scholarly journals Integrated Genome Wide Association Study (GWAS) Identifies SNPs Associated with Outcome in Pediatric AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2758-2758
Author(s):  
Abdelrahman H Elsayed ◽  
Huiyun Wu ◽  
Xueyuan Cao ◽  
Soheil Meshinchi ◽  
Raul Ribeiro ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Solid Tumors ◽  
Rna Binding ◽  
Prognostic Significance ◽  
Integrated Analysis ◽  
Call Rate ◽  
Multiple Snps ◽  
Genome Wide ◽  
A Genome ◽  
Pediatric Aml

Abstract Acute myeloid leukemia (AML) treatment response remains poorly understood. Although multiple studies have focused on understanding the transcriptomic and epigenetic landscape of AML, a genome-wide analysis of SNPs in pediatric AML has not yet been investigated in depth. Thus, we sought to identify genetic variants predictive of AML response, relapse, and survival in pediatric AML patients. For this study, we generated genome-wide SNP data patients (n=160) treated on the multicenter AML02 clinical trial (ClinicalTrials.gov Identifier: NCT00136084) using Infinium Omni 2.5M Exome Beadchip. Standard GWAS QC procedure was followed in order to remove SNPs with call rate < 95%, monomorphic SNPs, SNPs with MAF<5% and samples with call rate<95%. Following QC, a risk-adjusted multi-outcome integrative GWAS was performed to identify SNPs associated with minimal residual disease (MRD) following induction I, relapse-free survival (RFS) and overall survival (OS). We performed a risk-adjusted analysis to identify 21 SNPs mapping to 14 genes at an endpoint-integrative p value <2x10-5. Table 1 provides list of genes with SNPs significantly associated with MRD, RFS, OS as well as in the integrated analysis at <2x10-5. Of interest multiple SNPs in DICER1, which is a key enzyme required for the biogenesis of microRNAs and small interfering RNAs were significantly associated with clinical outcome with promise integrated analysis at p = 0.000011, supported by associations with MRD, RFS and OS at p <0.002 (Figure 1A). DICER1 is over-expressed in AML with its expression under the influence of hematopoietic transcript factor, GATA1. RAI14, a retinoic acid induced 14 is a prognostic marker of poor response in solid tumors and has been associated with development of drug resistance. Multiple SNPs in RAI14 were significantly associated with clinical endpoints. Figure 1B shows RAI14 SNP rs336474 with C allele significantly associated with better RFS (p= 0.027) and OS (p=0.007), with an integrated p= 0.000004. SNP in upstream of RBFOX1, a RNA binding fox-1 homolog 1 and within intron of GRIN2A, glutamate ionotropic receptor NMDA type subunit 2A were significantly associated with MRD, RFS and OS (all p<0.005) and integrated p =0.00001 (Figure 1C). SNPs within genes involved in pyrimidine metabolism such as UPP2, a uridine phosphorylase; tumor suppressor genes such as JPH3, which codes for junctophilin; LILRB4 which encodes for a Leukocyte Immunoglobulin Like Receptor B4, that regulates inflammatory responses and cytotoxicity; HACE1 a potential tumor suppressor involved in the solid tumors pathophysiology; ANK2, an ankyrin family protein with role in cell proliferation and motility; BIRC8, which is implicated in CML disease progression etc. In conclusion, our results demonstrate significance of genome-wide investigation of SNPs to identify novel and clinically relevant SNPs of prognostic significance in childhood AML. We will present the in depth results of our integrated GWAS analysis as well as validation in independent patient cohorts. In summary, our results constitute one of the first integrated GWAS analyses to identify SNPs of prognostic significance in pediatric AML. Acknowledgments: We are thankful for funding from NIH R01-CA139246 and ALSAC. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Genome-Wide Association Study for Hypertensive Kidney Disease in Korean Men

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 751
Author(s):  
Hye-Rim Kim ◽  
Hyun-Seok Jin ◽  
Yong-Bin Eom
Keyword(s):  
Blood Pressure ◽  
Kidney Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Integrated Analysis ◽  
Eqtl Analysis ◽  
Strong Linkage Disequilibrium ◽  
Genome Wide ◽  
A Genome

Hypertension is one of the major risk factors for chronic kidney disease (CKD), and the coexistence of hypertension and CKD increases morbidity and mortality. Although many genetic factors have been identified separately for hypertension and kidney disease, studies specifically focused on hypertensive kidney disease (HKD) have been rare. Therefore, this study aimed to identify loci or genes associated with HKD. A genome-wide association study (GWAS) was conducted using two Korean cohorts, the Health Examinee (HEXA) and Korean Association REsource (KARE). Consequently, 19 single nucleotide polymorphisms (SNPs) were found to be significantly associated with HKD in the discovery and replication phases (p < 5 × 10−8, p < 0.05, respectively). We further analyzed HKD-related traits such as the estimated glomerular filtration rate (eGFR), creatinine, blood urea nitrogen (BUN), systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the 14q21.2 locus, which showed a strong linkage disequilibrium (LD). Expression quantitative trait loci (eQTL) analysis was also performed to determine whether HKD-related SNPs affect gene expression changes in glomerular and arterial tissues. The results suggested that the FANCM gene may affect the development of HKD through an integrated analysis of eQTL and GWAS and was the most significantly associated candidate gene. Taken together, this study indicated that the FANCM gene is involved in the pathogenesis of HKD. Additionally, our results will be useful in prioritizing other genes for further experiments.

Abstract 12192: MBNL1 Directly Regulates the Alternative Splicing of mRNAs That Promote Myofibroblast Differentiation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jennifer Davis ◽  
Michelle Sargent ◽  
Jianjian Shi ◽  
Lei Wei ◽  
Maurice S Swanson ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Cardiac Injury ◽  
Myofibroblast Differentiation ◽  
Genome Wide ◽  
A Genome

Rationale: During the cardiac injury response fibroblasts differentiate into myofibroblasts, a cell type that enhances extracellular matrix production and facilitates ventricular remodeling. To better understand the molecular mechanisms whereby myofibroblasts are generated in the heart we performed a genome-wide screen with 18,000 cDNAs, which identified the RNA-binding protein muscleblind-like splicing regulator 1 (MBNL1), suggesting a novel association between mRNA alternative splicing and the regulation of myofibroblast differentiation. Objective: To determine the mechanism whereby MBNL1 regulates myofibroblast differentiation and the cardiac fibrotic response. Methods and Results: Confirming the results from our genome wide screen, adenoviral-mediated overexpression of MBNL1 promoted transformation of rat cardiac fibroblasts and mouse embryonic fibroblasts (MEFs) into myofibroblasts, similar to the level of conversion obtained by the profibrotic agonist transforming growth factor β (TGFβ). Antithetically, Mbnl1 -/- MEFs were refractory to TGFβ-induced myofibroblast differentiation. MBNL1 expression is induced in transforming fibroblasts in response to TGFβ and angiotensin II. These results were extended in vivo by analysis of dermal wound healing, a process dependent on myofibroblast differentiation and their proper activity. By day 6 control mice had achieved 82% skin wound closure compared with only 40% in Mbnl1 -/- mice. Moreover, Mbnl1 -/- mice had reduced survival following myocardial infarction injury due to defective fibrotic scar formation and healing. High throughput RNA sequencing (RNAseq) and RNA immunoprecipitation revealed that MBNL1 directly regulates the alternative splicing of transcripts for myofibroblast signaling factors and cytoskeletal-assembly elements. Functional analysis of these factors as mediators of MBNL1 activity is also described here. Conclusions: Collectively, our data suggest that MBNL1 coordinates myofibroblast transformation by directly mediating the alternative splicing of an array of mRNAs encoding differentiation-specific signaling transcripts, which then alter the fibroblast proteome for myofibroblast structure and function.

Genome-Wide Studies in Sickle Cell Anemia Show Associations Between SNPs in the Olfactory Receptor Gene Cluster and Fetal Hemoglobin Concentration.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 821-821 ◽  
Author(s):  
Nadia Timofeev ◽  
Jacqueline N. Milton ◽  
Stephen W Hartley ◽  
Richard Sherva ◽  
Paola Sebastiani ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Olfactory Receptor ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Call Rate ◽  
Globin Gene Cluster ◽  
Genome Wide ◽  
A Genome ◽  
Or Genes ◽  
Genome Wide Significance

Abstract Abstract 821 Fetal hemoglobin (HbF) is the major modulator of sickle cell anemia (SCA, homozygosity for HBB glu6val) severity. In a genome-wide association study in African Americans with SCA we sought to identify single nucleotide polymorphisms (SNPs) associated with HbF concentrations. A discovery sample of 848 African American subjects and a primary replication study of 305 subjects were examined. DNA was genotyped with the Illumina Human610-Quad SNP; some replication set samples were genotyped with the Sentrix HumanCNV370 or the 317K array. For quality control we excluded SNPs with a call rate less than 95%; we excluded subjects with a call rate less than 93%; identity by descent measurements were computed to identify related individuals who were removed from analysis; we inferred gender using chromosome X SNPs removing subjects with gender mismatches; a genome-wide principal components analysis found no association between the phenotype and the first 10 principal components, indicating that the results were not affected by population substructure. The association between HbF and the genotype for each SNP was tested with a multiple linear regression analysis adjusting for sex and assuming an additive model using the software PLINK. SCA is a rare disease in developed countries and assembling large data sets is not feasible. Therefore, true associations with limited effect sizes might not reach “genome-wide” significance of 10-08. To identify genes enriched with moderately strong associations, we developed a SNP set enrichment analysis (SSEA) that computes the probability that a set of SNPs is selected as significant by chance and scores each gene by this probability. Two SNPs exceeded the strict genome-wide significance: SNP rs5006884 in a novel region on chromosome 11 upstream of the β-globin gene cluster locus control region (LCR) containing the olfactory receptor (OR) genes OR51B5 and OR51B6; SNP rs766432 in BCL11A, previously found to be associated with HbF in several different populations. Data for SNPs common to the discovery and replication sets were combined and analyzed jointly. Similarity of the regression beta coefficients across datasets and increased significance of the p-values compared with those observed in the analyses of individual datasets provide additional evidence that the associations were consistent in the both datasets. The Q-Q plot and a genomic inflation factor of 1.003 both suggest that the test statistics are not inflated and are distributed appropriately. SSEA identified 2 OR genes (OR51B5, OR51B6) and BCL11A as enriched in both the discovery and replication sets. The most significant SNP in the OR region (rs5006884) and BCL11A (rs766432) explained 15.6% of the variability in HbF. Also, in the interval Xp 22.2-22.3 we found moderate, but not “genome-wide” significance for 1 SNP in Xp22.2. Phylogenetic conservation of some OR genes and their flanking sequences suggests that this region might also have a role in controlling expression within the β-globin gene-like complex. Low linkage disequilibrium between SNPs in the β-globin locus and the OR genes suggests that one or more variants in the OR genes independently regulate HbF. The top SNP in the OR51B5/OR51B6 locus, rs5006884, was still associated with HbF (p = 1.5E-05) in a model adjusting both for sex and rs2071348, a SNP in tight LD with the HBG2 5' -158 C-T SNP, giving further evidence that the OR region provides important information in addition to the SNPs in the β-globin gene-like complex. Polymorphisms in the upstream OR region might conceivably modulate HbF levels by altering chromatin structure within the β-globin gene cluster. Conserved binding sites for the transcription factor CTCF flank the β-globin gene cluster and evidence suggests that these sites function as insulators. Polymorphisms in this region might affect the actions of enhancers, possibly through their effects on CTCF binding its receptors, thereby affecting the interaction of the globin genes with enhancers in the OR regions. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CAR T cells for solid tumors: genome-wide dysfunction signature confirms value of c-Jun overexpression, but signals heterogeneity

2020 ◽  
Author(s):  
Mostapha Benhenda
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Therapy ◽  
Cell Dysfunction ◽  
Car T Cells ◽  
Genome Wide ◽  
A Genome ◽  
Car T ◽  
T Cell Dysfunction

AbstractChimeric antigen receptor (CAR) T cells still have limited effects in cancer, and especially in solid tumors, due to T cell dysfunction and exhaustion. CAR T cells overexpressing c-Jun (JUN CAR T cells) have been introduced to solve this problem. In this paper, we analyze JUN CAR T cells scRNA-seq data in solid tumors, by applying a genome-wide signature of T cell dysfunction, TID. This signature comes from the bulk RNA-seq signature TIDE, introduced to predict immune checkpoint inhibitor response. Our analysis confirms that on average, JUN CAR T cells are less dysfunctional than non-JUN CAR T cells. However, it also shows heterogeneity within JUN CAR T cells, which brings uncertainty about possible tumor resistance. We conclude that genome-wide dysfunction signature TID helps de-risking CAR T cell therapy for solid tumors.

scholarly journals Interactions of CAF1-NOT complex components from Trypanosoma brucei

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 858 ◽  
Author(s):  
Chaitali Chakraborty ◽  
Abeer Fadda ◽  
Esteban Erben ◽  
Smiths Lueong ◽  
Jörg Hoheisel ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Animal Cells ◽  
Genome Wide ◽  
A Genome ◽  
Fragment Library ◽  
F Box Protein ◽  
Cyclin F ◽  
Potential Interactions

The CAF1-NOT complex of Trypanosoma brucei, like that of other eukaryotes, contains several NOT proteins (NOT1, NOT3, NOT3/5, NOT10, and NOT11), NOT9/CAF40, and the CAF1 deadenylase, which targets 3' poly(A) tails. Again like other eukaryotes, deadenylation is the first step in the degradation of most trypanosome mRNAs. In animal cells, destruction of unstable mRNAs is accelerated by proteins that bind the RNA in a sequence-specific fashion, and also recruit the CAF1-NOT complex. However, this has not yet been demonstrated for T. brucei. To find interaction partners for the trypanosome NOT complex, we did a genome-wide yeast two-hybrid screen, using a random shotgun protein fragment library, with the subunits CAF40, NOT2, NOT10 and NOT11 as baits. To assess interaction specificity, we compared the results with those from other trypanosome proteins, including the cyclin-F-box protein CFB1. The yeast 2-hybrid screen yielded four putatively interacting proteins for NOT2, eleven for NOT11, but only one for NOT9/CAF40. Both CFB1 and NOT10 had over a hundred potential interactions, indicating a lack of specificity. Nevertheless, a detected interaction between NOT10 and NOT11 is likely to be genuine. We also identified proteins that co-purify with affinity tagged NOT9/CAF40 by mass spectrometry. The co-purifying proteins did not include the 2-hybrid partner, but the results confirmed NOT9/CAF40 association with the CAF1-NOT complex, and suggested interactions with expression-repressing RNA-binding proteins (ZC3H8, ZC3H30, and ZC3H46) and the deadenylase PARN3.

scholarly journals Integrative analysis of genome-wide DNA methylation and single-nucleotide polymorphism identified ACSM5 as a suppressor of lumbar ligamentum flavum hypertrophy

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Yanlin Cao ◽  
Yenan Zhan ◽  
Sujun Qiu ◽  
Zhong Chen ◽  
Kaiqin Gong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Nucleotide Polymorphism ◽  
Ligamentum Flavum ◽  
Global Analysis ◽  
Integrated Analysis ◽  
Polymorphism Analysis ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide ◽  
A Genome

Abstract Background Hypertrophy of ligamentum flavum (HLF) is a common lumbar degeneration disease (LDD) with typical symptoms of low back pain and limb numbness owing to an abnormal pressure on spinal nerves. Previous studies revealed HLF might be caused by fibrosis, inflammatory, and other bio-pathways. However, a global analysis of HLF is needed severely. Methods A genome-wide DNA methylation and single-nucleotide polymorphism analysis were performed from five LDD patients with HLF and five LDD patients without HLF. Comprehensive integrated analysis was performed using bioinformatics analysis and the validated experiments including Sanger sequencing, methylation-specific PCR, qPCR and ROC analysis. Furthermore, the function of novel genes in ligamentum flavum cells (LFCs) was detected to explore the molecular mechanism in HLF through knock down experiment, overexpression experiment, CCK8 assay, apoptosis assay, and so on. Results We identified 69 SNP genes and 735 661 differentially methylated sites that were enriched in extracellular matrix, inflammatory, and cell proliferation. A comprehensive analysis demonstrated key genes in regulating the development of HLF including ACSM5. Furthermore, the hypermethylation of ACSM5 that was mediated by DNMT1 led to downregulation of ACSM5 expression, promoted the proliferation and fibrosis, and inhibited the apoptosis of LFCs. Conclusion This study revealed that DNMT1/ACSM5 signaling could enhance HLF properties in vitro as a potential therapeutic strategy for HLF.

scholarly journals Systematic discovery and functional interrogation of SARS-CoV-2 viral RNA-host protein interactions during infection

2020 ◽  
Author(s):  
Ryan A. Flynn ◽  
Julia A. Belk ◽  
Yanyan Qi ◽  
Yuki Yasumoto ◽  
Cameron O. Schmitz ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Protein Interactions ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Viral Rna ◽  
Host Protein ◽  
List Type ◽  
Genome Wide ◽  
A Genome

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a pandemic with growing global mortality. There is an urgent need to understand the molecular pathways required for host infection and anti-viral immunity. Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), we identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Integration of this data with viral ChIRP-MS data from three other positive-sense RNA viruses defined pan-viral and SARS-CoV-2-specific host interactions. Functional interrogation of these factors with a genome-wide CRISPR screen revealed that the vast majority of viral RNA-binding proteins protect the host from virus-induced cell death, and we identified known and novel anti-viral proteins that regulate SARS-CoV-2 pathogenicity. Finally, our RNA-centric approach demonstrated a physical connection between SARS-CoV-2 RNA and host mitochondria, which we validated with functional and electron microscopy data, providing new insights into a more general virus-specific protein logic for mitochondrial interactions. Altogether, these data provide a comprehensive catalogue of SARS-CoV-2 RNA-host protein interactions, which may inform future studies to understand the mechanisms of viral pathogenesis, as well as nominate host pathways that could be targeted for therapeutic benefit.Highlights· ChIRP-MS of SARS-CoV-2 RNA identifies a comprehensive viral RNA-host protein interaction network during infection across two species· Comparison to RNA-protein interaction networks with Zika virus, dengue virus, and rhinovirus identify SARS-CoV-2-specific and pan-viral RNA protein complexes and highlights distinct intracellular trafficking pathways· Intersection of ChIRP-MS and genome-wide CRISPR screens identify novel SARS-CoV-2-binding proteins with pro- and anti-viral function· Viral RNA-RNA and RNA-protein interactions reveal specific SARS-CoV-2-mediated mitochondrial dysfunction during infection

Abstract 051: Genome-wide Association Study Identifies 12 Loci for Habitual Consumption of Bitter and Sweet Beverages

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Victor W Zhong ◽  
Sandra Sanchez-Roige ◽  
Peter Kraft ◽  
Rob M Van Dam ◽  
Daniel I Chasman ◽  
...  
Keyword(s):  
Chronic Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genetic Model ◽  
Taste Perception ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Multiple Snps ◽  
Genome Wide ◽  
A Genome

Introduction: Widely consumed beverages (e.g., soft drinks, coffee, tea) are critical sources of energy, added sugar and phytochemicals and are associated with obesity and chronic disease. Taste perception and preferences are highly heritable and strong determinants of food and beverage choice. We aimed to identify novel loci underlying habitual bitter and sweet beverage intake. Methods: We performed a genome-wide association study (GWAS) of self-reported bitter and sweet beverage intake in participants of European ancestry in the UK Biobank. Diet was assessed via multiple 24-h diet recalls (n=84703, subset) or questionnaire (n=335909, all). Bitter beverage intake was the sum of coffee, tea and grapefruit juice. Sweet beverage intake was the sum of artificially and sugar sweetened beverages and other fruit juice. Multivariable linear regression under an additive genetic model was applied. GW-significant (P < 5х10 -8 ) SNPs were followed-up for replication in independent studies of European ancestry. Results: Multiple SNPs spanning 11 loci were associated with bitter beverage intake (P <5х10 -8 , Table 1), and at least 5 of them reflected the caffeine content of coffee and tea. Multiple SNPs in the obesity candidate gene FTO were associated with sweet beverage intake (P <5х10 -8 ). The effect size per allele ranged from 0.02 to 0.2 cup per day. Loci in/near AHR, CYP1A2, and FTO were associated with both bitter and sweet beverage intake but in opposite directions. Replication efforts are ongoing. So far, associations at all loci, except 1q25.2 and 2q36.2, were replicated (P range: 0.04 to 1.8x10 -8 ) in independent studies (n=17322) which provided 80% power for replicating 8 of these 12 loci at P=0.05. Conclusions: Loci linked to caffeine metabolism and obesity predisposition rather than taste are major determinants of beverage intake. These and other identified loci have been linked to chronic disease and risk factors, suggesting causal or pleiotropic effects. Our findings have potential public health and methodological implications.

scholarly journals A genome-wide microRNA screen identifies regulators of tetraploid cell proliferation

2018 ◽  
Vol 29 (14) ◽  
pp. 1682-1692 ◽  
Author(s):  
Marc A. Vittoria ◽  
Elizabeth M. Shenk ◽  
Kevin P. O’Rourke ◽  
Amanda F. Bolgioni ◽  
Sanghee Lim ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hippo Pathway ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Proliferative Capacity ◽  
Tetraploid Cell ◽  
Genome Doubling ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Studies

Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ∼40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, nontransformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these antiproliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive gain-of-function genome-wide screen to identify microRNAs (miRNAs) that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g., miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g., miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via down-regulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.

scholarly journals The tumor suppressor CDKN3 controls mitosis

2013 ◽  
Vol 201 (7) ◽  
pp. 997-1012 ◽  
Author(s):  
Grzegorz Nalepa ◽  
Jill Barnholtz-Sloan ◽  
Rikki Enzor ◽  
Dilip Dey ◽  
Ying He ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Spindle Checkpoint ◽  
Mitotic Exit ◽  
Small Interfering Rnas ◽  
Genome Wide ◽  
A Genome ◽  
Signaling Axis ◽  
Normal Mitosis ◽  
Early Mitosis

Mitosis is controlled by a network of kinases and phosphatases. We screened a library of small interfering RNAs against a genome-wide set of phosphatases to comprehensively evaluate the role of human phosphatases in mitosis. We found four candidate spindle checkpoint phosphatases, including the tumor suppressor CDKN3. We show that CDKN3 is essential for normal mitosis and G1/S transition. We demonstrate that subcellular localization of CDKN3 changes throughout the cell cycle. We show that CDKN3 dephosphorylates threonine-161 of CDC2 during mitotic exit and we visualize CDC2pThr-161 at kinetochores and centrosomes in early mitosis. We performed a phosphokinome-wide mass spectrometry screen to find effectors of the CDKN3-CDC2 signaling axis. We found that one of the identified downstream phosphotargets, CKβ phosphorylated at serine 209, localizes to mitotic centrosomes and controls the spindle checkpoint. Finally, we show that CDKN3 protein is down-regulated in brain tumors. Our findings indicate that CDKN3 controls mitosis through the CDC2 signaling axis. These results have implications for targeted anticancer therapeutics.

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