A Genome-Wide Library of MADM Mice for Single-Cell Genetic Mosaic Analysis
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Single Nucleotide Variants in Metastasis-Related Genes Are
View metadata, citation and similar papers at core.ac.uk brought to you by CORE HHS Public Access provided by CDC Stacks Author manuscript Author ManuscriptAuthor Manuscript Author Mol Carcinog Manuscript Author . Author manuscript; Manuscript Author available in PMC 2018 March 01. Published in final edited form as: Mol Carcinog. 2017 March ; 56(3): 1000–1009. doi:10.1002/mc.22565. Single nucleotide variants in metastasis-related genes are associated with breast cancer risk, by lymph node involvement and estrogen receptor status, in women with European and African ancestry Michelle R. Roberts1,2,3, Lara E. Sucheston-Campbell4, Gary R. Zirpoli5, Michael Higgins6, Jo L. Freudenheim3, Elisa V. Bandera7, Christine B. Ambrosone2, and Song Yao2 1Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 2Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 3Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY 4Division of Pharmacy Practice and Science, The Ohio State University, Columbus, OH 5Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 6Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 7Rutgers Cancer Institute of New Jersey, New Brunswick, NJ Abstract Background—Single nucleotide polymorphisms (SNPs) in pathways influencing lymph node (LN) metastasis and estrogen receptor (ER) status in breast cancer may partially explain inter- patient variability in prognosis. We examined 154 SNPs in 12 metastasis-related genes for associations with breast cancer risk, stratified by LN and ER status, in European-American (EA) and African-American (AA) women. Methods—2,671 women enrolled in the Women’s Circle of Health Study were genotyped. -
Antisense RNA Polymerase II Divergent Transcripts Are P-Tefb Dependent and Substrates for the RNA Exosome
Antisense RNA polymerase II divergent transcripts are P-TEFb dependent and substrates for the RNA exosome Ryan A. Flynna,1,2, Albert E. Almadaa,b,1, Jesse R. Zamudioa, and Phillip A. Sharpa,b,3 aDavid H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139; and bDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 Contributed by Phillip A. Sharp, May 12, 2011 (sent for review March 3, 2011) Divergent transcription occurs at the majority of RNA polymerase II PII carboxyl-terminal domain (CTD) at serine 2, DSIF, and (RNAPII) promoters in mouse embryonic stem cells (mESCs), and NELF results in the dissociation of NELF from the elongation this activity correlates with CpG islands. Here we report the char- complex and continuation of transcription (13). More recently acterization of upstream antisense transcription in regions encod- it was recognized, in mESCs, that c-Myc stimulates transcription ing transcription start site associated RNAs (TSSa-RNAs) at four at over a third of all cellular promoters by recruitment of P-TEFb divergent CpG island promoters: Isg20l1, Tcea1, Txn1, and Sf3b1. (12). Intriguingly in these same cells, NELF and DSIF have bi- We find that upstream antisense RNAs (uaRNAs) have distinct modal binding profiles at divergent TSSs. This suggests divergent capped 5′ termini and heterogeneous nonpolyadenylated 3′ ends. RNAPII complexes might be poised for signals controlling elon- uaRNAs are short-lived with average half-lives of 18 minutes and gation and opens up the possibility that in the antisense direction are present at 1–4 copies per cell, approximately one RNA per DNA P-TEF-b recruitment may be regulating release for productive template. -
Bilateral Gene Interaction Hierarchy Analysis of the Cell Death Gene
White et al. BMC Genomics (2016) 17:130 DOI 10.1186/s12864-016-2412-0 RESEARCH ARTICLE Open Access Bilateral gene interaction hierarchy analysis of the cell death gene response emphasizes the significance of cell cycle genes following unilateral traumatic brain injury Todd E. White1, Monique C. Surles-Zeigler1, Gregory D. Ford2, Alicia S. Gates1, Benem Davids1, Timothy Distel1,4, Michelle C. LaPlaca3 and Byron D. Ford1,4* Abstract Background: Delayed or secondary cell death that is caused by a cascade of cellular and molecular processes initiated by traumatic brain injury (TBI) may be reduced or prevented if an effective neuroprotective strategy is employed. Microarray and subsequent bioinformatic analyses were used to determine which genes, pathways and networks were significantly altered 24 h after unilateral TBI in the rat. Ipsilateral hemi-brain, the corresponding contralateral hemi-brain, and naïve (control) brain tissue were used for microarray analysis. Results: Ingenuity Pathway Analysis showed cell death and survival (CD) to be a top molecular and cellular function associated with TBI on both sides of the brain. One major finding was that the overall gene expression pattern suggested an increase in CD genes in ipsilateral brain tissue and suppression of CD genes contralateral to the injury which may indicate an endogenous protective mechanism. We created networks of genes of interest (GOI) and ranked the genes by the number of direct connections each had in the GOI networks, creating gene interaction hierarchies (GIHs). Cell cycle was determined from the resultant GIHs to be a significant molecular and cellular function in post-TBI CD gene response. -
Involvement of DPP9 in Gene Fusions in Serous Ovarian Carcinoma
Smebye et al. BMC Cancer (2017) 17:642 DOI 10.1186/s12885-017-3625-6 RESEARCH ARTICLE Open Access Involvement of DPP9 in gene fusions in serous ovarian carcinoma Marianne Lislerud Smebye1,2, Antonio Agostini1,2, Bjarne Johannessen2,3, Jim Thorsen1,2, Ben Davidson4,5, Claes Göran Tropé6, Sverre Heim1,2,5, Rolf Inge Skotheim2,3 and Francesca Micci1,2* Abstract Background: A fusion gene is a hybrid gene consisting of parts from two previously independent genes. Chromosomal rearrangements leading to gene breakage are frequent in high-grade serous ovarian carcinomas and have been reported as a common mechanism for inactivating tumor suppressor genes. However, no fusion genes have been repeatedly reported to be recurrent driver events in ovarian carcinogenesis. We combined genomic and transcriptomic information to identify novel fusion gene candidates and aberrantly expressed genes in ovarian carcinomas. Methods: Examined were 19 previously karyotyped ovarian carcinomas (18 of the serous histotype and one undifferentiated). First, karyotypic aberrations were compared to fusion gene candidates identified by RNA sequencing (RNA-seq). In addition, we used exon-level gene expression microarrays as a screening tool to identify aberrantly expressed genes possibly involved in gene fusion events, and compared the findings to the RNA-seq data. Results: We found a DPP9-PPP6R3 fusion transcript in one tumor showing a matching genomic 11;19-translocation. Another tumor had a rearrangement of DPP9 with PLIN3. Both rearrangements were associated with diminished expression of the 3′ end of DPP9 corresponding to the breakpoints identified by RNA-seq. For the exon-level expression analysis, candidate fusion partner genes were ranked according to deviating expression compared to the median of the sample set. -
Modulating Hallmarks of Cholangiocarcinoma
University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Fall 12-14-2018 Modulating Hallmarks of Cholangiocarcinoma Cody Wehrkamp University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Molecular Biology Commons Recommended Citation Wehrkamp, Cody, "Modulating Hallmarks of Cholangiocarcinoma" (2018). Theses & Dissertations. 337. https://digitalcommons.unmc.edu/etd/337 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. MODULATING HALLMARKS OF CHOLANGIOCARCINOMA by Cody J. Wehrkamp A DISSERTATION Presented to the Faculty of the University of Nebraska Graduate College in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Biochemistry and Molecular Biology Graduate Program Under the Supervision of Professor Justin L. Mott University of Nebraska Medical Center Omaha, Nebraska November 2018 Supervisory Committee: Kaustubh Datta, Ph.D. Melissa Teoh‐Fitzgerald, Ph.D. Richard G. MacDonald, Ph.D. Acknowledgements This endeavor has led to scientific as well as personal growth for me. I am indebted to many for their knowledge, influence, and support along the way. To my mentor, Dr. Justin L. Mott, you have been an incomparable teacher and invaluable guide. You upheld for me the concept that science is intrepid, even when the experience is trying. Through my training, and now here at the end, I can say that it has been an honor to be your protégé. When you have shaped your future graduates to be and do great, I will be privileged to say that I was your first one. -
SIPA1 Is a Modulator of HGF/MET Induced Tumour Metastasis Via the Regulation of Tight Junction-Based Cell to Cell Barrier Function
cancers Article SIPA1 Is a Modulator of HGF/MET Induced Tumour Metastasis via the Regulation of Tight Junction-Based Cell to Cell Barrier Function Chang Liu 1, Wenguo Jiang 1 , Lijian Zhang 2, Rachel Hargest 1,* and Tracey A. Martin 1,* 1 Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK; [email protected] (C.L.); [email protected] (W.J.) 2 Peking University School of Oncology and Peking University Cancer Hospital, Fucheng Road, Beijing 100142, China; [email protected] * Correspondence: [email protected] (R.H.); [email protected] (T.A.M.); Tel.: +44-29-2068-7130 (R.H.) Simple Summary: The role of Signal Induced Proliferation Associated 1 (SIPA1) in lung cancer remains largely unknown. This study aimed to evaluate the importance of SIPA1 in the development and progression of lung cancer, to demonstrate the cellular functions of SIPA1 and the molecular mechanisms involved. Abstract: Background: Lung cancer is the leading cause of cancer death. SIPA1 is a mitogen induced GTPase activating protein (GAP) and may hamper cell cycle progression. SIPA1 has been shown to be involved in MET signaling and may contribute to tight junction (TJ) function and cancer metastasis. Methods: Human lung tumour cohorts were analyzed. In vitro cell function assays were performed after knock down of SIPA1 in lung cancer cells with/without treatment. Quantitative Citation: Liu, C.; Jiang, W.G.; Zhang, polymerase chain reaction (qPCR) and western blotting were performed to analyze expression of L.; Hargest, R.; Martin, T.A. SIPA1 Is a HGF (hepatocyte growth factor), MET, and their downstream markers. -
Genetic Mosaic Dissection of Lis1 and Ndel1 in Neuronal Migration
Neuron Article Genetic Mosaic Dissection of Lis1 and Ndel1 in Neuronal Migration Simon Hippenmeyer,1,* Yong Ha Youn,2 Hyang Mi Moon,2,3 Kazunari Miyamichi,1 Hui Zong,1,5 Anthony Wynshaw-Boris,2,4 and Liqun Luo1,* 1Howard Hughes Medical Institute and Department of Biology, Stanford University, Stanford, CA 94305, USA 2Department of Pediatrics and Institute for Human Genetics 3Biomedical Sciences Graduate Program 4Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA 5Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA *Correspondence: [email protected] (S.H.), [email protected] (L.L.) DOI 10.1016/j.neuron.2010.09.027 SUMMARY studied. Cortical layering occurs in an ‘‘inside-out’’ fashion whereby earlier born neurons occupy deep layers and succes- Coordinated migration of newly born neurons to their sively later born neurons settle in progressively upper layers (An- prospective target laminae is a prerequisite for neural gevine and Sidman, 1961; Rakic, 1974). Upon radial glia progen- circuit assembly in the developing brain. The evolu- itor cell (RGPC)-mediated neurogenesis, newborn migrating tionarily conserved LIS1/NDEL1 complex is essential cortical projection neurons are bipolar-shaped in the ventricular for neuronal migration in the mammalian cerebral zone (VZ) but then convert to a multipolar morphology within the cortex. The cytoplasmic nature of LIS1 and NDEL1 subventricular zone (SVZ) and migrate into the intermediate zone (IZ). A switch from the multipolar state back to a bipolar proteins suggest that they regulate neuronal migra- morphology precedes radial glia-guided locomotion of projec- tion cell autonomously. -
Activation of Aurora-A Is Essential for Neuronal Migration Via Modulation of Microtubule Organization
11050 • The Journal of Neuroscience, August 8, 2012 • 32(32):11050–11066 Cellular/Molecular Activation of Aurora-A Is Essential for Neuronal Migration via Modulation of Microtubule Organization Takako Takitoh,1 Kanako Kumamoto,1 Chen-Chi Wang,2,4 Makoto Sato,2,3,4 Shiori Toba,1 Anthony Wynshaw-Boris,5 and Shinji Hirotsune1 1Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan, 2Division of Cell Biology and Neuroscience, Department of Morphological and Physiological Sciences, Faculty of Medical Sciences, University of Fukui, 3Child Development Research Center, Graduate School of Medical Sciences, University of Fukui, 4Research and Education Program for Life Science, University of Fukui, Fukui 910-1193, Japan, and 5Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, School of Medicine, San Francisco, California 94143 Neuronal migration is a critical feature to ensure proper location and wiring of neurons during cortical development. Postmitotic neurons migrate from the ventricular zone into the cortical plate to establish neuronal lamina in an “inside-out” gradient of maturation. Here, we report that the mitotic kinase Aurora-A is critical for the regulation of microtubule organization during neuronal migration via an Aurora-A–NDEL1 pathway in the mouse. Suppression of Aurora-A activity by inhibitors or siRNA resulted in severe impairment of neuronal migration of granular neurons. In addition, in utero injection of the Aurora-A kinase-dead mutant provoked defective migra- tion of cortical neurons. Furthermore, we demonstrated that suppression of Aurora-A impaired microtubule modulation in migrating neurons. Interestingly, suppression of CDK5 by an inhibitor or siRNA reduced Aurora-A activity and NDEL1 phosphorylation by Aurora-A, which led to defective neuronal migration. -
Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement. -
Pan-Cancer Analysis of Homozygous Deletions in Primary Tumours Uncovers Rare Tumour Suppressors
Corrected: Author correction; Corrected: Author correction ARTICLE DOI: 10.1038/s41467-017-01355-0 OPEN Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors Jiqiu Cheng1,2, Jonas Demeulemeester 3,4, David C. Wedge5,6, Hans Kristian M. Vollan2,3, Jason J. Pitt7,8, Hege G. Russnes2,9, Bina P. Pandey1, Gro Nilsen10, Silje Nord2, Graham R. Bignell5, Kevin P. White7,11,12,13, Anne-Lise Børresen-Dale2, Peter J. Campbell5, Vessela N. Kristensen2, Michael R. Stratton5, Ole Christian Lingjærde 10, Yves Moreau1 & Peter Van Loo 3,4 1234567890 Homozygous deletions are rare in cancers and often target tumour suppressor genes. Here, we build a compendium of 2218 primary tumours across 12 human cancer types and sys- tematically screen for homozygous deletions, aiming to identify rare tumour suppressors. Our analysis defines 96 genomic regions recurrently targeted by homozygous deletions. These recurrent homozygous deletions occur either over tumour suppressors or over fragile sites, regions of increased genomic instability. We construct a statistical model that separates fragile sites from regions showing signatures of positive selection for homozygous deletions and identify candidate tumour suppressors within those regions. We find 16 established tumour suppressors and propose 27 candidate tumour suppressors. Several of these genes (including MGMT, RAD17, and USP44) show prior evidence of a tumour suppressive function. Other candidate tumour suppressors, such as MAFTRR, KIAA1551, and IGF2BP2, are novel. Our study demonstrates how rare tumour suppressors can be identified through copy number meta-analysis. 1 Department of Electrical Engineering (ESAT) and iMinds Future Health Department, University of Leuven, Kasteelpark Arenberg 10, B-3001 Leuven, Belgium. -
Forschungsbericht Science Report
FORSCHUNGSBERICHT SCIENCE REPORT2017/2018 ST. ANNA KINDERKREBSFORSCHUNG ST. ANNA CHILDREN’S CANCER RESEARCH INSTITUTE TUMOR BIOLOGY Understanding tumor heterogeneity and relapse in neuroblastoma patients to allow adequate treatment options. MOLECULAR MICROBIOLOGY LCH BIOLOGY Clinically important Targeted resistant mutations in Philadelphia inhibition chromosome-positive leukemias. of the MAPK pathway leads to a STUDIES & STATISTICS rapid and sustained clinical response in severe multisystem LCH. Busulfan and melphalan is considered standard high-dose chemotherapy for high-risk neuroblastoma. GENETICS OF LEUKEMIAS A novel genetic MOLECULAR BIOLOGY OF SOLID TUMORS subtype of leukemia. Understanding mechanisms EPIGENOME-BASED PRECISION MEDICINE of tumor cell plasticity EPIGENETIC and its role in diversity in Ewing sarcoma metastasis. Ewing sarcoma. MORE SCIENCE REPORTS INSIDE >>> [ 06 ] Forschungsbericht St. Anna Kinderkrebsforschung | Science Report St. Anna Children’s Cancer Research Institute Inhalt Einleitung Vorwort des Institutsleiters 10 Vorwort des wissenschaftlichen Direktors 12 30 Jahre – unseren Spendern sei Dank! 14 Daten & Fakten Kompetitive Drittmittel 2018 20 Zuweisung der Geldmittel 2018 20 Finanzierung 2018 20 Nationen 21 Personelle Zusammensetzung 21 PatientInnenaufkommen im S2IRP 22 2-Jahres-Überlebensrate krebskranker Kinder 23 5-Jahres-Überlebensrate krebskranker Kinder 24 Forschungsnetzwerke 26 Inhalt Forschungsbericht I St. Anna Kinderkrebsforschung | Science Report St. Anna Cancer Research Institute [ 07 ] Science -
Lis1 and Ndel1 Influence the Timing of Nuclear Envelope Breakdown in Neural Stem Cells
University of South Carolina Scholar Commons Faculty Publications Biological Sciences, Department of 9-22-2008 Lis1 and Ndel1 Influence the Timing of Nuclear Envelope Breakdown in Neural Stem Cells Sachin Hebbar University of South Carolina - Columbia Mariano T. Mesngon University of South Carolina - Columbia Aimee M. Guillotte University of South Carolina - Columbia Bhavim Desai University of South Carolina - Columbia, [email protected] Ramses Ayala Mass General Institute for Neurodegenerative Disease See next page for additional authors Follow this and additional works at: https://scholarcommons.sc.edu/biol_facpub Part of the Biology Commons Publication Info The Journal of Cell Biology, Volume 182, Issue 6, 2008, pages 1063-1071. © 2008, the authors. Originally published in the Journal of Cell Biology by the Rockefeller University Press. This Article is brought to you by the Biological Sciences, Department of at Scholar Commons. It has been accepted for inclusion in Faculty Publications by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Author(s) Sachin Hebbar, Mariano T. Mesngon, Aimee M. Guillotte, Bhavim Desai, Ramses Ayala, and Deanna S. Smith This article is available at Scholar Commons: https://scholarcommons.sc.edu/biol_facpub/58 Published September 22, 2008 JCB: REPORT Lis1 and Ndel1 infl uence the timing of nuclear envelope breakdown in neural stem cells Sachin Hebbar , 1 Mariano T. Mesngon , 1 Aimee M. Guillotte , 1 Bhavim Desai , 1 Ramses Ayala , 2 and Deanna S. Smith 1 1 Department of Biological Sciences, University of South Carolina, Columbia, SC 29208 2 Neurology Department, Mass General Institute for Neurodegenerative Disease, Charlestown, MA 02120 is1 and Ndel1 are essential for animal development.