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A Genetic Screening Identifies a Component of the SWI/SNF Complex, Arid1b As a Senescence Regulator
A genetic screening identifies a component of the SWI/SNF complex, Arid1b as a senescence regulator Sadaf Khan A thesis submitted to Imperial College London for the degree of Doctor in Philosophy MRC Clinical Sciences Centre Imperial College London, School of Medicine July 2013 Statement of originality All experiments included in this thesis were performed by myself unless otherwise stated. Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives license. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the license terms of this work. 2 Abstract Senescence is an important tumour suppressor mechanism, which prevents the proliferation of stressed or damaged cells. The use of RNA interference to identify genes with a role in senescence is an important tool in the discovery of novel cancer genes. In this work, a protocol was established for conducting bypass of senescence screenings, using shRNA libraries together with next-generation sequencing. Using this approach, the SWI/SNF subunit Arid1b was identified as a regulator of cellular lifespan in MEFs. SWI/SNF is a large multi-subunit complex that remodels chromatin. Mutations in SWI/SNF proteins are frequently associated with cancer, suggesting that SWI/SNF components are tumour suppressors. Here the role of ARID1B during senescence was investigated. Depletion of ARID1B extends the proliferative capacity of primary mouse and human fibroblasts. -
The Connections of Wnt Pathway Components with Cell Cycle and Centrosome: Side Effects Or a Hidden Logic?
Critical Reviews in Biochemistry and Molecular Biology ISSN: 1040-9238 (Print) 1549-7798 (Online) Journal homepage: http://www.tandfonline.com/loi/ibmg20 The connections of Wnt pathway components with cell cycle and centrosome: side effects or a hidden logic? Vítězslav Bryja , Igor Červenka & Lukáš Čajánek To cite this article: Vítězslav Bryja , Igor Červenka & Lukáš Čajánek (2017): The connections of Wnt pathway components with cell cycle and centrosome: side effects or a hidden logic?, Critical Reviews in Biochemistry and Molecular Biology, DOI: 10.1080/10409238.2017.1350135 To link to this article: http://dx.doi.org/10.1080/10409238.2017.1350135 Published online: 25 Jul 2017. Submit your article to this journal Article views: 72 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ibmg20 Download by: [Masarykova Univerzita v Brne], [Lukas Cajanek] Date: 08 August 2017, At: 01:58 CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2017 https://doi.org/10.1080/10409238.2017.1350135 REVIEW ARTICLE The connections of Wnt pathway components with cell cycle and centrosome: side effects or a hidden logic? Vıtezslav Bryjaa , Igor Cervenka b and Lukas Caj anekc aDepartment of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; bMolecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; cDepartment of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic ABSTRACT ARTICLE HISTORY Wnt signaling cascade has developed together with multicellularity to orchestrate the develop- Received 10 April 2017 ment and homeostasis of complex structures. -
Next Generation Sequencing Panels for Disorders of Sex Development
Next Generation Sequencing Panels for Disorders of Sex Development Disorders of Sex Development – Overview Disorders of sex development (DSDs) occur when sex development does not follow the course of typical male or female patterning. Types of DSDs include congenital development of ambiguous genitalia, disjunction between the internal and external sex anatomy, incomplete development of the sex anatomy, and abnormalities of the development of gonads (such as ovotestes or streak ovaries) (1). Sex chromosome anomalies including Turner syndrome and Klinefelter syndrome as well as sex chromosome mosaicism are also considered to be DSDs. DSDs can be caused by a wide range of genetic abnormalities (2). Determining the etiology of a patient’s DSD can assist in deciding gender assignment, provide recurrence risk information for future pregnancies, and can identify potential health problems such as adrenal crisis or gonadoblastoma (1, 3). Sex chromosome aneuploidy and copy number variation are common genetic causes of DSDs. For this reason, chromosome analysis and/or microarray analysis typically should be the first genetic analysis in the case of a patient with ambiguous genitalia or other suspected disorder of sex development. Identifying whether a patient has a 46,XY or 46,XX karyotype can also be helpful in determining appropriate additional genetic testing. Abnormal/Ambiguous Genitalia Panel Our Abnormal/Ambiguous Genitalia Panel includes mutation analysis of 72 genes associated with both syndromic and non-syndromic DSDs. This comprehensive panel evaluates a broad range of genetic causes of ambiguous or abnormal genitalia, including conditions in which abnormal genitalia are the primary physical finding as well as syndromic conditions that involve abnormal genitalia in addition to other congenital anomalies. -
Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression
International Journal of Molecular Sciences Review Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression Guang Yang, Rachel Shi and Qing Zhang * Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; [email protected] (G.Y.); [email protected] (R.S.) * Correspondence: [email protected]; Tel.: +1-214-645-4671 Received: 6 October 2020; Accepted: 29 October 2020; Published: 31 October 2020 Abstract: Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel–Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer. Keywords: hypoxia; PHDs; TETs; JmjCs; HIFs 1. Introduction Molecular oxygen serves as a co-factor in many biochemical processes and is fundamental for aerobic organisms to maintain intracellular ATP levels [1,2]. -
ONCOPANEL (Popv3)
ONCOPANEL (POPv3) TEST INFORMATION BACKGROUND: Somatic genetic alterations in oncogenes and tumor-suppressor genes contribute to the pathogenesis and evolution of human cancers. These alterations can provide prognostic and predictive information and stratify cancers for targeted therapeutic information. We classify these alterations into five tiers using the following guidelines: Tier 1: The alteration has well-established published evidence confirming clinical utility in this tumor type, in at least one of the following contexts: predicting response to treatment with an FDA-approved therapy; assessing prognosis; establishing a definitive diagnosis; or conferring an inherited increased risk of cancer to this patient and family. Tier 2: The alteration may have clinical utility in at least one of the following contexts: selection of an investigational therapy in clinical trials for this cancer type; limited evidence of prognostic association; supportive of a specific diagnosis; proven association of response to treatment with an FDA-approved therapy in a different type of cancer; or similar to a different mutation with a proven association with response to treatment with an FDA-approved therapyin this type of cancer. Tier 3: The alteration is of uncertain clinical utility, but may have a role as suggested by at least one of the following: demonstration of association with response to treatment in this cancer type in preclinical studies (e.g., in vitro studies or animal models); alteration in a biochemical pathway that has other known, therapeutically-targetable alterations; alteration in a highly conserved region of the protein predicted, in silico, to alter protein function; or selection of an investigational therapy for a different cancer type. -
SPACE Exploration of Chromatin Proteome to Reveal Associated RNA- Binding Proteins
bioRxiv preprint doi: https://doi.org/10.1101/2020.07.13.200212; this version posted July 15, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SPACE exploration of chromatin proteome to reveal associated RNA- binding proteins Mahmoud-Reza Rafiee1*, Julian A Zagalak1,2, Giulia Tyzack1,3,4, Rickie Patani1,3,4, Jernej Ule1,2, Nicholas M Luscombe1,5,6* 1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. 2 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. 3 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. 4 Department of Neuroinflammation, UCL Institute of Neurology, Queen Square, London WC1N 1PJ, UK. 5 UCL Genetics Institute, University College London, Gower Street, London WC1E 6BT, UK. 6 Okinawa Institute of Science & Technology Graduate University, Okinawa 904-0495, Japan * corresponding authors Abstract Chromatin is composed of many proteins that mediate intermolecular transactions with the genome. Comprehensive knowledge of these components and their interactions is necessary for insights into gene regulation and other activities; however, reliable identification of chromatin-associated proteins remains technically challenging. Here, we present SPACE (Silica Particle Assisted Chromatin Enrichment), a stringent and straightforward chromatin- purification method that helps identify direct DNA-binders separately from chromatin- associated proteins. We demonstrate SPACE’s unique strengths in three experimental set- ups: the sensitivity to detect novel chromatin-associated proteins, the quantitative nature to measure dynamic protein use across distinct cellular conditions, and the ability to handle 10- 25 times less starting material than competing methods. -
Mutant IDH, (R)-2-Hydroxyglutarate, and Cancer
Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer Julie-Aurore Losman1 and William G. Kaelin Jr.1,2,3 1Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA; 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA Mutations in metabolic enzymes, including isocitrate whether altered cellular metabolism is a cause of cancer dehydrogenase 1 (IDH1) and IDH2, in cancer strongly or merely an adaptive response of cancer cells in the face implicate altered metabolism in tumorigenesis. IDH1 of accelerated cell proliferation is still a topic of some and IDH2 catalyze the interconversion of isocitrate and debate. 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate The recent identification of cancer-associated muta- and an essential cofactor for many enzymes, including tions in three metabolic enzymes suggests that altered JmjC domain-containing histone demethylases, TET cellular metabolism can indeed be a cause of some 5-methylcytosine hydroxylases, and EglN prolyl-4-hydrox- cancers (Pollard et al. 2003; King et al. 2006; Raimundo ylases. Cancer-associated IDH mutations alter the enzymes et al. 2011). Two of these enzymes, fumarate hydratase such that they reduce 2OG to the structurally similar (FH) and succinate dehydrogenase (SDH), are bone fide metabolite (R)-2-hydroxyglutarate [(R)-2HG]. Here we tumor suppressors, and loss-of-function mutations in FH review what is known about the molecular mechanisms and SDH have been identified in various cancers, in- of transformation by mutant IDH and discuss their im- cluding renal cell carcinomas and paragangliomas. -
Dietary Chemoprevention Studies in Preclinical Models of Prostate Cancer: Bioactive Lipids and Vitamin D
Dietary Chemoprevention Studies in Preclinical Models of Prostate Cancer: Bioactive Lipids and Vitamin D. Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Justin Bruce Smolinski, B.S. Ohio State University Nutrition (OSUN) Graduate Program The Ohio State University 2010 Dissertation Committee: Professor Steven K. Clinton, Advisor Professor Charles L. Brooks Professor Kichoon Lee Professor Mark L. Failla i Copyright by Justin Bruce Smolinski 2010 ii ABSTRACT Epidemiological evidence suggests that prostate cancer can be modulated by diet. Data exists that implicate both bioactive lipids and the vitamin D/ calcium axis in prostate cancer pathogenesis. These data suggest that bioactive lipids such as omega-3 fatty acids protect against prostate cancer, whereas omega-6 fatty acids promote prostate cancer. Population studies also indicate that a diet high in vitamin D decreases prostate cancer risk while calcium increases risk for prostate cancer, possibly by lowering circulating levels of protective vitamin D. In contrast, recent epidemiological studies indicate that vitamin D does not protect against prostate cancer, indicating that the role of vitamin D and calcium in this disease process is far from established. Importantly, crucial animal experiments are lacking that may serve to provide mechanistic data for the roles of these nutrients. The objective of the first study conducted in this dissertation was to evaluate and compare prostate carcinogenesis in murine models that utilize the SV40 Tag transformation system- TRAMP and Apt121/Rbf. These are commonly used models in prostate cancer chemoprevention studies. We characterized these models with respect to time to tumor development, tumor size and metastasis. -
ARID1B Is a Specific Vulnerability in ARID1A-Mutant Cancers The
ARID1B is a specific vulnerability in ARID1A-mutant cancers The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. Citation Helming, K. C., X. Wang, B. G. Wilson, F. Vazquez, J. R. Haswell, H. E. Manchester, Y. Kim, et al. 2014. “ARID1B is a specific vulnerability in ARID1A-mutant cancers.” Nature medicine 20 (3): 251-254. doi:10.1038/nm.3480. http://dx.doi.org/10.1038/nm.3480. Published Version doi:10.1038/nm.3480 Accessed February 16, 2015 10:04:32 PM EST Citable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12987227 Terms of Use This article was downloaded from Harvard University's DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA (Article begins on next page) NIH Public Access Author Manuscript Nat Med. Author manuscript; available in PMC 2014 September 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Nat Med. 2014 March ; 20(3): 251–254. doi:10.1038/nm.3480. ARID1B is a specific vulnerability in ARID1A-mutant cancers Katherine C. Helming1,2,3,4,*, Xiaofeng Wang1,2,3,*, Boris G. Wilson1,2,3, Francisca Vazquez5, Jeffrey R. Haswell1,2,3, Haley E. Manchester1,2,3, Youngha Kim1,2,3, Gregory V. Kryukov5, Mahmoud Ghandi5, Andrew J. Aguirre5,6,7, Zainab Jagani8, Zhong Wang9, Levi A. Garraway6, William C. Hahn6,7, and Charles W. -
Genomic Profiling of Adult Acute Lymphoblastic Leukemia by Single
SUPPLEMENTARY APPENDIX Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric acute lymphoblastic leukemia Ryoko Okamoto,1 Seishi Ogawa,2 Daniel Nowak,1 Norihiko Kawamata,1 Tadayuki Akagi,1,3 Motohiro Kato,2 Masashi Sanada,2 Tamara Weiss,4 Claudia Haferlach,4 Martin Dugas,5 Christian Ruckert,5 Torsten Haferlach,4 and H. Phillip Koeffler1,6 1Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA; 2Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 3Department of Stem Cell Biology, Graduate School of Medical Science, Kanazawa University 4MLL Munich Leukemia Laboratory, Munich, Germany; 5Department of Medical Informatics and Biomathematics, University of Münster, Münster, Germany; 6Cancer Science Institute of Singapore, National University of Singapore, Singapore Citation: Okamoto R, Ogawa S, Nowak D, Kawamata N, Akagi T, Kato M, Sanada M, Weiss T, Haferlach C, Dugas M, Ruckert C, Haferlach T, and Koeffler HP. Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonu- cleotide microarray and comparison to pediatric acute lymphoblastic leukemia. Haematologica 2010;95(9):1481-1488. doi:10.3324/haematol.2009.011114 Online Supplementary Data ed by PCR of genomic DNA and subsequent direct sequencing of SNP in a region of CNN-LOH in an ALL sample versus the corresponding Design and Methods matched normal sample (Online Supplementary -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Pdf Sub-Classification of Patients with a Molecular Alteration Provides Better Response [57]
Theranostics 2021, Vol. 11, Issue 12 5759 Ivyspring International Publisher Theranostics 2021; 11(12): 5759-5777. doi: 10.7150/thno.57659 Research Paper Homeobox B5 promotes metastasis and poor prognosis in Hepatocellular Carcinoma, via FGFR4 and CXCL1 upregulation Qin He1, Wenjie Huang2, Danfei Liu1, Tongyue Zhang1, Yijun Wang1, Xiaoyu Ji1, Meng Xie1, Mengyu Sun1, Dean Tian1, Mei Liu1, Limin Xia1 1. Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. 2. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases; Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei, 430030, China. Corresponding author: Dr. Limin Xia, Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China; Phone: 86 27 6937 8507; Fax: 86 27 8366 2832; E-mail: [email protected]. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.12.29; Accepted: 2021.03.17; Published: 2021.03.31 Abstract Background: Since metastasis remains the main reason for HCC-associated death, a better understanding of molecular mechanism underlying HCC metastasis is urgently needed.