Increased Susceptibility to Tumorigenesis of Ski-Deficient
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The Ski Oncoprotein Interacts with Skip, the Human Homolog of Drosophila Bx42
Oncogene (1998) 16, 1579 ± 1586 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 The Ski oncoprotein interacts with Skip, the human homolog of Drosophila Bx42 Richard Dahl, Bushra Wani and Michael J Hayman Department of Microbiology, State University of New York, Stony Brook, New York 11794, USA The v-Ski avian retroviral oncogene is postulated to act Little is known about how Ski functions. Both the as a transcription factor. Since protein ± protein interac- cellular and the viral genes share transforming and tions have been shown to play an important role in the muscle inducing ability. Ski localizes to the nucleus and transcription process, we attempted to identify Ski is observed to associate with chromatin (Barkas et al., protein partners with the yeast two-hybrid system. Using 1986; Sutrave et al., 1990a). Because of its nuclear v-Ski sequence as bait, the human gene skip (Ski localization and its ability to induce expression of Interacting Protein) was identi®ed as encoding a protein muscle speci®c genes in quail cells (Colmenares and which interacts with both the cellular and viral forms of Stavnezer, 1989), Ski has been assumed to be a Ski in the two-hybrid system. Skip is highly homologous transcription factor. Consistent with this assumption, to the Drosophila melanogaster protein Bx42 which is c-Ski has been shown to bind DNA in vitro with the found associated with chromatin in transcriptionally help of an unknown protein factor (Nagase et al., active pus of salivary glands. The Ski-Skip interaction 1990), and has been recently shown to enhance MyoD is potentially important in Ski's transforming activity dependent transactivation of a myosin light chain since Skip was demonstrated to interact with a highly enhancer linked reporter gene in muscle cells (Engert conserved region of Ski required for transforming et al., 1995). -
Mutations in SKI in Shprintzen–Goldberg Syndrome Lead to Attenuated TGF-B Responses Through SKI Stabilization
RESEARCH ARTICLE Mutations in SKI in Shprintzen–Goldberg syndrome lead to attenuated TGF-b responses through SKI stabilization Ilaria Gori1, Roger George2, Andrew G Purkiss2, Stephanie Strohbuecker3, Rebecca A Randall1, Roksana Ogrodowicz2, Virginie Carmignac4, Laurence Faivre4, Dhira Joshi5, Svend Kjær2, Caroline S Hill1* 1Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom; 2Structural Biology Facility, The Francis Crick Institute, London, United Kingdom; 3Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom; 4INSERM - Universite´ de Bourgogne UMR1231 GAD, FHU-TRANSLAD, Dijon, France; 5Peptide Chemistry Facility, The Francis Crick Institute, London, United Kingdom Abstract Shprintzen–Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys–Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-b signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-b signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-b responses, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-b- *For correspondence: induced transcriptional responses, and not enhancement, which has important implications for [email protected] other Marfan-related syndromes. Competing interests: The authors declare that no competing interests exist. -
PARANEOPLASTIC SYNDROMES: J Neurol Neurosurg Psychiatry: First Published As 10.1136/Jnnp.2004.040378 on 14 May 2004
PARANEOPLASTIC SYNDROMES: J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.040378 on 14 May 2004. Downloaded from WHEN TO SUSPECT, HOW TO CONFIRM, AND HOW TO MANAGE ii43 J H Rees J Neurol Neurosurg Psychiatry 2004;75(Suppl II):ii43–ii50. doi: 10.1136/jnnp.2004.040378 eurological manifestations of cancer are common, disabling, and often multifactorial (table 1). The concept that malignant disease can cause damage to the nervous system Nabove and beyond that caused by direct or metastatic infiltration is familiar to all clinicians looking after cancer patients. These ‘‘remote effects’’ or paraneoplastic manifestations of cancer include metabolic and endocrine syndromes such as hypercalcaemia, and the syndrome of inappropriate ADH (antidiuretic hormone) secretion. Paraneoplastic neurological disorders (PNDs) are remote effects of systemic malignancies that affect the nervous system. The term PND is reserved for those disorders that are caused by an autoimmune response directed against antigens common to the tumour and nerve cells. PNDs are much less common than direct, metastatic, and treatment related complications of cancer, but are nevertheless important because they cause severe neurological morbidity and mortality and frequently present to the neurologist in a patient without a known malignancy. Because of the relative rarity of PND, neurological dysfunction should only be regarded as paraneoplastic if a particular neoplasm associates with a remote but specific effect on the nervous system more frequently than would be expected by chance. For example, subacute cerebellar ataxia in the setting of ovarian cancer is sufficiently characteristic to be called paraneoplastic cerebellar degeneration, as long as other causes have been ruled out. -
Paraneoplastic Neurologic Syndromes
DO I:10.4274/tnd.05900 Turk J Neurol 2018;24:63-69 Case Report / Olgu Sunumu Paraneoplastic Neurologic Syndromes: Rare But More Common Than Expected Nine Cases with a Literature Review Paraneoplastik Nörolojik Sendromlar: Nadir Ancak Beklenenden Daha Sık Dokuz Olgu ile Literatür Derlemesi Hülya Uluğut Erkoyun, Sevgin Gündoğan, Yaprak Seçil, Yeşim Beckmann, Tülay Kurt İncesu, Hatice Sabiha Türe, Galip Akhan Izmir Katip Celebi University, Atatürk Training and Research Hospital, Department of Neurology, Izmir, Turkey Abstract Paraneoplastic neurologic syndromes (PNS) are rare disorders, which are remote effects of cancer that are not caused by the tumor, its metastasis or side effects of treatment. We had nine patients with PNS; two of our patients had limbic encephalitis, but one had autoimmune limbic encephalitis with no malignancy; two patients had subacute cerebellar degeneration; three had Stiff-person syndrome; one had Lambert-Eaton myasthenic syndrome; and the remaining patient had sensory neuronopathy. In most patients, the neurologic disorder develops before the cancer becomes clinically overt and the patient is referred to a neurologist. Five of our patients’ malignancies had been diagnosed in our clinic after their neurologic symptoms became overt. PNS are more common than expected and neurologists should be aware of the variety of the clinical presentations of these syndromes. When physicians suspect PNS, cancer screening should be conducted. The screening must continue even if the results are negative. Keywords: Paraneoplastic, neurologic syndromes, neurogenic autoantibodies Öz Paraneoplastik nörolojik sendromlar (PNS), kanserin doğrudan, metastaz ya da tedavi yan etkisine bağlı olmayan, uzak etkisi ile ortaya çıkan nadir hastalıklardır. Dokuz PNS’li hastanın ikisi limbik ensefalitti fakat bunlardan biri otoimmün limbik ensefalitti ve malignitesi yoktu. -
The New Melanoma: a Novel Model for Disease Progression
DISS. ETH NO. 17606 The new melanoma: A novel model for disease progression A dissertation submitted to SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZÜRICH for the degree of DOCTOR OF SCIENCES presented by Natalie Schlegel Master of Science, Otago University (New Zealand) born on January 20th 1976 citizen of Zürich (ZH) accepted on the recommendation of Professor Sabine Werner, examinor Professor Reinhard Dummer, co-examinor Professor Josef Jiricny, co-examinor 2008 22 Table of Contents Abstract ...................................................................................................................................... 6 Résumé....................................................................................................................................... 8 Abbreviations ........................................................................................................................... 10 1. Introduction ...................................................................................................................... 13 1.1 Definition ................................................................................................................. 14 1.2 Clinical features........................................................................................................ 14 1.3 Pathological features and staging............................................................................. 16 1.3.2 Clark’s level of invasion and Breslow’s thickness........................................... 16 1.3.3 TNM staging ................................................................................................... -
The Role of Drosophila Bx42/SKIP in Cell Cycle
The Role of Drosophila Bx42/SKIP in Cell Cycle D i s s e r t a t i o n zur Erlangung des akademischen Grades d o c t o r r e r u m n a t u r a l i u m (Dr. rer. nat.) im Fach Biologie eingereicht an der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin von Diplom-Biologin Shaza Dehne Präsidentin der Humboldt-Universität zu Berlin Prof. Dr.-Ing. Dr. Sabine Kunst Dekanin/Dekan der Lebenswissenschaftlichen Fakultät Prof. Dr. Richard Lucius Gutachter/innen: 1. Prof. Dr. Harald Saumweber 2. Prof. Dr. Christian Schmitz-Linneweber 3. Prof. Dr. Achim Leutz Tag der mündlichen Prüfung: 30.11.2016 Contents Abstract Abstrakt 1 Introduction .................................................................. 10 1.1 Bx42: Identification, protein structure and function .................................................. 11 1.2 Bx42/SNW/SKIP is an essential protein family, conserved in evolution and involved in several biological processes ............................................................................................ 13 1.2.1 Involvement of Bx42/SNW/SKIP in signaling pathways ................................ 16 1.2.1.1 Involvement in nuclear receptor pathways ................................................ 16 1.2.1.2 Involvement in the Notch signaling pathway ............................................ 17 1.2.1.3 Involvement in the TGF-ß/Dpp signal pathway ........................................ 19 1.2.2 Involvement of Bx42/SNW/SKIP in RNA splicing ......................................... 20 1.2.3 Bx42/SNW/SKIP protein family and cell cycle regulation .............................. 22 1.2.3.1 Short overview on cell cycle regulation. ................................................... 22 1.2.3.2 Evidence for Bx42/SNW/SKIP contribution to cell cycle regulation ....... 24 1.3 Drosophila eye imaginal disc: a model to study proliferation and cell cycle regulation during development. -
(Cxxc5) a Thesis Submitted to the Graduate
STRUCTURAL AND FUNCTIONAL CHARACTERIZATION OF THE CXXC-TYPE ZINC FINGER PROTEIN 5 (CXXC5) A THESIS SUBMITTED TO THE GRADUATE SCHOOL OF NATURAL AND APPLIED SCIENCES OF MIDDLE EAST TECHNICAL UNIVERSITY BY GAMZE AYAZ ŞEN IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN BIOLOGY NOVEMBER 2018 Approval of the thesis: STRUCTURAL AND FUNCTIONAL CHARACTERIZATION OF THE CXXC-TYPE ZINC FINGER PROTEIN 5 (CXXC5) submitted by GAMZE AYAZ ŞEN in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biology Department, Middle East Technical University by, Prof. Dr. Halil Kalıpçılar Dean, Graduate School of Natural and Applied Sciences Prof. Dr. Orhan Adalı Head of Department, Biological Sciences Prof. Dr. Mesut Muyan Supervisor, Biological Sciences Dept., METU Examining Committee Members: Prof. Dr. A. Elif Erson Bensan Biological Sciences Dept., METU Prof. Dr. Mesut Muyan Biological Sciences Dept., METU Asst. Prof. Dr. Murat Alper Cevher Molecular Biology and Genetics Dept., Bilkent University Assoc. Prof. Dr. Nurcan Tunçbağ Informatics Institute, METU Asst. Prof. Dr. Onur Çizmecioğlu Molecular Biology and Genetics Dept., Bilkent University Date: 16.11.2018 I hereby declare that all information in this document has been obtained and presented in accordance with academic rules and ethical conduct. I also declare that, as required by these rules and conduct, I have fully cited and referenced all material and results that are not original to this work. Name, Last name: Gamze Ayaz Şen Signature: iv To All Women Who Pursue Their Dreams In Science v ABSTRACT STRUCTURAL AND FUNCTIONAL CHARACTERIZATION OF THE CXXC-TYPE ZINC FINGER PROTEIN 5 (CXXC5) Ayaz Şen, Gamze Ph.D., Biology Department Supervisor: Prof. -
The SMAD-Binding Domain of SKI: a Hotspot for De Novo Mutations Causing Shprintzen&Ndash
European Journal of Human Genetics (2015) 23, 224–228 & 2015 Macmillan Publishers Limited All rights reserved 1018-4813/15 www.nature.com/ejhg ARTICLE The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen–Goldberg syndrome Dorien Schepers1,20, Alexander J Doyle2,3,20,GretchenOswald2, Elizabeth Sparks2,LorethaMyers2,PatrickJWillems4, Sahar Mansour5, Michael A Simpson6,HelenaFrysira7, Anneke Maat-Kievit8,RickVanMinkelen8, Jeanette M Hoogeboom8, Geert R Mortier1, Hannah Titheradge9,LouiseBrueton9,LoisStarr10, Zornitza Stark11, Charlotte Ockeloen12, Charles Marques Lourenco13,EdBlair14, Emma Hobson15,JaneHurst16, Isabelle Maystadt17, Anne Destre´e17, Katta M Girisha18, Michelle Miller19,HarryCDietz2,3,BartLoeys1,20 and Lut Van Laer*,1,20 Shprintzen–Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys–Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFb activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). -
Volume Doubling Time Does Not Predict Cancer in Follicular Neoplasm Nodules
® Clinical Thyroidology for the Public VOLUME 12 | ISSUE 12 | DECEMBER 2019 THYROID NODULES Volume doubling time does not predict cancer in follicular neoplasm nodules BACKGROUND patients had specific reasons to delay surgery, including Although thyroid nodules are very common, only 5-7% pregnancy, other co-existent cancers, patient preference, of them are cancerous. Biopsy of a thyroid nodule can and initial biopsy showing a lower risk cytology. Therefore, help to differentiate between benign and cancerous the thyroid nodules were monitored by ultrasound prior nodules, however, its ability to predict cancer is not to the surgery. The thyroid nodule dimensions were 100%. Using the Bethesda System, 90-95% of biopsy measured on ultrasound and the growth was assessed by samples are satisfactory for interpretation with 55-74% calculating the tumor volume doubling time (TVDT). being reported as benign, 2-5% being reported as cancer and the rest being reported as indeterminate, meaning After the thyroid surgery, 58% of the thyroid nodules a diagnosis cannot be made based on looking at the with FN cytology were found to be benign and 42% cells alone. Biopsy performs well for benign or cancer were cancer. The average patient age was 50 years, cytology results, as 97-100% of thyroid nodules with 82% were female, and the average nodule size at initial benign cytology being benign and 94-96% of thyroid ultrasound was 2.0 cm and then 2.5 cm at the time of nodules with cancer cytology being cancer. Among the the surgery. None of these variables or the ultrasound thyroid nodules with indeterminate cytology, up to 25% appearance of the thyroid nodules were associated with are reported as follicular neoplasms (FNs). -
Uva-DARE (Digital Academic Repository)
UvA-DARE (Digital Academic Repository) Inside out Behavioral phenotyping in genetic syndromes Mulder, P.A. Publication date 2020 Document Version Other version License Other Link to publication Citation for published version (APA): Mulder, P. A. (2020). Inside out: Behavioral phenotyping in genetic syndromes. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:25 Sep 2021 6 Further delineation of Malan syndrome Authors: Priolo M, Schanze D, Tatton-Brown K, Mulder PA, Tenorio J, Kooblall K, Acero IH, Alkuraya FS, Arias P, Bernardini L, Bijlsma EK, Cole T, Coubes C, Dapia I, Davies S, Di Donato N, Elcioglu NH, Fahrner JA, Foster A, González NG, Huber I, Iascone M, Kaiser AS, Kamath A, Liebelt J, Lynch SA, Maas SM, Mammì C, Mathijssen IB, McKee S, Menke LA, Mirzaa GM, Montgomery T, Neubauer D, Neumann TE, Pintomalli L, Pisanti MA, Plomp AS, Price S, Salter C, Santos-Simarro F, Sarda P, Segovia M, Shaw-Smith C, Smithson S, Suri M, Valdez RM, Van Haeringen A, Van Hagen JM, Zollino M, Lapunzina P, Thakker RV, Zenker M, Hennekam RC. -
Thyroid Nodules MARY JO WELKER, M.D., and DIANE ORLOV, M.S., C.N.P
PRACTICAL THERAPEUTICS Thyroid Nodules MARY JO WELKER, M.D., and DIANE ORLOV, M.S., C.N.P. Ohio State University College of Medicine and Public Health, Columbus, Ohio Palpable thyroid nodules occur in 4 to 7 percent of the population, but nodules found incidentally on ultrasonography suggest a prevalence of 19 to 67 percent. The major- O A patient informa- ity of thyroid nodules are asymptomatic. Because about 5 percent of all palpable nod- tion handout on thy- roid nodules, written ules are found to be malignant, the main objective of evaluating thyroid nodules is to by the authors of this exclude malignancy. Laboratory evaluation, including a thyroid-stimulating hormone article, is provided on test, can help differentiate a thyrotoxic nodule from an euthyroid nodule. In euthyroid page 573. patients with a nodule, fine-needle aspiration should be performed, and radionuclide scanning should be reserved for patients with indeterminate cytology or thyrotoxico- sis. Insufficient specimens from fine-needle aspiration decrease when ultrasound guidance is used. Surgery is the primary treatment for malignant lesions, and the extent of surgery depends on the extent and type of disease. Ablation by postopera- tive radioactive iodine is done for high-risk patients—identified as those with metasta- tic or residual disease. While suppressive therapy with thyroxine is frequently used postoperatively for malignant lesions, its use for management of benign solitary thy- roid nodules remains controversial. (Am Fam Physician 2003;67:559-66,573-4. Copy- right© 2003 American Academy of Family Physicians.) Members of various thyroid nodule is a palpable jects 19 to 50 years of age had an incidental family practice depart- swelling in a thyroid gland with nodule on ultrasonography. -
Roles of the NFI/CTF Gene Family in Transcription and Development
Gene 249 (2000) 31–45 www.elsevier.com/locate/gene Review Roles of the NFI/CTF gene family in transcription and development Richard M. Gronostajski * Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation and Department of Biochemistry, 9500 Euclid Ave., Case Western Reserve University, Cleveland, OH 44195, USA Received 20 December 1999; received in revised form 15 February 2000; accepted 13 March 2000 Received by A.J. van Wijnen Abstract The Nuclear Factor I (NFI) family of site-specific DNA-binding proteins (also known as CTF or CAAT box transcription factor) functions both in viral DNA replication and in the regulation of gene expression. The classes of genes whose expression is modulated by NFI include those that are ubiquitously expressed, as well as those that are hormonally, nutritionally, and developmentally regulated. The NFI family is composed of four members in vertebrates (NFI-A, NFI-B, NFI-C and NFI-X ), and the four NFI genes are expressed in unique, but overlapping, patterns during mouse embryogenesis and in the adult. Transcripts of each NFI gene are diVerentially spliced, yielding as many as nine distinct proteins from a single gene. Products of the four NFI genes diVer in their abilities to either activate or repress transcription, likely through fundamentally diVerent mechanisms. Here, we will review the properties of the NFI genes and proteins and their known functions in gene expression and development. © 2000 Elsevier Science B.V. All rights reserved. Keywords: CAAT box transcription factor; Cancer; CTD; Gene expression; Nuclear Factor I 1. Introduction 2. Discovery of viral and cellular NFI-binding sites The Nuclear Factor I (NFI) family of site-specific After the initial observation that NFI protein isolated DNA-binding proteins plays wide reaching roles in from nuclear extracts of human HeLa cells greatly animal physiology, biochemistry and pathology.