Gene Summary

Gene:ESPL1; extra spindle pole bodies like 1, separase
Aliases: ESP1, SEPA
Summary:Stable cohesion between sister chromatids before anaphase and their timely separation during anaphase are critical for chromosome inheritance. In vertebrates, sister chromatid cohesion is released in 2 steps via distinct mechanisms. The first step involves phosphorylation of STAG1 (MIM 604358) or STAG2 (MIM 300826) in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 (RAD21; MIM 606462) by ESPL1, or separase, which initiates the final separation of sister chromatids (Sun et al., 2009 [PubMed 19345191]).[supplied by OMIM, Nov 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: ESPL1 (cancer-related)

Buechler SA, Gökmen-Polar Y, Badve SS
EarlyR signature predicts response to neoadjuvant chemotherapy in breast cancer.
Breast. 2019; 43:74-80 [PubMed] Related Publications
BACKGROUND: EarlyR gene signature uses ESPL1, SPAG5, MKI67, PLK1 and PGR to classify ER+ breast cancer (ER+ BC) into EarlyR-Low, EarlyR-Int, and EarlyR-High risk strata and is prognostic in patients treated with adjuvant chemotherapy. The ability of EarlyR to predict pathological complete response (pCR) and long-term survival following neoadjuvant chemotherapy (NACT) is evaluated herein.
MATERIALS: The ability of EarlyR gene signature to predict pCR was assessed in publicly available Affymetrix microarray datasets (Cohort A; n = 659; 74 pCR events) derived from NACT-treated ER+ BC patients. Distant relapse-free survival (DRFS) results were analyzed in patients treated with NACT and adjuvant hormone therapy (AHT) (n = 281) and compared with patients treated with AHT alone (n = 455) (Cohort B; n = 736; 142 events).
RESULTS: In cohort A, EarlyR was a significant predictor of pCR (p = 5.8 × 10
CONCLUSIONS: High EarlyR is strongly associated with pCR in patients treated with neoadjuvant chemotherapy. EarlyR also predicts poor DRFS outcomes for patients in EarlyR-High not receiving NACT, and improved survival in NACT-treated EarlyR-High patients. EarlyR is not only a prognostic assay but also a predictive assay that identifies patients, who are also likely to respond to chemotherapy.

Wang D, Zhu H, Guo M, et al.
Expression and prognostic value of cell-cycle-associated genes in gastric adenocarcinoma.
BMC Gastroenterol. 2018; 18(1):81 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gastric carcinoma is a malignant disease, and gastric adenocarcinoma (GAC) is the most common histological type. Molecular profiling of GAC has been extensively performed, but few have focused on the clinical significance of gene clusters of the cell cycle.
METHODS: We investigated the genetic profile of cell-cycle-associated genes in a GAC cohort. The mRNA expression and clinical data were downloaded from TCGA, according to cBioportal. We conducted a series of analyses to detect the relationships between these genes and GAC.
RESULTS: From all the patients, 5 clusters were identified based on mRNA expression of 122 cell-cycle-associated genes. Cluster 1 showed the worst prognosis and is characterized by extremely high expression of WEE2 and CCNE1. Comparison of the gene patterns showed that 16 genes expressed were distinctly varied between each cluster. In addition, investigations into the prognostic role of the 16 genes suggested that high expression of ESPL1 and MCM5 were significantly correlated with favorable outcomes. Moreover, we detected that ESPL1 and MCM5 gene expression were negatively correlated with GAC pathologic stage progression.
CONCLUSIONS: This study revealed a gene expression pattern of the cell cycle in different GAC subgroups, and suggested individual genes were associated with the clinical outcome and AJCC stages. These results suggest a novel prognostic strategy for GAC and provide information for patient stratification and trials of targeted therapies.

Zulfiqar M, Bluth MH, Bhalla A
Molecular Diagnostics in Esophageal and Gastric Neoplasms: 2018 Update.
Clin Lab Med. 2018; 38(2):357-365 [PubMed] Related Publications
Esophageal cancer (EC) is rapidly increasing in incidence in the United States. Genetic changes associated with the development of EC involve the p16, p53, and APC genes. Human epidermal growth factor 2 (HER-2) overexpression is seen in gastroesophageal junction carcinoma and a subset gastric carcinoma (GC). Interestingly, up to 50% cases of GC are related to Helicobacter pylori infection and up to 16% are related to EBV infection. Microsatellite instability is observed in up to 39% of GC and cell free nucleic acid analysis provides additional opportunities for diagnosis and prognosis of disease.

Bhalla A, Zulfiqar M, Bluth MH
Molecular Diagnostics in Colorectal Carcinoma: Advances and Applications for 2018.
Clin Lab Med. 2018; 38(2):311-342 [PubMed] Related Publications
The molecular pathogenesis and classification of colorectal carcinoma are based on the traditional adenomaecarcinoma sequence, serrated polyp pathway, and microsatellite instability (MSI). The genetic basis for hereditary nonpolyposis colorectal cancer is the detection of mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Genetic testing for Lynch syndrome includes MSI testing, methylator phenotype testing, BRAF mutation testing, and molecular testing for germline mutations in MMR genes. Molecular makers with predictive and prognostic implications include quantitative multigene reverse transcriptase polymerase chain reaction assay and KRAS and BRAF mutation analysis. Mismatch repair-deficient tumors have higher rates of programmed death-ligand 1 expression. Cell-free DNA analysis in fluids are proving beneficial for diagnosis and prognosis in these disease states towards effective patient management.

Wen DY, Lin P, Pang YY, et al.
Expression of the Long Intergenic Non-Protein Coding RNA 665 (LINC00665) Gene and the Cell Cycle in Hepatocellular Carcinoma Using The Cancer Genome Atlas, the Gene Expression Omnibus, and Quantitative Real-Time Polymerase Chain Reaction.
Med Sci Monit. 2018; 24:2786-2808 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Long non-coding RNAs (lncRNAs) have a role in physiological and pathological processes, including cancer. The aim of this study was to investigate the expression of the long intergenic non-protein coding RNA 665 (LINC00665) gene and the cell cycle in hepatocellular carcinoma (HCC) using database analysis including The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and quantitative real-time polymerase chain reaction (qPCR). MATERIAL AND METHODS Expression levels of LINC00665 were compared between human tissue samples of HCC and adjacent normal liver, clinicopathological correlations were made using TCGA and the GEO, and qPCR was performed to validate the findings. Other public databases were searched for other genes associated with LINC00665 expression, including The Atlas of Noncoding RNAs in Cancer (TANRIC), the Multi Experiment Matrix (MEM), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) networks. RESULTS Overexpression of LINC00665 in patients with HCC was significantly associated with gender, tumor grade, stage, and tumor cell type. Overexpression of LINC00665 in patients with HCC was significantly associated with overall survival (OS) (HR=1.47795%; CI: 1.046-2.086). Bioinformatics analysis identified 469 related genes and further analysis supported a hypothesis that LINC00665 regulates pathways in the cell cycle to facilitate the development and progression of HCC through ten identified core genes: CDK1, BUB1B, BUB1, PLK1, CCNB2, CCNB1, CDC20, ESPL1, MAD2L1, and CCNA2. CONCLUSIONS Overexpression of the lncRNA, LINC00665 may be involved in the regulation of cell cycle pathways in HCC through ten identified hub genes.

He X, Zhang C, Shi C, Lu Q
Meta-analysis of mRNA expression profiles to identify differentially expressed genes in lung adenocarcinoma tissue from smokers and non-smokers.
Oncol Rep. 2018; 39(3):929-938 [PubMed] Related Publications
Compared to other types of lung cancer, lung adenocarcinoma patients with a history of smoking have a poor prognosis during the treatment of lung cancer. How lung adenocarcinoma-related genes are differentially expressed between smoker and non-smoker patients has yet to be fully elucidated. We performed a meta-analysis of four publicly available microarray datasets related to lung adenocarcinoma tissue in patients with a history of smoking using R statistical software. The top 50 differentially expressed genes (DEGs) in smoking vs. non‑smoking patients are shown using heat maps. Additionally, we conducted KEGG and GO analyses. In addition, we performed a PPI network analysis for 8 genes that were selected during a previous analysis. We identified a total of 2,932 DEGs (1,806 upregulated, 1,126 downregulated) and five genes (CDC45, CDC20, ANAPC7, CDC6, ESPL1) that may link lung adenocarcinoma to smoking history. Our study may provide new insights into the complex mechanisms of lung adenocarcinoma in smoking patients, and our novel gene expression signatures will be useful for future clinical studies.

Suh YJ, Choe JY, Park HJ
Malignancy in Pheochromocytoma or Paraganglioma: Integrative Analysis of 176 Cases in TCGA.
Endocr Pathol. 2017; 28(2):159-164 [PubMed] Related Publications
Methods of diagnosing malignant pheochromocytoma (PCC) or paraganglioma (PGL) are needed. However, there are no reliable histopathologic criteria to distinguish malignant PCC/PGLs. The recent genomic analysis of The Cancer Genome Atlas (TCGA) provides in-depth information enabling more accurate diagnosis of disease entities. Therefore, we investigated genomic expression differences and mutational differences of malignant PCC/PGLs with TCGA. As of December 2014, TCGA had acquired multigenomic analysis of 176 PCC/PGL samples. Clinical information, mutation status, and 20,531 gene messenger RNA (mRNA) expression dataset of normalized RNA-sequencing mRNA read counts were downloaded from TCGA, and integrated into a table. Of the 176 PCC/PGL samples in the dataset, 14 had metastasis and 162 exhibited no metastasis. mRNA expression and mutations were compared in these two groups. There were 76 males in the dataset of 176 TCGA samples. Mean age was 47.6 ± 15.2 years (19-83 years). There was no significant gender or race difference between metastatic and non-metastatic groups. mRNA expression of malignant PCC/PGLs was upregulated in five pathways of cell cycle (BUB1, BUB1B, CCNB2, CDC2, ESPL1), calcium signaling (CCNB2, CDC2, PRKCB1), regulation of actin cytoskeleton (DIAPH3, FGF18, IQGAP3), gap junction (CDC2, PRKCB1), and phosphatidylinositol (PRKCB1, TTK). Disease-free survival rates were significantly correlated with the presence or absence of mutations, such as RP11-798G7.5, HERC2, SETD2, TGDS, TRHDE, FKBP9, and BMS1. TCGA showed differences in mRNA expression and mutations between metastatic and non-metastatic PCC/PGLs. The improved recognition of genetic causes can help to achieve proper diagnosis and provide appropriate treatment of PCC/PGL.

Zhang N, Pati D
Biology and insights into the role of cohesin protease separase in human malignancies.
Biol Rev Camb Philos Soc. 2017; 92(4):2070-2083 [PubMed] Related Publications
Separase, an enzyme that resolves sister chromatid cohesion during the metaphase-to-anaphase transition, plays a pivotal role in chromosomal segregation and cell division. Separase protein, encoded by the extra spindle pole bodies like 1 (ESPL1) gene, is overexpressed in numerous human cancers including breast, bone, brain, and prostate. Separase is oncogenic, and its overexpression is sufficient to induce mammary tumours in mice. Either acute or chronic overexpression of separase in mouse mammary glands leads to aneuploidy and tumorigenesis, and inhibition of separase enzymatic activity decreases the growth of human breast tumour xenografts in mice. This review focuses on the biology of and insights into the molecular mechanisms of separase as an oncogene, and its significance and implications for human cancers.

Kumar R
Separase: Function Beyond Cohesion Cleavage and an Emerging Oncogene.
J Cell Biochem. 2017; 118(6):1283-1299 [PubMed] Related Publications
Proper and timely segregation of genetic endowment is necessary for survival and perpetuation of every species. Mis-segregation of chromosomes and resulting aneuploidy leads to genetic instability, which can jeopardize the survival of an individual or population as a whole. Abnormality with segregation of genetic contents has been associated with several medical consequences including cancer, sterility, mental retardation, spontaneous abortion, miscarriages, and other birth related defects. Separase, by irreversible cleavage of cohesin complex subunit, paves the way for metaphase/anaphase transition during the cell cycle. Both over or reduced expression and altered level of separase have been associated with several medical consequences including cancer, as a result separase now emerges as an important oncogene and potential molecular target for medical intervenes. Recently, separase is also found to be essential in separation and duplication of centrioles. Here, I review the role of separase in mitosis, meiosis, non-canonical roles of separase, separase regulation, as a regulator of centriole disengagement, nonproteolytic roles, diverse substrates, structural insights, and association of separase with cancer. At the ends, I proposed a model which showed that separase is active throughout the cell cycle and there is a mere increase in separase activity during metaphase contrary to the common believes that separase is inactive throughout cell cycle except for metaphase. J. Cell. Biochem. 118: 1283-1299, 2017. © 2016 Wiley Periodicals, Inc.

Šmahelová J, Kaštánková I, Poláková KM, et al.
Expression of genes encoding centrosomal proteins and the humoral response against these proteins in chronic myeloid leukemia.
Oncol Rep. 2017; 37(1):547-554 [PubMed] Related Publications
As the extent of centrosome abnormalities in chronic myeloid leukemia (CML) correlates with disease stage and karyotype alterations, abnormal expression of genes encoding centrosomal proteins may be an early prognostic marker of disease progression. In the present study, we showed that in comparison with healthy controls, the expression of four centrosomal genes (AURKA, HMMR, PLK1 and ESPL1) in the peripheral blood of CML patients was significantly enhanced at diagnosis and decreased to the basal level in most patients treated with imatinib mesylate for three months. In the remaining patients (17%), this decrease was delayed and was associated with worse overall survival. The detection of antibodies in sera showed that patients with higher overall antibody production had superior outcomes in terms of achieving major molecular response and failure-free survival. These data suggest that the dynamics of the response of centrosomal genes should be considered as a risk factor and immunity against centrosomal proteins may contribute to treatment response.

Zhang C, Min L, Zhang L, et al.
Combined analysis identifies six genes correlated with augmented malignancy from non-small cell to small cell lung cancer.
Tumour Biol. 2016; 37(2):2193-207 [PubMed] Related Publications
With increased malignancy, lung cancer can be classified into adenocarcinoma (ADC), squamous cell carcinoma (SQC), large cell carcinoma (LCC), and the small cell subtype (SCLC); yet, elucidations to this augmented malignancy has not been addressed. In this study, we elucidated the molecular diversity among these subtypes by investigating large-scale sequencing datasets. Among genes upregulated from normal, ADC, SQC, LCC to SCLC, six hub genes were found closely correlated with adverse clinical outcome and were testified on cellular or tissue level with quantitative RT-PCR. Cox regression model was then built to generate a risk signature. The possible linkages among these genes were also explored. Transcript levels of BUB1, E2F1, ESPL1, GTSE1, RAB3B, and U2AF2 were found significantly elevated from normal, ADC, SQC, LCC to SCLC. Overexpression of one or multiple of these genes was correlated with adverse overall survival (OS) and relapse-free survival (RFS) in the whole patient cohort or groups stratified according to clinical variables, while most of all six genes were independent prognostic factors. When used as a six-gene risk signature, patients with high signature score displayed more unfavorable clinical variables and poorer outcome. Tight regulative relationships were found within these genes, while BUB1 and E2F1 were likely to be the drivers. We considered the augmented malignancy from non-small cell lung cancer (NSCLC) to SCLC might be due to the elevation of these six genes. We believe these genes were powerful cancer prognostic markers and potential therapeutic targets in lung cancer; moreover, changes of their level might be correlated with lung cancer phenotype plasticity.

Finetti P, Guille A, Adelaide J, et al.
ESPL1 is a candidate oncogene of luminal B breast cancers.
Breast Cancer Res Treat. 2014; 147(1):51-9 [PubMed] Related Publications
ESPL1/separase is a putative oncogene of luminal B breast cancers. Histoclinical correlations of its expression have never been explored in large series of breast tumors, and specifically in the luminal subtype. In a pooled series of invasive breast carcinomas profiled using DNA microarrays, we identified 3,074 luminal cases, including 1,307 luminal B tumors, in which we searched for correlations between ESPL1 mRNA expression and molecular and histoclinical features. Compared to normal breast samples, ESPL1 was overexpressed in 52 % of luminal tumors, and much more frequently in luminal B (83 %) than luminal A tumors (29 %). In luminal breast cancers, higher ESPL1 expression was associated with poor-prognosis criteria (age ≤ 50 years, ductal type, advanced stage, large tumor size, lymph node-positive status, high grade, PR-negative status, luminal B subtype) and with poor metastasis-free survival in both uni- and multivariate analyses. This independent prognostic value was also observed in luminal B tumors only, and persisted when compared with gene expression signatures (PAM50, Recurrence Score, Mammaprint, EndoPredict) currently proposed to refine the indications of adjuvant chemotherapy in hormone receptor-positive/HER2-negative breast cancer. We also confirmed the observations made with experimental mouse models: ESPL1-overexpressing luminal tumors showed complex genomic profiles and molecular features of chromosomal instability and loss of tumor suppressor genes (P53 and Rb). Our results reinforce the idea that ESPL1 is a candidate oncogene in luminal B cancers. Its expression may help improve the prognostication. Inhibiting ESPL1 may represent a promising therapeutic approach for these poor-prognosis tumors.

Solomon DA, Kim JS, Waldman T
Cohesin gene mutations in tumorigenesis: from discovery to clinical significance.
BMB Rep. 2014; 47(6):299-310 [PubMed] Free Access to Full Article Related Publications
Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations.

Dabydeen SA, Furth PA
Genetically engineered ERα-positive breast cancer mouse models.
Endocr Relat Cancer. 2014; 21(3):R195-208 [PubMed] Free Access to Full Article Related Publications
The majority of human breast cancers are estrogen receptor-positive (ER+), but this has proven challenging to model in genetically engineered mice. This review summarizes information on 21 mouse models that develop ER+ mammary cancer. Where available, information on cancer pathology and gene expression profiles is referenced to assist in understanding which histological subtype of ER+ human cancer each model might represent. ESR1, CCDN1, prolactin, TGFα, AIB1, ESPL1, and WNT1 overexpression, PIK3CA gain of function, as well as loss of P53 (Trp53) or STAT1 are associated with ER+ mammary cancer. Treatment with the PPARγ agonist efatutazone in a mouse with Brca1 and p53 deficiency and 7,12-dimethylbenz(a)anthracene exposure in combination with an activated myristoylated form of AKT1 also induce ER+ mammary cancer. A spontaneous mutant in nude mice that develops metastatic ER+ mammary cancer is included. Age of cancer development ranges from 3 to 26 months and the percentage of cancers that are ER+ vary from 21 to 100%. Not all models are characterized as to their estrogen dependency and/or response to anti-hormonal therapy. Strain backgrounds include C57Bl/6, FVB, BALB/c, 129S6/SvEv, CB6F1, and NIH nude. Most models have only been studied on one strain background. In summary, while a range of models are available for studies of pathogenesis and therapy of ER+ breast cancers, many could benefit from further characterization, and opportunity for development of new models remains.

Guo G, Sun X, Chen C, et al.
Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation.
Nat Genet. 2013; 45(12):1459-63 [PubMed] Related Publications
Bladder cancer is one of the most common cancers worldwide, with transitional cell carcinoma (TCC) being the predominant form. Here we report a genomic analysis of TCC by both whole-genome and whole-exome sequencing of 99 individuals with TCC. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, we identified additional altered genes and pathways that were implicated in TCC. Notably, we discovered frequent alterations in STAG2 and ESPL1, two genes involved in the sister chromatid cohesion and segregation (SCCS) process. Furthermore, we also detected a recurrent fusion involving FGFR3 and TACC3, another component of SCCS, by transcriptome sequencing of 42 DNA-sequenced tumors. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the SCCS process. Our analysis provides evidence that genetic alterations affecting the SCCS process may be involved in bladder tumorigenesis and identifies a new therapeutic possibility for bladder cancer.

Stepanenko AA, Vassetzky YS, Kavsan VM
Antagonistic functional duality of cancer genes.
Gene. 2013; 529(2):199-207 [PubMed] Related Publications
Cancer evolution is a stochastic process both at the genome and gene levels. Most of tumors contain multiple genetic subclones, evolving in either succession or in parallel, either in a linear or branching manner, with heterogeneous genome and gene alterations, extensively rewired signaling networks, and addicted to multiple oncogenes easily switching with each other during cancer progression and medical intervention. Hundreds of discovered cancer genes are classified according to whether they function in a dominant (oncogenes) or recessive (tumor suppressor genes) manner in a cancer cell. However, there are many cancer "gene-chameleons", which behave distinctly in opposite way in the different experimental settings showing antagonistic duality. In contrast to the widely accepted view that mutant NADP(+)-dependent isocitrate dehydrogenases 1/2 (IDH1/2) and associated metabolite 2-hydroxyglutarate (R)-enantiomer are intrinsically "the drivers" of tumourigenesis, mutant IDH1/2 inhibited, promoted or had no effect on cell proliferation, growth and tumorigenicity in diverse experiments. Similar behavior was evidenced for dozens of cancer genes. Gene function is dependent on genetic network, which is defined by the genome context. The overall changes in karyotype can result in alterations of the role and function of the same genes and pathways. The diverse cell lines and tumor samples have been used in experiments for proving gene tumor promoting/suppressive activity. They all display heterogeneous individual karyotypes and disturbed signaling networks. Consequently, the effect and function of gene under investigation can be opposite and versatile in cells with different genomes that may explain antagonistic duality of cancer genes and the cell type- or the cellular genetic/context-dependent response to the same protein. Antagonistic duality of cancer genes might contribute to failure of chemotherapy. Instructive examples of unexpected activity of cancer genes and "paradoxical" effects of different anticancer drugs depending on the cellular genetic context/signaling network are discussed.

Jiang L, Siu MK, Wong OG, et al.
iASPP and chemoresistance in ovarian cancers: effects on paclitaxel-mediated mitotic catastrophe.
Clin Cancer Res. 2011; 17(21):6924-33 [PubMed] Related Publications
PURPOSE: iASPP is a specific regulator of p53-mediated apoptosis. Herein, we provided the first report on the expression profile of iASPP in ovarian epithelial tumor and its effect on paclitaxel chemosensitivity.
EXPERIMENTAL DESIGN: Expression and amplification status of iASPP was examined in 203 clinical samples and 17 cell lines using immunohistochemistry, quantitative real-time PCR, and immunoblotting, and correlated with clinicopathologic parameters. Changes in proliferation, mitotic catastrophe, apoptosis, and underlying mechanism in ovarian cancer cells of different p53 status following paclitaxel exposure were also analyzed.
RESULTS: The protein and mRNA expression of iASPP was found to be significantly increased in ovarian cancer samples and cell lines. High iASPP expression was significantly associated with clear cell carcinoma subtype (P = 0.003), carboplatin and paclitaxel chemoresistance (P = 0.04), shorter overall (P = 0.003), and disease-free (P = 0.001) survival. Multivariate analysis confirmed iASPP expression as an independent prognostic factor. Increased iASPP mRNA expression was significantly correlated with gene amplification (P = 0.023). iASPP overexpression in ovarian cancer cells conferred resistance to paclitaxel by reducing mitotic catastrophe in a p53-independent manner via activation of separase, whereas knockdown of iASPP enhanced paclitaxel-mediated mitotic catastrophe through inactivating separase. Both securin and cyclin B1/CDK1 complex were involved in regulating separase by iASPP. Conversely, overexpressed iASPP inhibited apoptosis in a p53-dependent mode.
CONCLUSIONS: Our data show an association of iASPP overexpression with gene amplification in ovarian cancer and suggest a role of iASPP in poor patient outcome and chemoresistance, through blocking mitotic catastrophe. iASPP should be explored further as a potential prognostic marker and target for chemotherapy.

Mukherjee M, Ge G, Zhang N, et al.
Separase loss of function cooperates with the loss of p53 in the initiation and progression of T- and B-cell lymphoma, leukemia and aneuploidy in mice.
PLoS One. 2011; 6(7):e22167 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cohesin protease Separase plays a key role in faithful segregation of sister chromatids by cleaving the cohesin complex at the metaphase to anaphase transition. Homozygous deletion of ESPL1 gene that encodes Separase protein results in embryonic lethality in mice and Separase overexpression lead to aneuploidy and tumorigenesis. However, the effect of Separase haploinsufficiency has not been thoroughly investigated.
METHODOLOGY/PRINCIPAL FINDINGS: Here we examined the effect of ESPL1 heterozygosity using a hypomorphic mouse model that has reduced germline Separase activity. We report that while ESPL1 mutant (ESPL1 (+/hyp)) mice have a normal phenotype, in the absence of p53, these mice develop spontaneous T- and B-cell lymphomas, and leukemia with a significantly shortened latency as compared to p53 null mice. The ESPL1 hypomorphic, p53 heterozygous transgenic mice (ESPL1(+/hyp), p53(+/-)) also show a significantly reduced life span with an altered tumor spectrum of carcinomas and sarcomas compared to p53(+/-) mice alone. Furthermore, ESPL1(+/hyp), p53(-/-) mice display significantly higher levels of genetic instability and aneuploidy in normal cells, as indicated by the abnormal metaphase counts and SKY analysis of primary splenocytes.
CONCLUSIONS/SIGNIFICANCE: Our results indicate that reduced levels of Separase act synergistically with loss of p53 in the initiation and progression of B- and T- cell lymphomas, which is aided by increased chromosomal missegregation and accumulation of genomic instability. ESPL1(+/hyp), p53(-/-) mice provide a new animal model for mechanistic study of aggressive lymphoma and also for preclinical evaluation of new agents for its therapy.

Rouam S, Moreau T, Broët P
Identifying common prognostic factors in genomic cancer studies: a novel index for censored outcomes.
BMC Bioinformatics. 2010; 11:150 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: With the growing number of public repositories for high-throughput genomic data, it is of great interest to combine the results produced by independent research groups. Such a combination allows the identification of common genomic factors across multiple cancer types and provides new insights into the disease process. In the framework of the proportional hazards model, classical procedures, which consist of ranking genes according to the estimated hazard ratio or the p-value obtained from a test statistic of no association between survival and gene expression level, are not suitable for gene selection across multiple genomic datasets with different sample sizes. We propose a novel index for identifying genes with a common effect across heterogeneous genomic studies designed to remain stable whatever the sample size and which has a straightforward interpretation in terms of the percentage of separability between patients according to their survival times and gene expression measurements.
RESULTS: The simulations results show that the proposed index is not substantially affected by the sample size of the study and the censoring. They also show that its separability performance is higher than indices of predictive accuracy relying on the likelihood function. A simulated example illustrates the good operating characteristics of our index. In addition, we demonstrate that it is linked to the score statistic and possesses a biologically relevant interpretation.The practical use of the index is illustrated for identifying genes with common effects across eight independent genomic cancer studies of different sample sizes. The meta-selection allows the identification of four genes (ESPL1, KIF4A, HJURP, LRIG1) that are biologically relevant to the carcinogenesis process and have a prognostic impact on survival outcome across various solid tumors.
CONCLUSION: The proposed index is a promising tool for identifying factors having a prognostic impact across a collection of heterogeneous genomic datasets of various sizes.

La Starza R, Brandimarte L, Pierini V, et al.
A NUP98-positive acute myeloid leukemia with a t(11;12)(p15;q13) without HOXC cluster gene involvement.
Cancer Genet Cytogenet. 2009; 193(2):109-11 [PubMed] Related Publications
We report a case of adult acute myeloid leukemia with a new t(11;12)(p15;q13) underlying a NUP98 rearrangement without HOXC cluster gene involvement. We designed a specific double-color double-fusion FISH assay to discriminate between this t(11;12)(p15;q13) and those producing NUP98-HOXC11 or NUP98-HOXC13. Our fluorescence in situ hybridization (FISH) showed that putative candidate partners mapping 600 kilobases centromeric to HOXC were RARG (retinoic acid receptor gamma), MFSD5 (major facilitator superfamily domain containing 5), and ESPL1 (extra spindle pole bodies homolog 1). It is noteworthy that so far only ESPL1 has been implicated in human cancers. This FISH assay is useful for diagnostic screening of NUP98-positive leukemias.

Farina AR, Tacconelli A, Cappabianca L, et al.
The alternative TrkAIII splice variant targets the centrosome and promotes genetic instability.
Mol Cell Biol. 2009; 29(17):4812-30 [PubMed] Free Access to Full Article Related Publications
The hypoxia-regulated alternative TrkAIII splice variant expressed by human neuroblastomas exhibits oncogenic potential, driven by in-frame exon 6 and 7 alternative splicing, leading to omission of the receptor extracellular immunoglobulin C(1) domain and several N-glycosylation sites. Here, we show that the TrkAIII oncogene promotes genetic instability by interacting with and exhibiting catalytic activity at the centrosome. This function depends upon intracellular TrkAIII accumulation and spontaneous interphase-restricted activation, in cytoplasmic tyrosine kinase (tk) domain orientation, predominantly within structures that closely associate with the fully assembled endoplasmic reticulum intermediate compartment and Golgi network. This facilitates TrkAIII tk-mediated binding of gamma-tubulin, which is regulated by endogenous protein tyrosine phosphatases and geldanamycin-sensitive interaction with Hsp90, paving the way for TrkAIII recruitment to the centrosome. At the centrosome, TrkAIII differentially phosphorylates several centrosome-associated components, increases centrosome interaction with polo kinase 4, and decreases centrosome interaction with separase, the net results of which are centrosome amplification and increased genetic instability. The data characterize TrkAIII as a novel internal membrane-associated centrosome kinase, unveiling an important alternative mechanism to "classical" cell surface oncogenic receptor tk signaling through which stress-regulated alternative TrkAIII splicing influences the oncogenic process.

Brendle A, Brandt A, Johansson R, et al.
Single nucleotide polymorphisms in chromosomal instability genes and risk and clinical outcome of breast cancer: a Swedish prospective case-control study.
Eur J Cancer. 2009; 45(3):435-42 [PubMed] Related Publications
Chromosomal instability (CIN) is a major characteristic of many cancers. We investigated whether putatively functional single nucleotide polymorphisms (SNPs) in genes related to CIN (CENPF, ESPL1, NEK2, PTTG1, ZWILCH, ZWINT) affect breast cancer (BC) risk and clinical outcome in a Swedish cohort of 749 incident BC cases with detailed clinical data and up to 15 years of follow-up and 1493 matched controls. As a main observation, carriers of the A allele of the CENPF SNP rs438034 had a worse BC-specific survival compared to the wild type genotype GG carriers (hazard ratio (HR) 2.65, 95% confidence interval (CI) 1.19-5.90), although they were less likely to have regional lymph node metastases (odds ratio (OR) 0.71, 95% CI 0.51-1.01) and tumours of stage II-IV (OR 0.73, 95% CI 0.54-0.99). As there is increasing evidence that CENPF is associated with poor prognosis in patients with primary BC, further independent studies are needed to clarify the importance of genetic variation in the CENPF gene in the clinic.

Yu R, Cruz-Soto M, Li Calzi S, et al.
Murine pituitary tumor-transforming gene functions as a securin protein in insulin-secreting cells.
J Endocrinol. 2006; 191(1):45-53 [PubMed] Related Publications
Human pituitary tumor-transforming gene 1 (PTTG1) encodes a securin protein critically important in regulating chromosome separation. Murine PTTG (mPTTG) is 66% homologous to human PTTG1 and PTTG-null (PTTG-/-) mice exhibit pancreatic beta-cell hypoplasia and abnormal nuclear morphology with resultant diabetes. As we show that ductal beta-cell neogenesis is intact in PTTG-/- mice, we explored mechanism for defective beta-cell replication. We tested whether mPTTG exhibits securin properties in mouse insulin-secreting insulinoma MIN6 cells, using a live-cell system to monitor mitosis in cells transfected with an enhanced green fluorescent protein (EGFP)-tagged mPTTG conjugate (mPTTG-EGFP). To fulfill the criteria for securin properties, the protein should undergo degradation immediately before the metaphase-to-anaphase transition when expression levels are low, and should inhibit metaphase-to-anaphase transition when expression levels are high. EGFP itself did not undergo degradation throughout mitosis and high levels of EGFP per se did not affect normal mitosis progression (n=25). However, mPTTG-EGFP was degraded 2 min before the metaphase-to-anaphase transition when expression levels were low (n=19), and high mPTTG-EGFP levels blocked metaphase-to-anaphase transition in 13 cells. mPTTG-EGFP inhibited MIN6 cell proliferation and caused apoptosis. Immunocoprecipitation demonstrated binding of mPTTG-EGFP and separase. These results show that mPTTG exhibits properties consistent with a murine securin in insulin-secreting mouse cells and mPTTG overexpression inhibits cell proliferation, suggesting that defective beta-cell proliferation observed in PTTG-/- mice is likely due to abnormal cell-cycle progression.

Bae I, Rih JK, Kim HJ, et al.
BRCA1 regulates gene expression for orderly mitotic progression.
Cell Cycle. 2005; 4(11):1641-66 [PubMed] Related Publications
Germline mutations of the BRCA1 gene confer an increased risk for breast cancer and ovarian cancer. To study the contribution of BRCA1 to sporadic cancers, which often exhibit reduced BRCA1 expression, we tested the effect of knocking down BRCA1 on gene expression in human prostate (DU-145) and breast (MCF-7) cancer cells. DNA microarray and confirmatory RNA analyses revealed that BRCA1 small interfering (si) RNA caused down-regulation of multiple genes implicated in the mitotic spindle checkpoint (eg., BUB1B, HEC, and STK6), chromosome segregation (eg., ESPL1, NEK2, and PTTG1), centrosome function (eg., ASPM), cytokinesis (eg., PRC1, PLK, and KNSL2), and the progression into and through mitosis (eg., CDC2, and CDC20). Cells treated with BRCA1-siRNA showed attenuation of the mitotic spindle checkpoint; but not several G2 checkpoints. Finally, BRCA1 knockdown caused the accumulation of multinucleated cells, suggesting a defect in cytokinesis. We conclude that BRCA1 regulates gene expression for orderly mitotic progression.

Hainsworth PJ, Raphael KL, Stillwell RG, et al.
Rearrangement of chromosome 1p in breast cancer correlates with poor prognostic features.
Br J Cancer. 1992; 66(1):131-5 [PubMed] Free Access to Full Article Related Publications
In a cytogenetic study of breast cancer biopsies, clonal abnormalities of chromosome 1p were identified in 56% (14) of 25 informative patients. Translocations predominated, involving 1p22 (n = 1), 1p35 (n = 1) or 1p36 (n = 10) breakpoints. Chromosome 1p abnormalities were associated with estrogen receptor (ER) negativity (P = 0.03, 2-tailed Fisher Exact Probability test), high histological grade (P = 0.02, 2-tailed Mann-Whitney U-test) and an unfavourable Melbourne Prognostic Score (NEPA P = 0.02, SEPA P = 0.04, 2-tailed Mann-Whitney U-tests). These findings are consistent with the possibility that a gene located on chromosome 1p is implicated in tumour progression.

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