Wt1) – an Effector in Leukemogenesis?
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An Integrated Genome Screen Identifies the Wnt Signaling Pathway As a Major Target of WT1
An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1 Marianne K.-H. Kima,b, Thomas J. McGarryc, Pilib O´ Broind, Jared M. Flatowb, Aaron A.-J. Goldend, and Jonathan D. Lichta,b,1 aDivision of Hematology/Oncology and cFeinberg Cardiovascular Research Institute, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; bRobert H. Lurie Cancer Center, Northwestern University, Chicago, IL 60611; and dDepartment of Information Technology, National University of Ireland, Galway, Republic of Ireland Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved May 18, 2009 (received for review February 12, 2009) WT1, a critical regulator of kidney development, is a tumor suppressor control. A first generation of in vitro cotransfection and DNA for nephroblastoma but in some contexts functions as an oncogene. binding assays have given way to more biologically relevant exper- A limited number of direct transcriptional targets of WT1 have been iments where manipulation of WT1 levels has been accompanied identified to explain its complex roles in tumorigenesis and organo- by examination of candidate or global gene expression. Classes of genesis. In this study we performed genome-wide screening for direct WT1 targets thus identified consist of inducers of differentiation, WT1 targets, using a combination of ChIP–ChIP and expression arrays. regulators of cell growth and modulators of cell death. WT1 target Promoter regions bound by WT1 were highly G-rich and resembled genes include CDKN1A (22), a negative regulator of the cell cycle; the sites for a number of other widely expressed transcription factors AREG (23), a facilitator of kidney differentiation; WNT4 (24), a such as SP1, MAZ, and ZNF219. -
(NF1) Defects Are Common in Human Ovarian Serous Carcinomas and Co-Occur with TP53 Mutations
Volume 10 Number 12 December 2008 pp. 1362–1372 1362 www.neoplasia.com Neurofibromin 1 (NF1) Defects Navneet Sangha*, Rong Wu*, Rork Kuick†, Scott Powers‡, David Mu§, Diane Fiander*, Are Common in Human Ovarian Kit Yuen*, Hidetaka Katabuchi¶, Hironori Tashiro¶, Serous Carcinomas and Co-occur Eric R. Fearon*,†,# and Kathleen R. Cho*,†,# 1,2 with TP53 Mutations *Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA; †The Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, MI 48109, USA; ‡Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; §Department of Pathology, Penn State University College of Medicine, Hershey, PA 17033, USA; ¶Department of Gynecology, Kumamoto University, Kumamoto, 860-8556, Japan; #Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109, USA Abstract Ovarian serous carcinoma (OSC) is the most common and lethal histologic type of ovarian epithelial malignancy. Mutations of TP53 and dysfunction of the Brca1 and/or Brca2 tumor-suppressor proteins have been implicated in the molecular pathogenesis of a large fraction of OSCs, but frequent somatic mutations in other well-established tumor-suppressor genes have not been identified. Using a genome-wide screen of DNA copy number alterations in 36 primary OSCs, we identified two tumors with apparent homozygous deletions of the NF1 gene. Subsequently, 18 ovarian carcinoma–derived cell lines and 41 primary OSCs were evaluated for NF1 alterations. Markedly re- duced or absent expression of Nf1 protein was observed in 6 of the 18 cell lines, and using the protein truncation test and sequencing of cDNA and genomic DNA, NF1 mutations resulting in deletion of exons and/or aberrant splicing of NF1 transcripts were detected in 5 of the 6 cell lines with loss of NF1 expression. -
Biomarker Testing in Non- Small Cell Lung Cancer (NSCLC)
The biopharma business of Merck KGaA, Darmstadt, Germany operates as EMD Serono in the U.S. and Canada. Biomarker testing in non- small cell lung cancer (NSCLC) Copyright © 2020 EMD Serono, Inc. All rights reserved. US/TEP/1119/0018(1) Lung cancer in the US: Incidence, mortality, and survival Lung cancer is the second most common cancer diagnosed annually and the leading cause of mortality in the US.2 228,820 20.5% 57% Estimated newly 5-year Advanced or 1 survival rate1 metastatic at diagnosed cases in 2020 diagnosis1 5.8% 5-year relative 80-85% 2 135,720 survival with NSCLC distant disease1 Estimated deaths in 20201 2 NSCLC, non-small cell lung cancer; US, United States. 1. National Institutes of Health (NIH), National Cancer Institute. Cancer Stat Facts: Lung and Bronchus Cancer website. www.seer.cancer.gov/statfacts/html/lungb.html. Accessed May 20, 2020. 2. American Cancer Society. What is Lung Cancer? website. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html. Accessed May 20, 2020. NSCLC is both histologically and genetically diverse 1-3 NSCLC distribution by histology Prevalence of genetic alterations in NSCLC4 PTEN 10% DDR2 3% OTHER 25% PIK3CA 12% LARGE CELL CARCINOMA 10% FGFR1 20% SQUAMOUS CELL CARCINOMA 25% Oncogenic drivers in adenocarcinoma Other or ADENOCARCINOMA HER2 1.9% 40% KRAS 25.5% wild type RET 0.7% 55% NTRK1 1.7% ROS1 1.7% Oncogenic drivers in 0% 20% 40% 60% RIT1 2.2% squamous cell carcinoma Adenocarcinoma DDR2 2.9% Squamous cell carcinoma NRG1 3.2% Large cell carcinoma -
Wilms' Tumor Gene 1 in Different Types of Cancer
UMEÅ UNIVERSITY MEDICAL DISSERTATIONS New Series No.1717 ISSN 0346-6612 ISBN 978-91-7601-263-5 Wilms’ tumor gene 1 in different types of cancer Xingru Li Department of Medical Biosciences, Clinical Chemistry Umeå University, Sweden Umeå 2015 Copyright © 2015 Xingru Li ISBN: 978-91-7601-263-5 ISSN: 0346-6612 Printed by: Print & Media Umeå, Sweden, 2015 To my family Table of Contents Abstract .......................................................................................................... 1 Original Articles ............................................................................................. 2 Abbreviations ................................................................................................. 3 Introduction .................................................................................................... 4 WT1 (Wilms’ tumor gene 1) ...................................................................... 4 Structure of WT1 ..................................................................................... 4 WT1, the transcription factor ................................................................. 5 WT1 and its interacting partners ............................................................ 5 WT1 function .......................................................................................... 8 The tumor suppressor ........................................................................ 8 An oncogene ...................................................................................... 8 Mutations and -
Identification of Transcriptional Mechanisms Downstream of Nf1 Gene Defeciency in Malignant Peripheral Nerve Sheath Tumors Daochun Sun Wayne State University
Wayne State University DigitalCommons@WayneState Wayne State University Dissertations 1-1-2012 Identification of transcriptional mechanisms downstream of nf1 gene defeciency in malignant peripheral nerve sheath tumors Daochun Sun Wayne State University, Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Recommended Citation Sun, Daochun, "Identification of transcriptional mechanisms downstream of nf1 gene defeciency in malignant peripheral nerve sheath tumors" (2012). Wayne State University Dissertations. Paper 558. This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. IDENTIFICATION OF TRANSCRIPTIONAL MECHANISMS DOWNSTREAM OF NF1 GENE DEFECIENCY IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS by DAOCHUN SUN DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2012 MAJOR: MOLECULAR BIOLOGY AND GENETICS Approved by: _______________________________________ Advisor Date _______________________________________ _______________________________________ _______________________________________ © COPYRIGHT BY DAOCHUN SUN 2012 All Rights Reserved DEDICATION This work is dedicated to my parents and my wife Ze Zheng for their continuous support and understanding during the years of my education. I could not achieve my goal without them. ii ACKNOWLEDGMENTS I would like to express tremendous appreciation to my mentor, Dr. Michael Tainsky. His guidance and encouragement throughout this project made this dissertation come true. I would also like to thank my committee members, Dr. Raymond Mattingly and Dr. John Reiners Jr. for their sustained attention to this project during the monthly NF1 group meetings and committee meetings, Dr. -
Beyond Traditional Morphological Characterization of Lung
Cancers 2020 S1 of S15 Beyond Traditional Morphological Characterization of Lung Neuroendocrine Neoplasms: In Silico Study of Next-Generation Sequencing Mutations Analysis across the Four World Health Organization Defined Groups Giovanni Centonze, Davide Biganzoli, Natalie Prinzi, Sara Pusceddu, Alessandro Mangogna, Elena Tamborini, Federica Perrone, Adele Busico, Vincenzo Lagano, Laura Cattaneo, Gabriella Sozzi, Luca Roz, Elia Biganzoli and Massimo Milione Table S1. Genes Frequently mutated in Typical Carcinoids (TCs). Mutation Original Entrez Gene Gene Rate % eukaryotic translation initiation factor 1A X-linked [Source: HGNC 4.84 EIF1AX 1964 EIF1AX Symbol; Acc: HGNC: 3250] AT-rich interaction domain 1A [Source: HGNC Symbol;Acc: HGNC: 4.71 ARID1A 8289 ARID1A 11110] LDL receptor related protein 1B [Source: HGNC Symbol; Acc: 4.35 LRP1B 53353 LRP1B HGNC: 6693] 3.53 NF1 4763 NF1 neurofibromin 1 [Source: HGNC Symbol;Acc: HGNC: 7765] DS cell adhesion molecule like 1 [Source: HGNC Symbol; Acc: 2.90 DSCAML1 57453 DSCAML1 HGNC: 14656] 2.90 DST 667 DST dystonin [Source: HGNC Symbol;Acc: HGNC: 1090] FA complementation group D2 [Source: HGNC Symbol; Acc: 2.90 FANCD2 2177 FANCD2 HGNC: 3585] piccolo presynaptic cytomatrix protein [Source: HGNC Symbol; Acc: 2.90 PCLO 27445 PCLO HGNC: 13406] erb-b2 receptor tyrosine kinase 2 [Source: HGNC Symbol; Acc: 2.44 ERBB2 2064 ERBB2 HGNC: 3430] BRCA1 associated protein 1 [Source: HGNC Symbol; Acc: HGNC: 2.35 BAP1 8314 BAP1 950] capicua transcriptional repressor [Source: HGNC Symbol; Acc: 2.35 CIC 23152 CIC HGNC: -
The NF2 Tumor Suppressor Merlin Interacts with Ras and Rasgap, Which May Modulate Ras Signaling
Oncogene (2019) 38:6370–6381 https://doi.org/10.1038/s41388-019-0883-6 ARTICLE The NF2 tumor suppressor merlin interacts with Ras and RasGAP, which may modulate Ras signaling 1 1 2 1 1 1 Yan Cui ● Susann Groth ● Scott Troutman ● Annemarie Carlstedt ● Tobias Sperka ● Lars Björn Riecken ● 2 3 1 Joseph L. Kissil ● Hongchuan Jin ● Helen Morrison Received: 5 July 2018 / Revised: 31 March 2019 / Accepted: 1 May 2019 / Published online: 16 July 2019 © The Author(s) 2019. This article is published with open access Abstract Inactivation of the tumor suppressor NF2/merlin underlies neurofibromatosis type 2 (NF2) and some sporadic tumors. Previous studies have established that merlin mediates contact inhibition of proliferation; however, the exact mechanisms remain obscure and multiple pathways have been implicated. We have previously reported that merlin inhibits Ras and Rac activity during contact inhibition, but how merlin regulates Ras activity has remained elusive. Here we demonstrate that merlin can directly interact with both Ras and p120RasGAP (also named RasGAP). While merlin does not increase the catalytic activity of RasGAP, the interactions with Ras and RasGAP may fine-tune Ras signaling. In vivo, loss of RasGAP in 1234567890();,: 1234567890();,: Schwann cells, unlike the loss of merlin, failed to promote tumorigenic growth in an orthotopic model. Therefore, modulation of Ras signaling through RasGAP likely contributes to, but is not sufficient to account for, merlin’s tumor suppressor activity. Our study provides new insight into the mechanisms of merlin-dependent Ras regulation and may have additional implications for merlin-dependent regulation of other small GTPases. Introduction ependymomas, and astrocytomas [1]. -
Hirbe AC, Kaushal M, Sharma MK
Original Article Clinical Genomic Profiling Identifies TYK2 Mutation and Overexpression in Patients With Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors Angela C. Hirbe, MD, PhD1; Madhurima Kaushal, MS2; Mukesh Kumar Sharma, PhD2; Sonika Dahiya, MD2; Melike Pekmezci, MD3; Arie Perry, MD3,4; and David H. Gutmann, MD, PhD5 BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise at an estimated frequency of 8% to 13% in individuals with neurofibromatosis type 1 (NF1). Compared with their sporadic counterparts, NF1-associated MPNSTs (NF1-MPNSTs) develop in young adults, frequently recur (approximately 50% of cases), and carry a dismal prognosis. As such, most individuals affected with NF1-MPNSTs die within 5 years of diagnosis, despite surgical resection combined with radiotherapy and che- motherapy. METHODS: Clinical genomic profiling was performed using 1000 ng of DNA from 7 cases of NF1-MPNST, and bioinformatic analyses were conducted to identify genes with actionable mutations. RESULTS: A total of 3 women and 4 men with NF1-MPNST were identified (median age, 38 years). Nonsynonymous mutations were discovered in 4 genes (neurofibromatosis type 1 [NF1], ROS proto-oncogene 1 [ROS1], tumor protein p53 [TP53], and tyrosine kinase 2 [TYK2]), which in addition were mutated in other MPNST cases in this sample set. Consistent with their occurrence in individuals with NF1, all tumors had at least 1 mutation in the NF1 gene. Whereas TP53 gene mutations are frequently observed in other cancers, ROS1 mutations are common in melanoma (15%-35%), anoth- er neural crest-derived malignancy. In contrast, TYK2 mutations are uncommon in other malignancies (<7%). -
Dysregulation of Meox2 Following Wt1 Mutation in Kidney Development and Wilms Tumorigenesis
The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2011 DYSREGULATION OF MEOX2 FOLLOWING WT1 MUTATION IN KIDNEY DEVELOPMENT AND WILMS TUMORIGENESIS LaGina M. Nosavanh LaGina Merie Nosavanh Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Medicine and Health Sciences Commons Recommended Citation Nosavanh, LaGina M. and Nosavanh, LaGina Merie, "DYSREGULATION OF MEOX2 FOLLOWING WT1 MUTATION IN KIDNEY DEVELOPMENT AND WILMS TUMORIGENESIS" (2011). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 203. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/203 This Thesis (MS) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. DYSREGULATION OF MEOX2 FOLLOWING WT1 MUTATION IN KIDNEY DEVELOPMENT AND WILMS TUMORIGENESIS by LaGina Merie Nosavanh, B.S. -
Wilms' Tumor Suppressor Gene WT1: from Structure to Renal
J Am Soc Nephrol 11: S106–S115, 2000 Wilms’ Tumor Suppressor Gene WT1: From Structure to Renal Pathophysiologic Features CHRISTIAN MROWKA*† and ANDREAS SCHEDL* *Max Delbru¨ck Center for Molecular Medicine and †Franz Volhard Clinic, Humboldt University of Berlin, Berlin-Buch, Germany. Abstract. Normal development of the kidney is a highly com- current understanding of the structural features of WT1, how plex process that requires precise orchestration of proliferation, they modulate the transcriptional and post-transcriptional ac- differentiation, and apoptosis. In the past few years, a number tivities of the protein, and how mutations affecting individual of genes that regulate these processes, and hence play pivotal isoforms can lead to diseased kidneys is summarized. In addi- roles in kidney development, have been identified. The Wilms’ tion, results from transgenic experiments, which have yielded tumor suppressor gene WT1 has been shown to be one of these important findings regarding the function of WT1 in vivo, are essential regulators of kidney development, and mutations in discussed. Finally, data on the unusual feature of RNA editing this gene result in the formation of tumors and developmental of WT1 transcripts are presented, and the relevance of RNA abnormalities such as the Denys-Drash and Frasier syndromes. editing for the normal functioning of the WT1 protein in the A fascinating aspect of the WT1 gene is the multitude of kidney is discussed. isoforms produced from its genomic locus. In this review, our The kidney is crucial for survival. The molecular mechanisms Structural Features underlying the development of this organ, however, are only The human WT1 gene spans approximately 50 kb and in- beginning to be elucidated. -
Wt1 Directs the Lineage Specification of Sertoli and Granulosa Cells By
© 2017. Published by The Company of Biologists Ltd | Development (2017) 144, 44-53 doi:10.1242/dev.144105 RESEARCH ARTICLE Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression Min Chen1,*, Lianjun Zhang1,2,*, Xiuhong Cui1, Xiwen Lin1, Yaqiong Li1,2, Yaqing Wang3, Yanbo Wang1,2, Yan Qin1,2, Dahua Chen1, Chunsheng Han1, Bin Zhou4, Vicki Huff5 and Fei Gao1,‡ ABSTRACT Leydig cells and theca-interstitial cells are the steroidogenic cells Supporting cells (Sertoli and granulosa) and steroidogenic cells in male and female gonads, respectively. The steroid hormones (Leydig and theca-interstitium) are two major somatic cell types in produced by steroidogenic cells play essential roles in germ cell mammalian gonads, but the mechanisms that control their development and in maintaining secondary sexual characteristics. differentiation during gonad development remain elusive. In this Leydig cells first appear in testes at E12.5, whereas theca-interstitial study, we found that deletion of Wt1 in the ovary after sex cells are observed postnatally in the ovaries along with the determination caused ectopic development of steroidogenic cells at development of ovarian follicles. The origins of Leydig cells the embryonic stage. Furthermore, differentiation of both Sertoli and (Weaver et al., 2009; Barsoum and Yao, 2010; DeFalco et al., 2011) granulosa cells was blocked when Wt1 was deleted before sex and theca cells (Liu et al., 2015) have been studied previously. determination and most genital ridge somatic cells differentiated into However, the underlying mechanism that regulates the steroidogenic cells in both male and female gonads. Further studies differentiation between supporting cells and steroidogenic cells revealed that WT1 repressed Sf1 expression by directly binding to the during gonad development is poorly understood. -
Activation of the Wt1 Wilms' Tumor Suppressor Gene by NF-Кb
Oncogene (1998) 16, 2033 ± 2039 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Activation of the wt1 Wilms' tumor suppressor gene by NF-kB Mohammed Dehbi1, John Hiscott2 and Jerry Pelletier1,3 1Department of Biochemistry and 3Department of Oncology, McGill University, 3655 Drummond St., MontreÂal, QueÂbec, Canada, H3G 1Y6, and 2Lady Davis Institute for Medical Research, 3755 CoÃte Ste-Catherine, Montreal, QueÂbec, Canada, H3T 1E2 The Wilm's tumor suppressor gene, wt1, is expressed in the glutamine/proline rich amino (N-) terminus of a very de®ned spatial-temporal fashion and plays a key WT1, whereas the second alternatively spliced exon role in development of the urogenital system. Trans- results in the insertion of three amino acids, KTS, acting factors governing wt1 expression are poorly between the third and the fourth zinc ®ngers (for a de®ned. The presence of putative kB binding sites within review, see Reddy and Licht, 1996). WT1 has several the wt1 gene prompted us to investigate whether key structural features of a transcription factor such as members of the NF-kB/Rel family of transcription nuclear localization, a proline/glutamine N-terminal factors are involved in regulating wt1 expression. In rich region, and a DNA-binding domain consisting of transient transfection assays, ectopic expression of p50 four zinc ®ngers. Three of the four zinc ®ngers (II, III and p65 subunits of NF-kB stimulated wt1 promoter and IV) share extensive homology with those of the activity 10 ± 30-fold. Deletion mutagenesis revealed that early growth response (EGR) family of transcription NF-kB responsiveness is mediated by a short DNA factors and consequently, WT1 can bind to, and fragment located within promoter proximal sequences of regulate, the expression of numerous genes through the major transcription start site.