Intragenic Integration in DLC1 Sustains Factor VIII Expression in Primary Human Cells Without Insertional Oncogenicity
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Funktionelle in Vitro Und in Vivo Charakterisierung Des Putativen Tumorsuppressorgens SFRP1 Im Humanen Mammakarzinom
Funktionelle in vitro und in vivo Charakterisierung des putativen Tumorsuppressorgens SFRP1 im humanen Mammakarzinom Von der Fakult¨at fur¨ Mathematik, Informatik und Naturwissenschaften der RWTH Aachen University zur Erlangung des akademischen Grades einer Doktorin der Naturwissenschaften genehmigte Dissertation vorgelegt von Diplom-Biologin Laura Huth (geb. Franken) aus Julich¨ Berichter: Universit¨atsprofessor Dr. rer. nat. Edgar Dahl Universit¨atsprofessor Dr. rer. nat. Ralph Panstruga Tag der mundlichen¨ Prufung:¨ 6. August 2014 Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfugbar.¨ Zusammenfassung Krebserkrankungen stellen weltweit eine der h¨aufigsten Todesursachen dar. Aus diesem Grund ist die Aufkl¨arung der zugrunde liegenden Mechanismen und Ur- sachen ein essentielles Ziel der molekularen Onkologie. Die Tumorforschung der letzten Jahre hat gezeigt, dass die Entstehung solider Karzinome ein Mehrstufen- Prozess ist, bei dem neben Onkogenen auch Tumorsuppresorgene eine entschei- dende Rolle spielen. Viele der heute bekannten Gene des WNT-Signalweges wur- den bereits als Onkogene oder Tumorsuppressorgene charakterisiert. Eine Dere- gulation des WNT-Signalweges wird daher mit der Entstehung und Progression vieler humaner Tumorentit¨aten wie beispielsweise auch dem Mammakarzinom, der weltweit h¨aufigsten Krebserkrankung der Frau, assoziiert. SFRP1, ein nega- tiver Regulator der WNT-Signalkaskade, wird in Brusttumoren haupts¨achlich durch den epigenetischen Mechanismus der Promotorhypermethylierung -
Supplemental Tables4.Pdf
Yano_Supplemental_Table_S4 Gene ontology – Biological process 1 of 9 Fold List Pop Pop GO Term Count % PValue Bonferroni Benjamini FDR Genes Total Hits Total Enrichment DLC1, CADM1, NELL2, CLSTN1, PCDHGA8, CTNNB1, NRCAM, APP, CNTNAP2, FERT2, RAPGEF1, PTPRM, MPDZ, SDK1, PCDH9, PTPRS, VEZT, NRXN1, MYH9, GO:0007155~cell CTNNA2, NCAM1, NCAM2, DDR1, LSAMP, CNTN1, 50 5.61 2.14E-08 510 311 7436 2.34 4.50E-05 4.50E-05 3.70E-05 adhesion ROR2, VCAN, DST, LIMS1, TNC, ASTN1, CTNND2, CTNND1, CDH2, NEO1, CDH4, CD24A, FAT3, PVRL3, TRO, TTYH1, MLLT4, LPP, NLGN1, PCDH19, LAMA1, ITGA9, CDH13, CDON, PSPC1 DLC1, CADM1, NELL2, CLSTN1, PCDHGA8, CTNNB1, NRCAM, APP, CNTNAP2, FERT2, RAPGEF1, PTPRM, MPDZ, SDK1, PCDH9, PTPRS, VEZT, NRXN1, MYH9, GO:0022610~biological CTNNA2, NCAM1, NCAM2, DDR1, LSAMP, CNTN1, 50 5.61 2.14E-08 510 311 7436 2.34 4.50E-05 4.50E-05 3.70E-05 adhesion ROR2, VCAN, DST, LIMS1, TNC, ASTN1, CTNND2, CTNND1, CDH2, NEO1, CDH4, CD24A, FAT3, PVRL3, TRO, TTYH1, MLLT4, LPP, NLGN1, PCDH19, LAMA1, ITGA9, CDH13, CDON, PSPC1 DCC, ENAH, PLXNA2, CAPZA2, ATP5B, ASTN1, PAX6, ZEB2, CDH2, CDH4, GLI3, CD24A, EPHB1, NRCAM, GO:0006928~cell CTTNBP2, EDNRB, APP, PTK2, ETV1, CLASP2, STRBP, 36 4.04 3.46E-07 510 205 7436 2.56 7.28E-04 3.64E-04 5.98E-04 motion NRG1, DCLK1, PLAT, SGPL1, TGFBR1, EVL, MYH9, YWHAE, NCKAP1, CTNNA2, SEMA6A, EPHA4, NDEL1, FYN, LRP6 PLXNA2, ADCY5, PAX6, GLI3, CTNNB1, LPHN2, EDNRB, LPHN3, APP, CSNK2A1, GPR45, NRG1, RAPGEF1, WWOX, SGPL1, TLE4, SPEN, NCAM1, DDR1, GRB10, GRM3, GNAQ, HIPK1, GNB1, HIPK2, PYGO1, GO:0007166~cell RNF138, ROR2, CNTN1, -
DLC1 Expression Is Reduced in Human Cutaneous Melanoma And
Modern Pathology (2014) 27, 1203–1211 & 2014 USCAP, Inc. All rights reserved 0893-3952/14 $32.00 1203 DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival Cecilia Sjoestroem1, Shahram Khosravi1, Yabin Cheng1, Gholamreza Safaee Ardekani1, Magdalena Martinka2 and Gang Li1 1Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada and 2Department of Pathology, Vancouver General Hospital, Vancouver, BC, Canada Deleted in Liver Cancer-1 (DLC1) is a Rho-GTPase-activating protein known to be downregulated and function as a tumor suppressor in numerous solid and hematological cancers. Its expression status in melanoma is currently unknown however, prompting us to examine this. Using immunohistochemistry and tissue microarrays containing a large set of melanocytic lesions (n ¼ 539), we examined the expression profile of DLC1 in melanoma progression, as well as the association between DLC1 and patient survival. We detected both cytoplasmic and nuclear DLC1 expression, and found that whereas cytoplasmic DLC1 was significantly downregulated in metastatic melanoma compared with nevi and primary melanoma, nuclear DLC1 expression was significantly down in primary melanoma compared with nevi, and then further down in metastatic melanoma. Loss of cytoplasmic DLC1 was significantly associated with poorer overall and disease-specific 5-year survival rates of all melanoma (Po0.001 and P ¼ 0.001, respectively) and metastatic melanoma patients (P ¼ 0.020 and 0.008, respectively), and similar results were seen for nuclear DLC1 (Po0.001 for both overall and disease-specific survival for all melanoma patients, and P ¼ 0.004 for metastatic melanoma patients). -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Cooperative Antiproliferative Effect of Coordinated Ectopic Expression Of
ONCOLOGY LETTERS 12: 1591-1596, 2016 Cooperative antiproliferative effect of coordinated ectopic expression of DLC1 tumor suppressor protein and silencing of MYC oncogene expression in liver cancer cells: Therapeutic implications XUYU YANG1,2, XIAOLING ZHOU1,3, PAUL TONE4, MARIAN E. DURKIN1,5 and NICHOLAS C. POPESCU1,5 1Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health; 2Section on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Development; 3Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 2089-4262; 4Department of Medicine, Richmond University Medical Center, Staten Island, NY 10310; 5Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4262, USA Received November 11, 2015; Accepted June 3, 2016 DOI: 10.3892/ol.2016.4781 Abstract. Human hepatocellular carcinoma (HCC) is one of the injection to mice bearing subcutaneous xenografts of Huh7 cells most common types of cancer and has a very poor prognosis; transfected with shMyc or control shRNA. A cooperative thus, the development of effective therapies for the treatment of inhibitory effect of DLC1 expression and c-Myc knockdown on advanced HCC is of high clinical priority. In the present study, the growth of Huh7-derived tumors was observed, suggesting the anti-oncogenic effect of combined knockdown of c-Myc that targeted liver cell delivery of DLC1 and c-Myc shRNA expression and ectopic restoration of deleted in liver cancer 1 may serve as a possible gene therapy modality for the treatment (DLC1) expression was investigated in human liver cancer of human HCC. -
Transcriptome Analysis of Human Diabetic Kidney Disease
ORIGINAL ARTICLE Transcriptome Analysis of Human Diabetic Kidney Disease Karolina I. Woroniecka,1 Ae Seo Deok Park,1 Davoud Mohtat,2 David B. Thomas,3 James M. Pullman,4 and Katalin Susztak1,5 OBJECTIVE—Diabetic kidney disease (DKD) is the single cases, mild and then moderate mesangial expansion can be leading cause of kidney failure in the U.S., for which a cure has observed. In general, diabetic kidney disease (DKD) is not yet been found. The aim of our study was to provide an considered a nonimmune-mediated degenerative disease unbiased catalog of gene-expression changes in human diabetic of the glomerulus; however, it has long been noted that kidney biopsy samples. complement and immunoglobulins sometimes can be de- — tected in diseased glomeruli, although their role and sig- RESEARCH DESIGN AND METHODS Affymetrix expression fi arrays were used to identify differentially regulated transcripts in ni cance is not clear (4). 44 microdissected human kidney samples. The DKD samples were The understanding of DKD has been challenged by multi- significant for their racial diversity and decreased glomerular ple issues. First, the diagnosis of DKD usually is made using filtration rate (~20–30 mL/min). Stringent statistical analysis, using clinical criteria, and kidney biopsy often is not performed. the Benjamini-Hochberg corrected two-tailed t test, was used to According to current clinical practice, the development of identify differentially expressed transcripts in control and diseased albuminuria in patients with diabetes is sufficient to make the glomeruli and tubuli. Two different Web-based algorithms were fi diagnosis of DKD (5). We do not understand the correlation used to de ne differentially regulated pathways. -
Identification of a Region of Homozygous Deletion on 8P22–23.1 in Medulloblastoma
Oncogene (2002) 21, 1461 ± 1468 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Identi®cation of a region of homozygous deletion on 8p22 ± 23.1 in medulloblastoma Xiao-lu Yin1, Jesse Chung-sean Pang1 and Ho-keung Ng*,1 1Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China To identify critical tumor suppressor loci that are radiotherapy and chemotherapy, have greatly improved associated with the development of medulloblastoma, the outcomes of patients. In the past 30 years, the 5- we performed a comprehensive genome-wide allelotype year survival rate has increased from 10 to about 50%. analysis in a series of 12 medulloblastomas. Non-random However, long-term survival in children with advanced allelic imbalances were identi®ed on chromosomes 7q disease is only about 30% (Giangaspero et al., 2000; (58.3%), 8p (66.7%), 16q (58.3%), 17p (58.3%) and Heideman et al., 1997). Further enhancement of 17q (66.7%). Comparative genomic hybridization analy- survival will rely on a better understanding of the sis con®rmed that allelic imbalances on 8p, 16q and 17p biology of this malignant disease to improve current were due to loss of genetic materials. Finer deletion treatments or to develop novel therapy. mapping in an expanded series of 23 medulloblastomas Non-random loss of genetic material from chromo- localized the common deletion region on 8p to an interval somal loci is a common feature in the development of of 18.14 cM on 8p22 ± 23.2. -
Looking for Missing Proteins in the Proteome Of
Looking for Missing Proteins in the Proteome of Human Spermatozoa: An Update Yves Vandenbrouck, Lydie Lane, Christine Carapito, Paula Duek, Karine Rondel, Christophe Bruley, Charlotte Macron, Anne Gonzalez de Peredo, Yohann Coute, Karima Chaoui, et al. To cite this version: Yves Vandenbrouck, Lydie Lane, Christine Carapito, Paula Duek, Karine Rondel, et al.. Looking for Missing Proteins in the Proteome of Human Spermatozoa: An Update. Journal of Proteome Research, American Chemical Society, 2016, 15 (11), pp.3998-4019. 10.1021/acs.jproteome.6b00400. hal-02191502 HAL Id: hal-02191502 https://hal.archives-ouvertes.fr/hal-02191502 Submitted on 19 Mar 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Journal of Proteome Research 1 2 3 Looking for missing proteins in the proteome of human spermatozoa: an 4 update 5 6 Yves Vandenbrouck1,2,3,#,§, Lydie Lane4,5,#, Christine Carapito6, Paula Duek5, Karine Rondel7, 7 Christophe Bruley1,2,3, Charlotte Macron6, Anne Gonzalez de Peredo8, Yohann Couté1,2,3, 8 Karima Chaoui8, Emmanuelle Com7, Alain Gateau5, AnneMarie Hesse1,2,3, Marlene 9 Marcellin8, Loren Méar7, Emmanuelle MoutonBarbosa8, Thibault Robin9, Odile Burlet- 10 Schiltz8, Sarah Cianferani6, Myriam Ferro1,2,3, Thomas Fréour10,11, Cecilia Lindskog12,Jérôme 11 1,2,3 7,§ 12 Garin , Charles Pineau . -
A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre- Clinical Discoveries
Cancers 2019 S1 of S18 Supplementary Materials: A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre- Clinical Discoveries Danilo Fiore, Luca Vincenzo Cappelli, Paul Zumbo, Jude M. Phillip, Zhaoqi Liu, Shuhua Cheng, Liron Yoffe, Paola Ghione, Federica Di Maggio, Ahmet Dogan, Inna Khodos, Elisa de Stanchina, Joseph Casano, Clarisse Kayembe, Wayne Tam, Doron Betel, Robin Foa’, Leandro Cerchietti, Raul Rabadan, Steven Horwitz, David M. Weinstock and Giorgio Inghirami A B C Figure S1. (A) Histology micrografts on IL89 PDTX show overall similarity between T1 T3 and T7 passages (upper panels). Immunohistochemical stains with the indicated antibodies (anti-CD3, anti- CD25 and anti-CD8 [x20]) (lower panels). (B) Flow cytometry panel comprehensive of the most represented surface T-cell lymphoma markers, including: CD2, CD3, CD4, CD5, CD8, CD16, CD25, CD30, CD56, TCRab, TCRgd. IL89 PDTX passage T3 is here depicted for illustration purposes. (C) Analysis of the TCR gamma specific rearrangement clonality in IL89 diagnostic sample and correspondent PDTX after 1 and 5 passages (T1 and T5). A WT Primary p.G1097D IL89 T1 p.G1097D IL89 T5 p.G1097D IL89 cell line B Figure S2. (A) Sanger sequencing confirms the presence of the JAK1 p.G1097D mutation in IL89 PDTX samples and in the cell line, but the mutation is undetectable in the primary due to the low sensitivity of the technique. (B) Manual backtracking of mutations in the primary tumor using deep sequencing data allowed for the identification of several hits at a very low VAF compared to the PDTX-T5. A B IL89 CTRL 30 CTRL Ruxoli?nib S 20 M Ruxoli?nib A R G 10 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 1 1 1 1 1 WEEKS AFTER ENGRAFTMENT Figure S3. -
Purification of Full-Length Bcl-2 Family Proteins and Molecular Analysis of Bim-DLC1 Interaction
Purification of full-length Bcl-2 family proteins and molecular analysis of Bim-DLC1 interaction Inaugural-Dissertation zur Erlangung des akademischen Grades des Doktors der Naturwissenschaften (Dr. rer. nat.) an der Fakultät für Biologie der Albert-Ludwigs-Universität Freiburg im Breisgau vorgelegt von Aristomenis Roukounakis geboren in Heraklion, Griechenland Freiburg im Breisgau Februar 2018 Die Untersuchungen zur vorliegenden Arbeit wurden von Oktober 2013 bis Februar 2018 am Institut für Medizinische Mikrobiologie und Hygiene des Universitätsklinikums der Albert- Ludwigs-Universität Freiburg unter der Leitung von Prof. Dr. Georg Häcker durchgeführt. Dekan der Fakultät für Biologie: Prof. Dr. Bettina Warscheid Promotionsvorsitzender: Prof. Dr. Andreas Hiltbrunner Betreuer der Arbeit: Prof. Dr. Georg Häcker Referent: Prof. Dr. Georg Häcker Koreferent: Prof. Dr. Tilman Brummer Drittprüfer: Prof. Dr. Christof Meisinger Datum der mündlichen Prüfung: 07.05.2018 Publication Major part of this thesis has been published in Genes & Development journal (doi: 10.1101/gad.302497.117). Dynein light chain 1 induces assembly of large Bim complexes on mitochondria that stabilize Mcl-1 and regulate apoptosis Prafull Kumar Singh* Aristomenis Roukounakis* Daniel O. Frank, Susanne Kirschnek, Kushal Kumar Das, Simon Neumann, Josef Madl, Winfried Römer, Carina Zorzin, Christoph Borner, Ana Garcia-Saez, Arnim Weber and Georg Häcker* *equal contribution Table of contents I. Summary ............................................................................................................................. -
Characterizing Genomic Duplication in Autism Spectrum Disorder by Edward James Higginbotham a Thesis Submitted in Conformity
Characterizing Genomic Duplication in Autism Spectrum Disorder by Edward James Higginbotham A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Molecular Genetics University of Toronto © Copyright by Edward James Higginbotham 2020 i Abstract Characterizing Genomic Duplication in Autism Spectrum Disorder Edward James Higginbotham Master of Science Graduate Department of Molecular Genetics University of Toronto 2020 Duplication, the gain of additional copies of genomic material relative to its ancestral diploid state is yet to achieve full appreciation for its role in human traits and disease. Challenges include accurately genotyping, annotating, and characterizing the properties of duplications, and resolving duplication mechanisms. Whole genome sequencing, in principle, should enable accurate detection of duplications in a single experiment. This thesis makes use of the technology to catalogue disease relevant duplications in the genomes of 2,739 individuals with Autism Spectrum Disorder (ASD) who enrolled in the Autism Speaks MSSNG Project. Fine-mapping the breakpoint junctions of 259 ASD-relevant duplications identified 34 (13.1%) variants with complex genomic structures as well as tandem (193/259, 74.5%) and NAHR- mediated (6/259, 2.3%) duplications. As whole genome sequencing-based studies expand in scale and reach, a continued focus on generating high-quality, standardized duplication data will be prerequisite to addressing their associated biological mechanisms. ii Acknowledgements I thank Dr. Stephen Scherer for his leadership par excellence, his generosity, and for giving me a chance. I am grateful for his investment and the opportunities afforded me, from which I have learned and benefited. I would next thank Drs. -
SRC and ERK Cooperatively Phosphorylate DLC1 and Attenuate Its Rho-GAP and Tumor Suppressor Functions
ARTICLE SRC and ERK cooperatively phosphorylate DLC1 and attenuate its Rho-GAP and tumor suppressor functions Brajendra K. Tripathi1,MeghanF.Anderman1, Xiaolan Qian1,MingZhou2, Dunrui Wang1, Alex G. Papageorge1, and Douglas R. Lowy1 SRC and ERK kinases control many cell biological processes that promote tumorigenesis by altering the activity of oncogenic and tumor suppressor proteins. We identify here a physiological interaction between DLC1, a focal adhesion protein and tumor suppressor, with SRC and ERK. The tumor suppressor function of DLC1 is attenuated by phosphorylation of tyrosines Y451 and Y701 by SRC, which down-regulates DLC1’s tensin-binding and Rho-GAP activities. ERK1/2 phosphorylate DLC1 on serine S129, which increases both the binding of SRC to DLC1 and SRC-dependent phosphorylation of DLC1. SRC inhibitors exhibit potent antitumor activity in a DLC1-positive transgenic cancer model and a DLC1-positive tumor xenograft model, due to reactivation of the tumor suppressor activities of DLC1. Combined treatment of DLC1-positive tumors with SRC plus AKT inhibitors has even greater antitumor activity. Together, these findings indicate cooperation between the SRC, ERK1/2, and AKT kinases to reduce DLC1 Rho-GAP and tumor suppressor activities in cancer cells, which can be reactivated by the kinase inhibitors. Introduction The SRC gene is the prototypic member of the SRC family kinases 2014; Takahashi et al., 2017). In addition, SRC phosphorylation of (SFKs), whose nine members encode nonreceptor tyrosine- other targets, such as PP2A and caveolin-1, can attenuate their protein kinases that share a similar structure and have key tumor suppressor activities. roles in normal physiology and cancer (Sen and Johnson, 2011).