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Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade
Published OnlineFirst May 4, 2017; DOI: 10.1158/2159-8290.CD-17-0292 RESEARCH ARTICLE Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade Yi-Feng Gu1,2, Shannon Cohn1,2, Alana Christie2, Tiffani McKenzie2,3, Nicholas Wolff1,2, Quyen N. Do4, Ananth J. Madhuranthakam4, Ivan Pedrosa2,4, Tao Wang2,5, Anwesha Dey6, Meinrad Busslinger7, Xian-Jin Xie2,8, Robert E. Hammer9, Renée M. McKay1,2, Payal Kapur2,3, and James Brugarolas1,2 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. 17-CD-17-0292_p900-917.indd 900 7/20/17 10:05 AM Published OnlineFirst May 4, 2017; DOI: 10.1158/2159-8290.CD-17-0292 ABSTRACT Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 muta- tions, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl ) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with PAX8, a transcription factor frequently overexpressed in ccRCC, led to ccRCC of different grades. Bap1 -defi cient tumors were of high grade and showed greater mTORC1 activation than Pbrm1 -defi cient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1 , in Pbrm1 -defi cient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specifi c drivers of ccRCC and histologic grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCCs arise from Bowman capsule cells. -
Genomic Misconception
1 Genomic Misconception: A fresh look at the biosafety of transgenic and conventional crops. a plea for a process agnostic regulation Klaus Ammann, University of Bern, [email protected] , Neuchâtel, Switzerland December 9, 2012 names. A shorter version has been published in New Biotechnology Ammann, K. (2014), Genomic Misconception: a fresh look at the biosafety of transgenic and conventional crops. A plea for a process agnostic regulation, New Biotechnology, 31, 1, pp. 1-17, http://www.ask-force.org/web/NewBiotech/Ammann-Genomic-Misconception-printed-2014.pdf Abstract: .......................................................................................................................................... 1 1. The scientific basis of the process agnostic regulation ................................................................... 2 2. How the Genomic Misconception was evolving ............................................................................. 4 2.1. How the ‘Genomic Misconception’ was erroneously maintained in the European Regulation and the Cartagena Protocol on Biosafety ....................................................................................... 6 a) Europe, the development of the transatlantic divide with the United States ........................ 6 b) Legislative History of the Cartagena Protocol and its Genomic Misinterpretation of Transgenesis ................................................................................................................................ 8 3. Conclusions ................................................................................................................................... -
Kaderschmiede
2 |12 Kaderschmiede FWF START/Wittgenstein 2012: Exzellenz9 » TRP: Wider besseres Wissen » Frau in der Wissenschaft: Verena Jantsch- Plunger » Interview: Helmut Denk » Persönliche Paradigmen: Gerhard Herndl INHALT 20 TRP: WIDer BESSERES WISSEN 30 FraU IN Der WISSENSCHAFT: VERENA JANTSCH- PLUNGER KaDER- SCHMIEDE 6 FWF 12 STAWI 2012: EXZELLENZ9 KONTEXT EDITORIAL 27 ERC-Broschüre: Excellent Prospects 4 PROJEKTVORSTELLUNGEN 28–29 Statement of Principles for Scientific 5 BRIEF DES PRÄSIDENTEN Merit Review 35 THEMA INTERVIEW: 6–11 Kaderschmiede FWF PANOPTIKUM HELMUT DENK 30–34 Frau in der Wissenschaft FOKUS Verena Jantsch-Plunger 12–15 STAWI 2012: Exzellenz9 35–39 Interview 16–18 Kursbestätigung Helmut Denk 19 Das letzte NFN 40–41 International ausgezeichnet 20–21 Wider besseres Wissen Meinrad Busslinger 22–23 FWF-Infoveranstaltungen: 42–45 Persönliche Paradigmen Auf ein Neues! Friedrich Stadler im Gespräch 24 FWF-E-Book-Library mit Gerhard Herndl 25 Aufwertung der studentischen Mitarbeit 46–47 Unterwegs 26 The Journal of Universal Rejection Around the World EDITORIAL 42 PERSÖNLICHE PARADIGMEN: GERHARD HERNDL TRP: WIDer BESSERES WISSEN ms mas stb Der Forschungs-Kader » Bei der Verwendung des Wortes „Kader“ muss man als Autor vorsichtig sein. Zu ambivalent ist der Begriff besetzt, das Spek- trum reicht von negativ besetzten militärischen oder politischen Zusammenhängen bis hin zu positiv assoziierten Bereichen wie Sport sowie „positiv besetzten“ Eliten. Die Spitzenforschung mit ihren hoch qua- lifizierten Wissenschafterinnen und Wissenschaftern ist so eine Elite. Eine Kaderschmiede zu sein, ist also in ausgewählten Bereichen eine Auszeich- nung. So versteht es auch der FWF, wenn er im Zusammenhang mit seiner „Qualitätsselektion“ im Bereich wissenschaftlicher Projekte und ihrer da- hinter stehenden Personen als Kaderschmiede für Spitzenforschung be- 46 zeichnet wird. -
Steven Henikoff Position
CURRICULUM VITAE: Steven Henikoff Position: Investigator, Howard Hughes Medical Institute Member, Basic Sciences Division Address: Fred Hutchinson Cancer Research Center 1100 Fairview Ave N. Seattle, Washington 98109-1024 Phone (206) 667-4515; FAX (206) 667-5889 E-mail: [email protected] http://blocks.fhcrc.org/~steveh/ Education 1964-68 University of Chicago, Chicago, Illinois. BS in Chemistry. Research on optical properties of biopolymers, Dr. G. Holzwarth, advisor. 1971-77 Harvard University, Cambridge, Massachusetts. PhD in Biochemistry and Molecular Biology. Dr. M. Meselson, advisor. Thesis: RNA from heat induced puff sites in Drosophila. 1977-80 University of Washington, Seattle, Washington. Postdoctoral fellow in Zoology. Research on position-effect variegation in Drosophila, Dr. C. Laird, advisor, Leukemia Society of America fellow. Professional Experience 1981-85 Fred Hutchinson Cancer Research Center, Seattle, Washington. Assistant Member in Basic Sciences. 1981- University of Washington, Seattle. Affiliate Assistant, Associate and Full Professor of Genetics/Genome Sciences. 1985-88 Fred Hutchinson Cancer Research Center, Seattle, Washington. Associate Member in Basic Sciences. 1988- Fred Hutchinson Cancer Research Center, Seattle, Washington. Member in Basic Sciences. 1990- Investigator, Howard Hughes Medical Institute. Current Research Nucleosome dynamics Transcriptional regulation Centromeric chromatin and centromere evolution Epigenomic technologies Honors (since 2000) 2001 Keynote, 13th International Arabidopsis Conference, -
Developmental Biology Using Purified Genes
LASKER~KOSHLAND SPECIAL ACHIEVEMENT ESSAY IN MEDICAL SCIENCE AWARD Developmental biology using purified genes Donald D Brown Some history Control Anucleolate Magnesium From the NIH I went to the Pasteur Institute mutant deficient After three years of college I entered the in Paris to study bacterial gene regulation in University of Chicago Medical School in the 1959, the year after the Lac repressor had been fall of 1952 and discovered biochemistry and discovered. Before leaving Bethesda, by the research. Lloyd Kozloff, a member of the greatest luck I learned about a small research bacteriophage group in the Department of institution in Baltimore that was associated Biochemistry, guided my research. While in at that time with the Johns Hopkins Medical medical school I began searching for a future School called the Department of Embryology of research subject, thinking it should be an the Carnegie Institution of Washington. I con- important medically related problem but unex- tacted Jim Ebert, the director, and arranged an plored by what were then the modern methods advanced postdoctoral fellowship after my year of biochemistry. in Paris. It is hard to imagine two more diverse The field of embryology, newly named research institutions. ‘developmental biology’, caught my attention. The Pasteur Institute was at the forefront of Reproductive biology was barely discussed, biology, involved in the founding of molecular and descriptive embryology was taught in two biology. Every day at lunch Jacques Monod, lectures as a part of gross anatomy. In 1953, I François Jacob and André Lwoff presided attended a biochemistry journal club discus- over an exciting discussion usually augmented Figure 1 Comparison of control (left), anucleolate sion of the Watson-Crick Nature paper describ- by a prominent visitor. -
Enhancers, Enhancers – from Their Discovery to Today’S Universe of Transcription Enhancers
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by RERO DOC Digital Library Biol. Chem. 2015; 396(4): 311–327 Review Walter Schaffner* Enhancers, enhancers – from their discovery to today’s universe of transcription enhancers Abstract: Transcriptional enhancers are short (200–1500 one had ever postulated their existence, simply because base pairs) DNA segments that are able to dramatically there seemed to be no need for them. Now that introns boost transcription from the promoter of a target gene. and enhancers are part of the scientific world, one cannot Originally discovered in simian virus 40 (SV40), a small imagine how higher forms of life could ever have evolved DNA virus, transcription enhancers were soon also found without the multitude of tailored proteins that can be in immunoglobulin genes and other cellular genes as produced by alternative splicing, or without the sophisti- key determinants of cell-type-specific gene expression. cated patterns of remote transcription control by enhanc- Enhancers can exert their effect over long distances of ers. Indeed, the complexity of an organism is primarily thousands, even hundreds of thousands of base pairs, determined by the variety of gene regulation mechanisms, either from upstream, downstream, or from within a tran- rather than by the number of genes. scription unit. The number of enhancers in eukaryotic genomes correlates with the complexity of the organism; a typical mammalian gene is likely controlled by several enhancers to fine-tune its expression at different devel- The holy grail opmental stages, in different cell types and in response In the fall of 1978, I returned to Zurich University from to different signaling cues. -
Steven Henikoff Position
CURRICULUM VITAE: Steven Henikoff Position: Investigator, Howard Hughes Medical Institute Member, Basic Sciences Division Address: Fred Hutchinson Cancer Research Center 1100 Fairview Ave N. Seattle, Washington 98109-1024 Phone (206) 667-4515; FAX (206) 667-5889 E-mail: [email protected] http://research.fhcrc.org/henikoff/en.html Education 1964-68 UniversitY of Chicago, Chicago, Illinois. BS in ChemistrY. Research on optical properties of biopolymers, Dr. G. Holzwarth, advisor. 1971-77 Harvard UniversitY, Cambridge, Massachusetts. PhD in BiochemistrY and Molecular BiologY. Dr. M. Meselson, advisor. Thesis: RNA from heat induced puff sites in Drosophila. 1977-80 UniversitY of Washington, Seattle, Washington. Postdoctoral fellow in Zoology. Research on position-effect variegation in Drosophila, Dr. C. Laird, advisor, Leukemia SocietY of America fellow. Professional Experience 1981-85 Fred Hutchinson Cancer Research Center, Seattle, Washington. Assistant Member in Basic Sciences. 1981- UniversitY of Washington, Seattle. Affiliate Assistant, Associate and Full Professor of Genetics/Genome Sciences. 1985-88 Fred Hutchinson Cancer Research Center, Seattle, Washington. Associate Member in Basic Sciences. 1988- Fred Hutchinson Cancer Research Center, Seattle, Washington. Member in Basic Sciences. 1990- Investigator, Howard Hughes Medical Institute. Current Research Nucleosome dYnamics Transcriptional regulation Centromeric chromatin and centromere evolution Epigenomic technologies Ongoing Funding Howard Hughes Medical Institute Investigator 04/1/1990 -
Tumor Suppressor Gene Cooperates with BCR-ABL in a Transgenic Model of Acute Lymphoblastic Leukemia
Letters to the Editor 1200 1 2 1 3 SRo¨ttgers , M Gombert , A Teigler-Schlegel , K Busch , 2 Bullrich F, Morris SW, Hummel M, Pileri S, Stein H, Croce CM. 4 5 1 2 U Gamerdinger , R Slany , J Harbott and A Borkhardt Nucleophosmin (NPM) gene rearrangements in Ki-1-positive 1Department of Pediatric Hematology and Oncology, lymphomas. Cancer Res 1994; 54: 2873–2877. Oncogenetic Laboratory, University Hospital, Justus Liebig 3 Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S University Giessen, Giessen, Germany; et al. Identification of the transforming EML4-ALK fusion gene in 2Clinic of Pediatric Hematology, Oncology and Clinical non-small-cell lung cancer. Nature 2007; 448: 561–566. Immunology, Heinrich-Heine University Duesseldorf, 4 Jazii FR, Najafi Z, Malekzadeh R, Conrads TP, Ziaee AA, Duesseldorf, Germany; Abnet C et al. Identification of squamous cell carcinoma asso- 3Hessian State Office of Criminal InvestigationFWiesbaden, ciated proteins by proteomics and loss of beta tropomyosin Wiesbaden, Germany; expression in esophageal cancer. World J Gastroenterol 2006; 12: 4Department of Pathology, University Hospital, Giessen, 7104–7112. Germany and 5 Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The 5 anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Department of Genetics, Friedrich-Alexander University Cancer 2008; 8: 11–23. Erlangen, Erlangen, Germany 6 Trumper L, Pfreundschuh M, Bonin FV, Daus H. Detection of the E-mail: [email protected] t(2;5)-associated NPM/ALK fusion cDNA in peripheral blood cells of healthy individuals. Br J Haematol 1998; 103: 1138–1144. -
DNA Methylation Patterns and Cancer
restriction/modification system, which brought Werner Arber, Daniel Nathans and Hamilton Smith the 1978 Nobel Prize in Physiology or Medicine, and made restriction enzymes the primary tools of Charles Rodolphe Brupbacher Foundation molecular biology. Four decades have passed since then, but the role of 5-methylcytosine in eukaryotic DNA metabolism is still shrouded in mystery. We know that the sperm methylation pattern is largely The erased after fertilization and that methylation is gradually reintroduced Charles Rodolphe Brupbacher Prize during embryogenesis and differentiation, but the processes that for Cancer Research 2017 regulate the cell type- and tissue-specific methylation patterns remain is awarded to to be elucidated. We have also learned that DNA can be not only methylated, but also demethylated, and that aberrant methylation can lead to disease - including cancer. Again, how these processes are regulated remains to be discovered. However, we have learnt a great Sir Adrian Peter Bird, deal about 5-methylcytosine metabolism during the past three decades and much of our knowledge came from the laboratory of Adrian Bird. PhD Adrian spent his doctoral and postdoctoral time in Max Birnstiel’s for his contributions to our understanding laboratory, first in Edinburgh and then in Zurich, studying the amplification of ribosomal DNA in Xenopus laevis. In this organism, of the role of DNA methylation in genomic rDNA in somatic tissues is highly methylated, while the development and disease extrachromosomal amplicons are unmethylated. When he returned to Edinburgh to establish his own group, Adrian set out to study The President The President of the Foundation of the Scientific Advisory Board the methylation pattern of these loci using the newly-available methylation-sensitive restriction enzymes. -
A1983qz35500002
— — — CC/NUMBER 31 This Week’s Citation Classic AUGUST 1,1983 [irown I) D & Dawld I B. Specific gene amplification in oocytes. I Science 160:272-80, 1968. IDepartment of Embryology, Carnegie Institution of Washington, Baltimore, MD) The genes for 18S and 28S ribosomal RNA are “An international meeting on the nucleo- amplified specifically in oocyte nuclei of amphib- lus was held in Montevideo, Uruguay, in iarss forming more than a thousand nucleoli in each nucleus. These extra genes support enormous 1965. Without a doubt, the highlight of that rates of ribosomal RNA synthesis during meeting was Birnstiel’s demonstration of oogenesis. [The SCI® indicates that this paper has how he had used physicochemical tech4- been cited in over 530 publications since 1968.1 niques to isolate the ribosomal RNA genes. At that conference I heard Oscar Miller, then a staff member at the Oak Ridge Labo- Donald D. Brown ratories, describe the presence of circular chromosomes in the many nucleoli of frog Department of Embryology 5 Carnegie Institution of Washington oocyte nuclei. I knew instantly from the Baltimore, MD 21210 previous correlations of ribosomal RNA genes and the nucleolus that these must be July 7, 1983 extra copies of ribosomal RNA genes. lgor Dawid, a fellow staff member at Carnegie, “This paper and one published indepen1 - and I set out to prove this idea. dently at the same time by Joseph Gall “A key experiment described in our Sci- were the first to demonstrate specific gene ence paper depended upon the isolation by amplification — an event programmed into hand of ten thousand nuclei from Xenopus the development of a cell. -
Career Jump for Professor Kim Nasmyth
Press Release March 24th, 2004 Career jump for Professor Kim Nasmyth Prof. Kim Nasmyth, Director of the IMP Vienna, Boehringer Ingelheim’s Basic Research Institute, to take up prestigious Oxford Chair. The Research Institute of Molecular Pathology (IMP) which belongs to the international pharmaceutical company Boehringer Ingelheim has already served as starting point or stepping stone for several internationally outstanding scientific careers. Now a call from one of the best Universities in Europe has reached IMP Director Kim Nasmyth. In January 2006 he will take over the Whitley Chair of Biochemistry at the University of Oxford from Edwin Southern. One year later he will follow Raymond Dwek as Head of the Department of Biochemistry. He will then lead one of the largest departments of Biochemistry in the western world with approximately 850 employees and students. The Whitley Chair has an excellent reputation: founded in 1920, the position has been held by a succession of outstanding scientists, including Nobel laureates Hans Krebs and Rodney Porter. “The appointment certainly honours me personally but is also proof of the IMP’s excellent reputation in the scientific world” says Nasmyth. Prof. Kim Nasmyth Director of the Research Institute of Molecular Pathology (IMP) (Foto: IMP). Dr. Dr. Andreas Barner – vice Chairman of the Board of Directors of Boehringer Ingelheim and responsible for the corporate divisions Pharma Research, Development and Medicine, sees Prof. Nasmyth’s appointment as confirmation of the internationally- recognised outstanding research performed at the IMP: “The Research Institute of Molecular Pathology is a major contribution from Boehringer Ingelheim to basic research at the highest level and has achieved world renown with outstanding scientists working there under Prof. -
Pax-5 Encodes the Transcription Factor BSAP and Is Expressed in B Lymphocytes, the Developing CNS, and Adult Testis
Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis Ben Adams, l'z Petra D6rfler, 1 Adriano Aguzzi, 1 Zbynek Kozmik, Pavel Urbfinek, Ingrid Maurer-Fogy, 3 and Meinrad Busslinger 4 Institute of Molecular Pathology, A-1030 Vienna, Austria; ~Ernst Boehringer Institute, A-1120 Vienna, Austria BSAP has been identified previously as a transcription factor that is expressed at early, but not late, stages of B-cell differentiation. Biochemical purification and cDNA cloning has now revealed that BSAP belongs to the family of paired domain proteins. BSAP is encoded by the Pax-5 gene and has been highly conserved between human and mouse. An intact paired domain was shown to be both necessary and sufficient for DNA binding of BSAP. Binding studies with several BSAP recognition sequences demonstrated that the sequence specificity of BSAP differs from that of the distantly related paired domain protein Pax-1. During embryogenesis, the BSAP gene is transiently expressed in the mesencephalon and spinal cord with a spatial and temporal expression pattern that is distinct from that of other Pax genes in the developing central nervous system (CNS). Later, the expression of the BSAP gene shifts to the fetal liver where it correlates with the onset of B lymphopoiesis. BSAP expression persists in B lymphocytes and is also seen in the testis of the adult mouse. All of this evidence indicates that the transcription factor BSAP may not only play an important role in B-cell differentiation but also in neural development and spermatogenesis.