DOCSLIB.ORG

Original Article Variants in SNAI1, AMDHD1 and CUBN in Vitamin D

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Original Article Variants in SNAI1, AMDHD1 and CUBN in Vitamin D Am J Cancer Res 2020;10(7):2160-2173 www.ajcr.us /ISSN:2156-6976/ajcr0116772 Original Article Variants in SNAI1, AMDHD1 and CUBN in vitamin D pathway genes are associated with breast cancer risk: a large-scale analysis of 14 GWASs in the DRIVE study Haijiao Wang1,2,3*, Lingling Zhao2,3,4*, Hongliang Liu2,3, Sheng Luo5, Tomi Akinyemiju3, Shelley Hwang6, Qingyi Wei2,3,7 1Department of Gynecology Oncology, The First Hospital of Jilin University, Changchun 130021, Jilin, China; 2Duke Cancer Institute, Duke University Medical Center, Durham 27710, NC, USA; 3Department of Population Health Sciences, Duke University School of Medicine, Durham 27710, NC, USA; 4Cancer Center, The First Hospital of Jilin University, Changchun 130021, Jilin, China; 5Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham 27710, NC, USA; 6Department of Surgery, Duke University School of Medicine, Durham 27710, NC, USA; 7Department of Medicine, Duke University School of Medicine, Durham 27710, NC, USA. *Equal contributors. Received June 22, 2020; Accepted June 30, 2020; Epub July 1, 2020; Published July 15, 2020 Abstract: Vitamin D has a potential anticarcinogenic role, possibly through regulation of cell proliferation and differ- entiation, stimulation of apoptosis, immune modulation and regulation of estrogen receptor levels. Because breast cancer (BC) risk varies among individuals exposed to similar risk factors, we hypothesize that genetic variants in the vitamin D pathway genes are associated with BC risk. To test this hypothesis, we performed a larger meta-analysis using 14 published GWAS datasets in the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Study. We assessed associations between 2,994 (237 genotyped in the DRIVE study and 2,757 imputed from the 1000 Genomes Project) single nucleotide polymorphisms (SNPs) in 33 vitamin D pathway genes and BC risk. In unconditional logistic regression analysis, we found 11 noteworthy SNPs to be associated with BC risk after multiple comparison correction by the Bayesian false-discovery probability method (<0.80). In stepwise logistic regression analysis, with adjustment for age, principal components and previously published SNPs in the same study popula- tions, we identified three independent SNPs (SNAI1 rs1047920 C>T, AMDHD1 rs11826 C>T and CUBN rs3914238 C>T) to be associated with BC risk (P = 0.0014, 0.0020 and 0.0022, respectively). Additional expression quantita- tive trait loci analysis revealed that the rs73276407 A allele, in a high LD with the rs1047920 T allele, was associ- ated with decreased SNAI1 mRNA expression levels, while the rs11826 T allele was significantly associated with elevated AMDHD1 mRNA expression levels. Once replicated by other investigators and additional mechanistic stud- ies, these genetic variants may serve as new biomarkers for susceptibility to BC. Keywords: Breast cancer susceptibility, single nucleotide polymorphism, Vitamin D, expression quantitative trait loci analysis Introduction treatments, the incidence rate is still rising each year (https://seer.cancer.gov/statfacts/ Breast cancer (BC) is the most common malig- html/breast.html). Therefore, it is urgent to nancy and the second leading cause of cancer search for additional risk factors to identify indi- deaths in women in the United States [1]. In viduals who are at high risk of BC for early 2019, there were about 268,600 cases esti- screening and prevention that will reduce the mated to be diagnosed with BC in the United incidence and mortality of BC. States, accounting for 15.2% of all new cancer cases, while an estimated 41,760 individuals There are several risk factors for developing died from BC, accounting for 6.9% of all cancer female BC, including aging, unhealthy lifestyle, deaths [2]. Although the mortality of BC has estrogen status, germ-line mutations and fami- declined due to early detection and advanced ly history [3]. Genetic variation, such as single SNPs in vitamin D pathway and breast cancer risk nucleotide polymorphisms (SNPs) as reported genes are associated with BC risk, and we test- by genome-wide association studies (GWASs) is ed this hypothesis in a larger meta-analysis of believed to contribute to BC risk. However, the 53,107 BC case-control study subjects with risk contribution of individual SNPs is consid- genotyping datasets from 14 previously pub- ered small [4] as identified in the hypothesis- lished GWAS datasets in the DRIVE study. free GWASs, which have always focused on the most important SNPs with a rigorous P value Materials and methods after the most stringent multiple test correc- tion. Furthermore, few of the GWAS-identified Study subjects SNPs are found to be functionally annotated. In the post-GWAS era, hypothesis-driven and The subjects in this case-control meta-analysis combined analyses of all published GWASs are were from 14 out of 17 previously published BC performed to identify cancer-risk associated GWASs from the DRIVE study (phs001265. functional SNPs in a combination of pathway v1.p1), which is different from previously us- analysis, meta-analysis, and functional analy- ed by others named the DRIVE-Genome-Wide sis. With such a hypothesis-driven approach, Association meta-analysis (phs001263.v1.p1); investigators can focus on SNPs with potential and the details of the specific differences biological functions by using available genotyp- between the two studies have been previously ing data from previously published GWAS data- described [19]. The DRIVE study we used was sets with the hope to be able to identify truly one of five projects funded by the NCI’s Gene- cancer-risk associated functional variants. tic Associations and Mechanisms in Oncology (GAME-ON) in 2010. We removed three studi- Vitamin D is a fat-soluble steroid hormone es out of the 17 GWASs: one was “Women of obtained from both dietary sources and sun African Ancestry Breast Cancer Study (WAAB- exposure to ultraviolet B radiation, and once CS)”, because it was on African ancestry study present in the body, it regulates the expression with a relatively small study population, and of genes in many types of tissue [5-7]. In addi- the other two were “The Sister Study (SISTER)” tion, vitamin D may have a potential anticarci- and “the Two Sister Study (2 SISTER)”, becau- nogenic role, by regulating cell proliferation and se they had different research designs from differentiation, apoptosis, immune modulation others and used cases’ sisters as controls. As and estrogen receptor levels [8, 9]. Therefore, a result, all the subjects of European ancestry the vitamin D pathway plays a role in regulating in 14 GWAS studies were included in the fi- cell growth and immune function, relevant to nal analysis, including 28,758 BC cases and tumor progression. For example, studies have 24,349 controls, whose characteristics are demonstrated that the vitamin D pathway has presented in Supplementary Table 1. an effect on T cell function, monocyte/macro- phage differentiation and cytokine production These 14 GWASs included Breast Oncology [10-12]. Other studies have found that vitamin Galicia Network (BREOGAN); Copenhagen Ge- D may affect the pathogenesis, prognosis and neral Population Study (CGPS); Cancer Preven- survival of BC at the cellular level [13, 14]. tion Study-II Nutrition Cohort (CPSII); European Many epidemiological studies have also atte- Prospective Investigation Into Cancer and Nu- mpted to determine associations of vitamin D trition (EPIC); Melbourne Collaborative Cohort levels with risk and mortality of various types of Study (MCCS); Multiethnic Cohort (MEC); Na- cancer [15-17]. In a Brazilian study of post- shville Breast Health Study (NBHS); Nurses’ menopausal BC patients, low vitamin D levels Health Study (NHS); Nurses’ Health Study 2 were found to be a risk factor for individuals (NHS2); NCI Polish Breast Cancer Study (PBCS); negative for estrogen receptor with a higher The Prostate, Lung, Colorectal and Ovarian rate of cell proliferation and positive axillary Cancer Screening Trial (PLCO); Study of Epi- lymph node [18]. However, few studies have demiology and Risk factors in Cancer Heredi- comprehensively investigated the effect of ge- ty (SEARCH); Swedish Mammography Cohort netic variation in vitamin D pathway genes on (SMC); and Women’s Health Initiative (WHI). BC risk. Illumina Infinium OncoArray-500k BeadChip ge- notyping platforms were used for these GWAS Considering the importance of the vitamin D datasets, and information on both sex and age pathway in cancer development, we hypothe- at interview was obtained for all the subjects. size that genetic variants in vitamin D pathway For the cases, there were three other variables 2161 Am J Cancer Res 2020;10(7):2160-2173 SNPs in vitamin D pathway and breast cancer risk including age at diagnosis, estrogen receptor SNP, we calculated odds ratios (ORs) and 95% status, and tumor histology type; for age vari- confidence intervals (CIs) with adjustment for ables, we used the age at diagnosis for the covariates (age and PCs with significant asso- cases and the age at interview for the controls. ciations) by unconditional logistic regression. A written informed consent was obtained from We also adjusted for the four SNPs we previ- subjects by each of the original studies that ously published from the DRIVE Study to iden- were approved by the Institutional Review tify additional independent SNPs. A meta-anal- Boards of the Participating institutions. ysis was further performed using the
Load more

Recommended publications
  • Functional Characterization of the New 8Q21 Asthma Risk Locus
    Functional characterization of the new 8q21 Asthma risk locus Cristina M T Vicente B.Sc, M.Sc A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2017 Faculty of Medicine Abstract Genome wide association studies (GWAS) provide a powerful tool to identify genetic variants associated with asthma risk. However, the target genes for many allergy risk variants discovered to date are unknown. In a recent GWAS, Ferreira et al. identified a new association between asthma risk and common variants located on chromosome 8q21. The overarching aim of this thesis was to elucidate the biological mechanisms underlying this association. Specifically, the goals of this study were to identify the gene(s) underlying the observed association and to study their contribution to asthma pathophysiology. Using genetic data from the 1000 Genomes Project, we first identified 118 variants in linkage disequilibrium (LD; r2>0.6) with the sentinel allergy risk SNP (rs7009110) on chromosome 8q21. Of these, 35 were found to overlap one of four Putative Regulatory Elements (PREs) identified in this region in a lymphoblastoid cell line (LCL), based on epigenetic marks measured by the ENCODE project. Results from analysis of gene expression data generated for LCLs (n=373) by the Geuvadis consortium indicated that rs7009110 is associated with the expression of only one nearby gene: PAG1 - located 732 kb away. PAG1 encodes a transmembrane adaptor protein localized to lipid rafts, which is highly expressed in immune cells. Results from chromosome conformation capture (3C) experiments showed that PREs in the region of association physically interacted with the promoter of PAG1.
    [Show full text]
  • Downloaded from JASPAR (JASPAR ID: MA0527.1) Across All Identified Peaks Using the Matrix-Scan Module from RSAT [20]
    bioRxiv preprint doi: https://doi.org/10.1101/585653; this version posted March 24, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. ZBTB33 (Kaiso) methylated binding sites are associated with primed heterochromatin Quy Xiao Xuan Lin1, Khadija Rebbani1, Sudhakar Jha1,2, Touati Benoukraf1,3* 1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore 2Department of Biochemistry, National University of Singapore, Singapore, Singapore 3Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada *Correspondence to: Touati Benoukraf, Ph.D. Faculty of Medicine, Discipline of Genetics Cancer Science Institute of Singapore Craig L. Dobbin Genetics Research Centre National University of Singapore Room 5M317 Centre for Translational Medicine, Memorial University of Newfoundland 14 Medical Drive, #12-01 St. John's, NL A1B 3V6 Singapore 117599 Canada Phone: +1 (709) 864-6671 Email: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/585653; this version posted March 24, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Background: ZBTB33, also known as Kaiso, is a member of the zinc finger and BTB/POZ family. In contrast to many transcription factors, ZBTB33 has the ability to bind both a sequence-specific consensus and methylated DNA.
    [Show full text]
  • Transcription of Platelet-Derived Growth Factor Receptor a in Leydig Cells Involves Specificity Protein 1 and 3
    125 Transcription of platelet-derived growth factor receptor a in Leydig cells involves specificity protein 1 and 3 Francis Bergeron1, Edward T Bagu1 and Jacques J Tremblay1,2 1Reproduction, Perinatal and Child Health, CHUQ Research Centre, CHUL Room T1-49, 2705 Laurier Boulevard, Que´bec, Que´bec, Canada G1V 4G2 2Department of Obstetrics and Gynecology, Faculty of Medicine, Centre for Research in Biology of Reproduction, Universite´ Laval, Que´bec, Que´bec, Canada G1V 0A6 (Correspondence should be addressed to J J Tremblay; Email: [email protected]) Abstract Platelet-derived growth factor (PDGF) A is secreted by Sertoli cells and acts on Leydig precursor cells, which express the receptor PDGFRA, triggering their differentiation into steroidogenically active Leydig cells. There is, however, no information regarding the molecular mechanisms that govern Pdgfra expression in Leydig cells. In this study, we isolated and characterized a 2.2 kb fragment of the rat Pdgfra 50-flanking sequence in the TM3 Leydig cell line, which endogenously expresses Pdgfra. A series of 50 progressive deletions of the Pdgfra promoter was generated and transfected in TM3 cells. Using this approach, two regions (K183/K154 and K154/K105), each conferring 46% of Pdgfra promoter activity, were identified. To better define the regulatory elements, trinucleotide mutations spanning the K154/K105 region were introduced by site-directed mutagenesis in the context of the K2.2kb Pdgfra promoter. Mutations that altered the TCCGAGGGAAAC sequence at K138 bp significantly decreased Pdgfra promoter activity in TM3 cells. Several proteins from TM3 nuclear extracts were found to bind to this G(C/A) motif in electromobility shift assay.
    [Show full text]
  • Accompanies CD8 T Cell Effector Function Global DNA Methylation
    Global DNA Methylation Remodeling Accompanies CD8 T Cell Effector Function Christopher D. Scharer, Benjamin G. Barwick, Benjamin A. Youngblood, Rafi Ahmed and Jeremy M. Boss This information is current as of October 1, 2021. J Immunol 2013; 191:3419-3429; Prepublished online 16 August 2013; doi: 10.4049/jimmunol.1301395 http://www.jimmunol.org/content/191/6/3419 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/08/20/jimmunol.130139 Material 5.DC1 References This article cites 81 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/191/6/3419.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Global DNA Methylation Remodeling Accompanies CD8 T Cell Effector Function Christopher D. Scharer,* Benjamin G. Barwick,* Benjamin A. Youngblood,*,† Rafi Ahmed,*,† and Jeremy M.
    [Show full text]
  • 1,25 Dihydroxyvitamin D-Mediated Orchestration of Anticancer
    Kovalenko et al. BMC Genomics 2010, 11:26 http://www.biomedcentral.com/1471-2164/11/26 RESEARCH ARTICLE Open Access 1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostate epithelial cell line, RWPE1 Pavlo L Kovalenko1, Zhentao Zhang1, Min Cui1, Steve K Clinton2, James C Fleet1* Abstract Background: Prostate cancer is the second leading cause of cancer mortality among US men. Epidemiological evidence suggests that high vitamin D status protects men from prostate cancer and the active form of vitamin D, 1a,25 dihydroxyvitamin D3 (1,25(OH)2D) has anti-cancer effects in cultured prostate cells. Still, the molecular mechanisms and the gene targets for vitamin D-mediated prostate cancer prevention are unknown. Results: We examined the effect of 1,25(OH)2D (+/- 100 nM, 6, 24, 48 h) on the transcript profile of proliferating RWPE1 cells, an immortalized, non-tumorigenic prostate epithelial cell line that is growth arrested by 1,25(OH)2D (Affymetrix U133 Plus 2.0, n = 4/treatment per time and dose). Our analysis revealed many transcript level changes at a 5% false detection rate: 6 h, 1571 (61% up), 24 h, 1816 (60% up), 48 h, 3566 (38% up). 288 transcripts were regulated similarly at all time points (182 up, 80 down) and many of the promoters for these transcripts contained putative vitamin D response elements. Functional analysis by pathway or Gene Set Analysis revealed early suppression of WNT, Notch, NF-kB, and IGF1 signaling. Transcripts related to inflammation were suppressed at 6 h (e.g.
    [Show full text]
  • Association of Gene Ontology Categories with Decay Rate for Hepg2 Experiments These Tables Show Details for All Gene Ontology Categories
    Supplementary Table 1: Association of Gene Ontology Categories with Decay Rate for HepG2 Experiments These tables show details for all Gene Ontology categories. Inferences for manual classification scheme shown at the bottom. Those categories used in Figure 1A are highlighted in bold. Standard Deviations are shown in parentheses. P-values less than 1E-20 are indicated with a "0". Rate r (hour^-1) Half-life < 2hr. Decay % GO Number Category Name Probe Sets Group Non-Group Distribution p-value In-Group Non-Group Representation p-value GO:0006350 transcription 1523 0.221 (0.009) 0.127 (0.002) FASTER 0 13.1 (0.4) 4.5 (0.1) OVER 0 GO:0006351 transcription, DNA-dependent 1498 0.220 (0.009) 0.127 (0.002) FASTER 0 13.0 (0.4) 4.5 (0.1) OVER 0 GO:0006355 regulation of transcription, DNA-dependent 1163 0.230 (0.011) 0.128 (0.002) FASTER 5.00E-21 14.2 (0.5) 4.6 (0.1) OVER 0 GO:0006366 transcription from Pol II promoter 845 0.225 (0.012) 0.130 (0.002) FASTER 1.88E-14 13.0 (0.5) 4.8 (0.1) OVER 0 GO:0006139 nucleobase, nucleoside, nucleotide and nucleic acid metabolism3004 0.173 (0.006) 0.127 (0.002) FASTER 1.28E-12 8.4 (0.2) 4.5 (0.1) OVER 0 GO:0006357 regulation of transcription from Pol II promoter 487 0.231 (0.016) 0.132 (0.002) FASTER 6.05E-10 13.5 (0.6) 4.9 (0.1) OVER 0 GO:0008283 cell proliferation 625 0.189 (0.014) 0.132 (0.002) FASTER 1.95E-05 10.1 (0.6) 5.0 (0.1) OVER 1.50E-20 GO:0006513 monoubiquitination 36 0.305 (0.049) 0.134 (0.002) FASTER 2.69E-04 25.4 (4.4) 5.1 (0.1) OVER 2.04E-06 GO:0007050 cell cycle arrest 57 0.311 (0.054) 0.133 (0.002)
    [Show full text]
  • Functional Characterisation of MYT1L, a Brain-Specific Transcriptional Regulator
    This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Functional characterisation of MYT1L, a brain-specific transcriptional regulator Kepa, Agnieszka Maria Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 04. Oct. 2021 Functional characterisation of MYT1L, a brain-specific transcriptional regulator Agnieszka Kępa 2014 A thesis submitted to King’s College London for the degree of Doctor of Philosophy MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry ABSTRACT Abnormalities in brain development and maladaptive plasticity are thought to underlay a range of neurodevelopmental and neurological disabilities and disorders, such as autism spectrum disorders, schizophrenia and learning disability.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2006/0068395 A1 Wood Et Al
    US 2006.0068395A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0068395 A1 Wood et al. (43) Pub. Date: Mar. 30, 2006 (54) SYNTHETIC NUCLEIC ACID MOLECULE (21) Appl. No.: 10/943,508 COMPOSITIONS AND METHODS OF PREPARATION (22) Filed: Sep. 17, 2004 (76) Inventors: Keith V. Wood, Mt. Horeb, WI (US); Publication Classification Monika G. Wood, Mt. Horeb, WI (US); Brian Almond, Fitchburg, WI (51) Int. Cl. (US); Aileen Paguio, Madison, WI CI2O I/68 (2006.01) (US); Frank Fan, Madison, WI (US) C7H 2L/04 (2006.01) (52) U.S. Cl. ........................... 435/6: 435/320.1; 536/23.1 Correspondence Address: SCHWEGMAN, LUNDBERG, WOESSNER & (57) ABSTRACT KLUTH 1600 TCF TOWER A method to prepare synthetic nucleic acid molecules having 121 SOUTHEIGHT STREET reduced inappropriate or unintended transcriptional charac MINNEAPOLIS, MN 55402 (US) teristics when expressed in a particular host cell. Patent Application Publication Mar. 30, 2006 Sheet 1 of 2 US 2006/0068395 A1 Figure 1 Amino Acid Codon Phe UUU, UUC Ser UCU, UCC, UCA, UCG, AGU, AGC Tyr UAU, UAC Cys UGU, UGC Leu UUA, UUG, CUU, CUC, CUA, CUG Trp UGG Pro CCU, CCC, CCA, CCG His CAU, CAC Arg CGU, CGC, CGA, CGG, AGA, AGG Gln CAA, CAG Ile AUU, AUC, AUA Thr ACU, ACC, ACA, ACG ASn AAU, AAC LyS AAA, AAG Met AUG Val GUU, GUC, GUA, GUG Ala GCU, GCC, GCA, GCG Asp GAU, GAC Gly GGU, GGC, GGA, GGG Glu GAA, GAG Patent Application Publication Mar. 30, 2006 Sheet 2 of 2 US 2006/0068395 A1 Spd Sequence pGL4B-4NN3.
    [Show full text]
  • 1714 Gene Comprehensive Cancer Panel Enriched for Clinically Actionable Genes with Additional Biologically Relevant Genes 400-500X Average Coverage on Tumor
    xO GENE PANEL 1714 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes 400-500x average coverage on tumor Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11 IL6R KAT5 ACVR2A
    [Show full text]
  • BMC Developmental Biology Biomed Central
    BMC Developmental Biology BioMed Central Research article Open Access Identification of known and novel pancreas genes expressed downstream of Nkx2.2 during development Keith R Anderson1, Peter White3,4, Klaus H Kaestner3 and Lori Sussel*1,2 Address: 1Department of Biochemistry and Program in Molecular Biology, University of Colorado Health Science Center, Denver, CO, 80045, USA, 2Department of Genetics and Development, Columbia University, New York, NY 10032, USA, 3Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, 752B CRB, 415 Curie Blvd, Philadelphia, Pennsylvania 19104, USA and 4The Research Institute at Nationwide Children's Hospital, 700 Childrens Drive, Columbus, OH 43205, USA Email: Keith R Anderson - [email protected]; Peter White - [email protected]; Klaus H Kaestner - [email protected]; Lori Sussel* - [email protected] * Corresponding author Published: 10 December 2009 Received: 27 May 2009 Accepted: 10 December 2009 BMC Developmental Biology 2009, 9:65 doi:10.1186/1471-213X-9-65 This article is available from: http://www.biomedcentral.com/1471-213X/9/65 © 2009 Anderson et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The homeodomain containing transcription factor Nkx2.2 is essential for the differentiation of pancreatic endocrine cells. Deletion of Nkx2.2 in mice leads to misspecification of islet cell types; insulin-expressing β cells and glucagon-expressing α cells are replaced by ghrelin- expressing cells.
    [Show full text]
  • Upregulation of Myt1 Promotes Acquired Resistance of Cancer Cells to Wee1 Inhibition Cody W
    Published OnlineFirst October 8, 2019; DOI: 10.1158/0008-5472.CAN-19-1961 Cancer Molecular Cell Biology Research Upregulation of Myt1 Promotes Acquired Resistance of Cancer Cells to Wee1 Inhibition Cody W. Lewis1,2,3, Amirali B. Bukhari1,2,3, Edric J. Xiao1,3, Won-Shik Choi1,2,3, Joanne D. Smith1,2,3, Ellen Homola4, John R. Mackey1,5, Shelagh D. Campbell4, Armin M. Gamper1,2,3, and Gordon K. Chan1,2,3 Abstract Adavosertib (also known as AZD1775 or MK1775) is a tion of Cdk1 induced aberrant mitosis and cell death by small-molecule inhibitor of the protein kinase Wee1, with mitotic catastrophe. Cancer cells with intrinsic adavosertib single-agent activity in multiple solid tumors, including sar- resistance had higher levels of Myt1 compared with sensitive coma, glioblastoma, and head and neck cancer. Adavosertib cells. Furthermore, cancer cells that acquired resistance fol- also shows promising results in combination with genotoxic lowing short-term adavosertib treatment had higher levels of agents such as ionizing radiation or chemotherapy. Previous Myt1 compared with mock-treated cells. Downregulating studies have investigated molecular mechanisms of primary Myt1 enhanced ectopic Cdk1 activity and restored sensitivity resistance to Wee1 inhibition. Here, we investigated mechan- to adavosertib. These data demonstrate that upregulating Myt1 isms of acquired resistance to Wee1 inhibition, focusing on the is a mechanism by which cancer cells acquire resistance to role of the Wee1-related kinase Myt1. Myt1 and Wee1 kinases adavosertib. were both capable of phosphorylating and inhibiting Cdk1/ cyclin B, the key enzymatic complex required for mitosis, Significance: Myt1 is a candidate predictive biomarker of demonstrating their functional redundancy.
    [Show full text]
  • Trna GENES AFFECT MULTIPLE ASPECTS of LOCAL CHROMOSOME BEHAVIOR
    tRNA GENES AFFECT MULTIPLE ASPECTS OF LOCAL CHROMOSOME BEHAVIOR by Matthew J Pratt-Hyatt A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Cellular and Molecular Biology) in The University of Michigan 2008 Doctoral Committee: Professor David R. Engelke, Chair Professor Robert S. Fuller Associate Professor Mats E. Ljungman Associate Professor Thomas E. Wilson Assistant Professor Daniel A. Bochar © Matthew J. Pratt-Hyatt All rights reserved 2008 . To my loving family Who’ve helped me so much ii Acknowledgements I would first like to thank my mentor, David Engelke. His help has been imperative to the development of my scientific reasoning, writing, and public speaking. He has been incredibly supportive at each phase of my graduate career here at the University of Michigan. Second, I would like to thank the past and present members of the Engelke lab. I would especially like to thank Paul Good, May Tsoi, Glenn Wozniak, Kevin Kapadia, and Becky Haeusler for all of their help. For this dissertation I would like to thank the following people for their assistance. For Chapter II, I would like to thank Kevin Kapadia and Paul Good for technical assistance. I would also like to thank David Engelke and Tom Wilson for help with critical thinking and writing. For Chapter III, I would like to thank David Engelke and Rebecca Haeusler for their major writing contribution. I would also like to acknowledge that Rebecca Haeusler did the majority of the work that led to figures 1-3 in that chapter. For Chapter IV, I would like to thank Anita Hopper, David Engelke and Rebecca Haeusler for their writing contributions.
    [Show full text]