.com and MCF10CA1a cells. Consistent with these results, the Nek2C upregulation in MCF10A and MCF10AT cells using plasmid transfection increased the survival ability of these cells. Our results also revealed a correlation between Nek2C mRNA expression levels and tumor grade. Taken together, our findings suggest that Nek2C plays a signicficant role in breast cancer development and that Nek2C inhibition may be a useful therapeutic approach to targeting human breast tumors.

Drozdov I, Bornschein J, Wex T, et al.
Functional and topological properties in hepatocellular carcinoma transcriptome.
PLoS One. 2012; 7(4):e35510 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality. However, little is known about the precise molecular mechanisms involved in tumor formation and pathogenesis. The primary goal of this study was to elucidate genome-wide molecular networks involved in development of HCC with multiple etiologies by exploring high quality microarray data. We undertook a comparative network analysis across 264 human microarray profiles monitoring transcript changes in healthy liver, liver cirrhosis, and HCC with viral and alcoholic etiologies. Gene co-expression profiling was used to derive a consensus gene relevance network of HCC progression that consisted of 798 genes and 2,012 links. The HCC interactome was further confirmed to be phenotype-specific and non-random. Additionally, we confirmed that co-expressed genes are more likely to share biological function, but not sub-cellular localization. Analysis of individual HCC genes revealed that they are topologically central in a human protein-protein interaction network. We used quantitative RT-PCR in a cohort of normal liver tissue (n = 8), hepatitis C virus (HCV)-induced chronic liver disease (n = 9), and HCC (n = 7) to validate co-expressions of several well-connected genes, namely ASPM, CDKN3, NEK2, RACGAP1, and TOP2A. We show that HCC is a heterogeneous disorder, underpinned by complex cross talk between immune response, cell cycle, and mRNA translation pathways. Our work provides a systems-wide resource for deeper understanding of molecular mechanisms in HCC progression and may be used further to define novel targets for efficient treatment or diagnosis of this disease.

Wang S, Li W, Liu N, et al.
Nek2A contributes to tumorigenic growth and possibly functions as potential therapeutic target for human breast cancer.
J Cell Biochem. 2012; 113(6):1904-14 [PubMed] Related Publications
Nek2A (NIMA-related kinases 2A) has been known as an important centrosome regulatory factor. The aim of this study was to investigate the expression of Nek2A and the role it played in different stages of breast cancer. We detected the expression of Nek2A in both mRNA and protein levels in MCF10 cell lines including MCF-10A, MCF-10DCIS.com, MCF-10CA1a and in human breast samples which contained normal breast tissue (NBT), breast ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). Our study revealed that the mRNA and protein expression of Nek2A were significantly up-regulated in MCF-10DCIS.com and MCF-10CA1a cell lines as well as in human primary breast cancer tissue (DCIS and IDC). Our study also presented a correlation between Nek2A mRNA expression and some clinic pathological factors. We found that Nek2A mRNA expression was associated with molecular subtypes, ER, PR and Ki-67 immunoreactivity (P<0.05) in DCIS and associated with histological grade, lymph node metastasis, molecular subtypes, c-erbB-2, and Ki-67 expression (P<0.05) in IDC. In addition, we observed that ectopic expression of Nek2A in "normal" immortalized MCF-10A breast epithelial cell resulted in increased Nek2A which lead to abnormal centrosomes. Furthermore, knockdown of Nek2A in MCF-10DCIS.com could remarkably inhibit cell proliferation and induce cell cycle arrest in MCF-10DCIS.com cell line. These data suggested that Nek2A might bear a close relationship with development and progression of breast carcinoma, and highlighted its role as a novel potential biomarker for diagnosis and a possible therapeutic target for human breast cancer especially for DCIS.

Jankowitz RC, Cooper K, Erlander MG, et al.
Prognostic utility of the breast cancer index and comparison to Adjuvant! Online in a clinical case series of early breast cancer.
Breast Cancer Res. 2011; 13(5):R98 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
INTRODUCTION: Breast Cancer Index (BCI) combines two independent biomarkers, HOXB13:IL17BR (H:I) and the 5-gene molecular grade index (MGI), that assess estrogen-mediated signalling and tumor grade, respectively. BCI stratifies early-stage estrogen-receptor positive (ER+), lymph-node negative (LN-) breast cancer patients into three risk groups and provides a continuous assessment of individual risk of distant recurrence. Objectives of the current study were to validate BCI in a clinical case series and to compare the prognostic utility of BCI and Adjuvant!Online (AO).
METHODS: Tumor samples from 265 ER+LN- tamoxifen-treated patients were identified from a single academic institution's cancer research registry. The BCI assay was performed and scores were assigned based on a pre-determined risk model. Risk was assessed by BCI and AO and correlated to clinical outcomes in the patient cohort.
RESULTS: BCI was a significant predictor of outcome in a cohort of 265 ER+LN- patients (median age: 56-y; median follow-up: 10.3-y), treated with adjuvant tamoxifen alone or tamoxifen with chemotherapy (32%). BCI categorized 55%, 21%, and 24% of patients as low, intermediate and high-risk, respectively. The 10-year rates of distant recurrence were 6.6%, 12.1% and 31.9% and of breast cancer-specific mortality were 3.8%, 3.6% and 22.1% in low, intermediate, and high-risk groups, respectively. In a multivariate analysis including clinicopathological factors, BCI was a significant predictor of distant recurrence (HR for 5-unit increase = 5.32 [CI 2.18-13.01; P = 0.0002]) and breast cancer-specific mortality (HR for a 5-unit increase = 9.60 [CI 3.20-28.80; P < 0.0001]). AO was significantly associated with risk of recurrence. In a separate multivariate analysis, both BCI and AO were significantly predictive of outcome. In a time-dependent (10-y) ROC curve accuracy analysis of recurrence risk, the addition of BCI+AO increased predictive accuracy in all patients from 66% (AO only) to 76% (AO+BCI) and in tamoxifen-only treated patients from 65% to 81%.
CONCLUSIONS: This study validates the prognostic performance of BCI in ER+LN- patients. In this characteristically low-risk cohort, BCI classified high versus low-risk groups with ~5-fold difference in 10-year risk of distant recurrence and breast cancer-specific death. BCI and AO are independent predictors with BCI having additive utility beyond standard of care parameters that are encompassed in AO.

Li J, Zhan Q
The role of centrosomal Nlp in the control of mitotic progression and tumourigenesis.
Br J Cancer. 2011; 104(10):1523-8 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
The human centrosomal ninein-like protein (Nlp) is a new member of the γ-tubulin complexes binding proteins (GTBPs) that is essential for proper execution of various mitotic events. The primary function of Nlp is to promote microtubule nucleation that contributes to centrosome maturation, spindle formation and chromosome segregation. Its subcellular localisation and protein stability are regulated by several crucial mitotic kinases, such as Plk1, Nek2, Cdc2 and Aurora B. Several lines of evidence have linked Nlp to human cancer. Deregulation of Nlp in cell models results in aberrant spindle, chromosomal missegregation and multinulei, and induces chromosomal instability and renders cells tumourigenic. Overexpression of Nlp induces anchorage-independent growth and immortalised primary cell transformation. In addition, we first demonstrate that the expression of Nlp is elevated primarily due to NLP gene amplification in human breast cancer and lung carcinoma. Consistently, transgenic mice overexpressing Nlp display spontaneous tumours in breast, ovary and testicle, and show rapid onset of radiation-induced lymphoma, indicating that Nlp is involved in tumourigenesis. This review summarises our current knowledge of physiological roles of Nlp, with an emphasis on its potentials in tumourigenesis.

Kohler ME, Johnson BD, Palen K, et al.
Tumor antigen analysis in neuroblastoma by serological interrogation of bioinformatic data.
Cancer Sci. 2010; 101(11):2316-24 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
The identification of tumor antigens remains a major objective in tumor immunology, especially in pediatric malignancies where solid tumors often do not express a single dominant antigen. Methods such as the Serological Screening of Recombinant cDNA Expression Libraries (SEREX) have been used in the discovery of tumor-expressed proteins by virtue of their ability to induce an antibody response. To focus and accelerate this approach, we first identified candidate antigens by gene expression profiling data from clinical neuroblastoma specimens and then used an animal model to generate an antibody response to an engineered cell-based vaccine. Candidate tumor antigens were expressed as recombinant proteins in a mammalian system and screened for antibody recognition using serum from mice vaccinated with a neuroblastoma cell-based vaccine engineered to express CD80 and CD86, with or without Treg depletion. Through this procedure, the never in mitosis A (NIMA)-related kinase NEK2 was identified as a tumor-associated antigen. Direct testing of serum from patients newly diagnosed with neuroblastoma showed specific serological responses in two of 20 patients. Although NEK2 was not universally recognized, it may serve as a tumor antigen for some patients.

Zeng X, Shaikh FY, Harrison MK, et al.
The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2.
Oncogene. 2010; 29(36):5103-12 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
Centrosome amplification (CA) contributes to carcinogenesis by generating aneuploidy. Elevated frequencies of CA in most benign breast lesions and primary tumors suggest a causative role for CA in breast cancers. Clearly, identifying which and how altered signal transduction pathways contribute to CA is crucial to breast cancer control. Although a causative and cooperative role for c-Myc and Ras in mammary tumorigenesis is well documented, their ability to generate CA during mammary tumor initiation remains unexplored. To answer that question, K-Ras(G12D) and c-Myc were induced in mouse mammary glands. Although CA was observed in mammary tumors initiated by c-Myc or K-Ras(G12D), it was detected only in premalignant mammary lesions expressing K-Ras(G12D). CA, both in vivo and in vitro, was associated with increased expression of the centrosome-regulatory proteins, cyclin D1 and Nek2. Abolishing the expression of cyclin D1, Cdk4 or Nek2 in MCF10A human mammary epithelial cells expressing H-Ras(G12V) abrogated Ras-induced CA, whereas silencing cyclin E1 or B2 had no effect. Thus, we conclude that CA precedes mammary tumorigenesis, and interfering with centrosome-regulatory targets suppresses CA.

Liu Q, Hirohashi Y, Du X, et al.
Nek2 targets the mitotic checkpoint proteins Mad2 and Cdc20: a mechanism for aneuploidy in cancer.
Exp Mol Pathol. 2010; 88(2):225-33 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
In mitosis, the duplicated chromosomes are separated and equally distributed to progeny cells under the guidance of the spindle, a dynamic microtubule network. Previous studies revealed a mitotic checkpoint that prevents segregation of the chromosomes until all of the chromosomes are properly attached to microtubules through the kinetochores. A variety of kinetochore-localized proteins, including Mad2 and Cdc20, have been implicated in controlling the mitotic checkpoint. Here we report that both Mad2 and Cdc20 can physically associate with Nek2, a serine/threonine kinase implicated in centrosome functions. We show that, similar to Nek2, the endogenous Cdc20 protein can be detected in the centrosome and the spindle poles. Both Cdc20 and Mad2 can be phosphorylated by Nek2. Moreover, our studies demonstrate that overexpression of Nek2 enhances the ability of Mad2 to induce a delay in mitosis. These observations indicate that Nek2 may act upon the Mad2-Cdc20 protein complex and play a critical role in regulating the mitotic checkpoint protein complex. We propose that overexpression of Nek2 may promote aneuploidy by disrupting the control of the mitotic checkpoint.

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