DOCSLIB.ORG

Gene, WT1, in Males with Genital Abnormalities

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Gene, WT1, in Males with Genital Abnormalities J Med Genet 1993 30: 767-772 767 Mutational screening of the Wilms's tumour J Med Genet: first published as 10.1136/jmg.30.9.767 on 1 September 1993. Downloaded from gene, WT1, in males with genital abnormalities Paul A Clarkson, Helen R Davies, Denise M Williams, Rakesh Chaudhary, Ieuan A Hughes, Mark N Patterson Abstract gene on chromosome 11 band p 3.34 Wilms's Several lines of evidence suggest that tumour is a childhood malignancy of the kid- the Wilms's tumour susceptibility gene, ney, and in several tumours intragenic muta- WT1, has an important role in genital as tions of the WT1 gene have been found, thus well as kidney development. WT1 is confirming that WT1 is one of the genes expressed in developing kidney and geni- involved in the development of Wilms's tu- tal tissues. Furthermore, mutations in mour."7 The WT1 gene comprises 10 exons WT1 have been detected in patients which encode a protein with amino acid se- with the Denys-Drash syndrome (DDS), quence motifs characteristic of a transcription which is characterised by nephropathy, factor.34 The four 3' exons each encode zinc genital abnormalities, and Wilms's tu- finger structures involved in DNA binding, mour. It is possible that WT1 mutations and the WT1 protein has been shown to bind may cause genital abnormalities in the specifically to the DNA sequence recognised absence of kidney dysfunction. We tested by the early growth response gene, EGRI.8 this hypothesis by screening the WT1 Furthermore, in transient transfection assays gene for mutation in 12 46,XY patients WT1 functions as a transcriptional repressor with various forms of genital abnormal- of genes containing the EGRI target se- ity. Using single strand conformation quence.9 A subset ofWilms's tumours is there- polymorphism (SSCP) we did not detect fore thought to arise from loss of function of any WT1 mutations in these patients. WT1, leading to the deregulated expression of However, in addition to the 12 patients, growth promoting genes and the uncontrolled three DDS patients were also analysed growth of embryonic kidney cells. using SSCP, and in all three cases hetero- The evidence that implicates WT 1 in genital zygous WT1 mutations were found which as well as kidney development comes from would be predicted to disrupt the DNA expression studies of WT1 and from genetic binding activity of WT1 protein. These data.'0 WT1 is expressed in fetal kidney, geni- results support the notion that DDS re- tal ridge, and fetal gonad." 12 The precise cell sults from a dominant WT1 mutation. specific pattern of expression has led to the http://jmg.bmj.com/ However, WT1 mutations are unlikely suggestion that WT1 is involved in mesenchy- to be a common cause of male genital mal-epithelial transitions in embryonic kidney abnormalities when these are not and genital structures." More recently, WT1 associated with kidney abnormalities. mutations have been identified in subjects with (J Med Genet 1993;30:767-72) Denys-Drash syndrome (DDS)."'>6 This rare condition is characterised by a specific nephro- Abnormalities of the genital system resulting pathy, often accompanied by gonadal/genital on October 5, 2021 by guest. Protected copyright. in an intersex phenotype are known to arise abnormalities or Wilms's tumour or both.'7 through a number of genetic mechanisms.' The syndrome affects both males and females. When the affected subject has a normal male The genital phenotype is very variable but karyotype (46,XY) the condition is described most often presents as male pseudohermaph- as male pseudohermaphroditism. Clinical mal- roditism, with micropenis, cryptorchidism, or formations include micropenis (or clitorome- perineal hypospadias. True hermaphroditism galy), cryptorchidism (undescended testes), has also been reported in DDS.'8 In almost all and hypospadias (a misplaced urethral open- cases studied, DDS subjects carry a heterozy- ing). Such phenotypes can arise from andro- gous mutation in WT1 which is predicted to Department of Paediatrics, gen biosynthetic defects, for example, 17f- affect the ability of the WT1 protein to bind University of hydroxysteroid dehydrogenase and 5a-reduc- DNA. Constitutional mutations in WT 1 were Cambridge, tase deficiency. Alternatively, there may be a also reported in two subjects with Wilms's Addenbrooke's defect in the response to as Hospital, Hills Road, hormonal signals, is tumour, hypospadias, and cryptorchidism, but Cambridge CB2 2QQ, seen in the androgen insensitivity syndrome, without nephropathy.'9 These observations UK. caused by mutations in the androgen receptor suggest that the genital abnormality in the P A Clarkson gene.2 In many cases neither hormonal syn- H R Davies WAGR syndrome (Wilms's tumour, aniridia, D M Williams thesis nor the response appears defective, sug- genitourinary abnormalities, mental retard- R Chaudhary gesting that a mutation in a gene which func- ation), which is associated with constitutional I A Hughes tions in another aspect of genital development deletion of 13 M N Patterson IIp is caused by deletion of the may be the cause of the phenotype. WT1 gene itself. Constitutional WT1 muta- Correspondence to A recent addition to the genes currently tions therefore appear to act as dominant mu- Dr Patterson. known to be involved in genital development is tations and are associated with nephropathy or Received 29 January 1993. Revised version accepted WT1, which was originally isolated as a candi- Wilms's tumour or both, in the presence or 30 April 1993. date for the Wilms's tumour predisposition absence of genital abnormalities. 768 Clarkson, Davies, Williams, Chaudhary, Hughes, Patterson The purpose of this study was to determine DENYS-DRASH SYNDROME PATIENTS whether WT1 mutations cause genital abnor- Three DDS patients were included in this malities in the absence of nephropathy or analysis, since mutations in WTI were J Med Genet: first published as 10.1136/jmg.30.9.767 on 1 September 1993. Downloaded from Wilms's tumour. As part of a previous study, expected. Subject S12 was born with perineal the androgen receptor gene was screened for hypospadias and cryptorchidism, suggestive of mutation in a group of 46,XY patients with an undervirilised male. The karyotype was various genital abnormalities compatible with 46,XY and ultrasound showed normal male a diagnosis of androgen insensitivity syn- internal genital anatomy and no Mullerian drome.20 In the majority of patients with phe- structures. There was a normal response to a notypes such as cryptorchidism, micropenis, three day hCG stimulation test. The initial and hypospadias, mutations in the androgen diagnosis in this patient was partial androgen receptor gene were not found. It is therefore insensitivity syndrome (PAIS). At 9 months of possible that other genetic defects account for age, however, S 12 presented with Wilms's the phenotypes in these patients. Given the tumour and diffuse mesangial sclerosis, typical association between WT1 mutations and the of DDS. This patient was investigated in an genital abnormalities in DDS, we screened independent study.23 Patient R6 (also 46,XY) WT 1 for mutation in a cohort of 46,XY was born with the appearance of virilised patients with various genital abnormalities, female external genitalia (clitoromegaly, in- but without any kidney dysfunction. complete fusion of the labia, and rugose labio- scrotal folds). Gonadal histology showed nor- mal infantile testes, and there was a normal Patients testosterone response to hCG. Pelvic ultra- PATIENTS WITH GENITAL ABNORMALITIES sound showed no Mullerian structures and a The phenotypes of the patients studied are diagnosis of PAIS was again made. At 5 summarised in table 1. Each had a normal months of age she presented in established 46,XY karyotype. All non-DDS patients were renal failure. A renal biopsy showed diffuse also analysed for androgen binding activity, mesangial sclerosis, and a diagnosis of DDS and qualitatively normal binding was seen. was made. While awaiting renal transplantation, Two patients (P1 and P4) had low levels of she developed peritonitis and overwhelming binding, but since this phenomenon has been sepsis as a complication of her dialysis and died observed in Denys-Drash syndrome, these at 61 months of age. Patient CAM114 (46,XY) patients were included.2" The androgen recep- was born with normal external female genitalia tor gene had also been screened for mutation and presented at 6 months of age with nephro- by PCR-SSCP in some of the patients, and in tic syndrome. Histological examination of a each case no evidence for mutation was found. renal biopsy showed diffuse mesangial sclero- The majority of the patients presented with sis and a diagnosis of DD S was made.24 severe undervirilisation (either predominantly CAMi 14 was found at laparotomy to have male with perineal hypospadias, crypt- internal female genital structures. This patient was also investigated in an independent study orchidism, and micropenis, or predominantly http://jmg.bmj.com/ female with clitoromegaly). The majority of (corresponding to patient LB).'5 patients also had apparently normal testes by histology or the hCG stimulation test which provides a measure of the ability of the testes Materials and methods to synthesise androgen in response to gonado- ANDROGEN BINDING ASSAY trophin.22 We also included one patient with Fibroblast cell lines were established for all true hermaphroditism (F14). This patient also patients from genital skin biopsies, obtained at presented with other congenital abnormalities,
Load more

Recommended publications
  • Expression of Aromatase, Estrogen Receptor and , Androgen
    0031-3998/06/6006-0740 PEDIATRIC RESEARCH Vol. 60, No. 6, 2006 Copyright © 2006 International Pediatric Research Foundation, Inc. Printed in U.S.A. Expression of Aromatase, Estrogen Receptor ␣ and ␤, Androgen Receptor, and Cytochrome P-450scc in the Human Early Prepubertal Testis ESPERANZA B. BERENSZTEIN, MARI´A SONIA BAQUEDANO, CANDELA R. GONZALEZ, NORA I. SARACO, JORGE RODRIGUEZ, ROBERTO PONZIO, MARCO A. RIVAROLA, AND ALICIA BELGOROSKY Research Laboratory [E.B.B., M.S.B., C.R.G., N.I.S., J.R., M.A.R., A.B.], Hospital de Pediatria Garrahan, Buenos Aires C124 5AAM, Argentina; Centro de Investigaciones en Reproduccion [R.P.], Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C112 1ABG, Argentina ABSTRACT: The expression of aromatase, estrogen receptor ␣ might affect adult testicular cell mass, as well as testicular (ER␣) and ␤ (ER␤), androgen receptor (AR), and cytochrome P-450 function (8). side chain cleavage enzyme (cP450scc) was studied in prepubertal In humans (9), there are three growth phases of LCs testis. Samples were divided in three age groups (GRs): GR1, during testicular development. Fetal LCs produce testoster- ϭ newborns (1- to 21-d-old neonates, n 5); GR2, postnatal activation one required for fetal masculinization and Insl-3, necessary ϭ stage (1- to 7-mo-old infants, n 6); GR3, childhood (12- to for testicular descent (10). They regress during the third ϭ ␣ 60-mo-old boys, n 4). Absent or very poor detection of ER by trimester of pregnancy. A second wave of infantile LCs has immunohistochemistry in all cells and by mRNA expression was been described during the postnatal surge of luteinizing observed.
    [Show full text]
  • Wt1) – an Effector in Leukemogenesis?
    WILMS’ TUMOUR GENE 1 PROTEIN (WT1) – AN EFFECTOR IN LEUKEMOGENESIS? Vidovic, Karina 2010 Link to publication Citation for published version (APA): Vidovic, K. (2010). WILMS’ TUMOUR GENE 1 PROTEIN (WT1) – AN EFFECTOR IN LEUKEMOGENESIS?. Lund University: Faculty of Medicine. Total number of authors: 1 General rights Unless other specific re-use rights are stated the following general rights apply: Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Read more about Creative commons licenses: https://creativecommons.org/licenses/ Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 Download date: 07. Oct. 2021 Division of Hematology and Transfusion Medicine Lund University, Lund, Sweden WILMS’ TUMOUR GENE 1 PROTEIN (WT1) – AN EFFECTOR IN LEUKEMOGENESIS? Karina Vidovic Thesis 2010 Contact adress Karina Vidovic Division of Hematology and Transfusion Medicine BMC, C14 Klinikgatan 28 SE- 221 84 Lund Sweden Phone +46 46 222 07 30 e-mail: [email protected] ISBN 978-91-86443-99-3 ! Karina Vidovic Printed by Media-Tryck, Lund, Sweden 2 ”The journey of a thousand miles begins with one step” Lao Tzu (Chinese taoist), 600-531 BC 3 4 LIST OF PAPERS This thesis is based on the following papers, referred to in the text by their Roman numerals I.
    [Show full text]
  • 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.
    [Show full text]
  • Influence of Androgen Receptor on the Prognosis of Breast Cancer
    Journal of Clinical Medicine Article Influence of Androgen Receptor on the Prognosis of Breast Cancer 1, , 2, 1 2 3 Ki-Tae Hwang * y , Young A Kim y , Jongjin Kim , Jeong Hwan Park , In Sil Choi , Kyu Ri Hwang 4 , Young Jun Chai 1 and Jin Hyun Park 3 1 Department of Surgery, Seoul Metropolitan Government Seoul National University Boramae Medical Center, 39, Boramae-Gil, Dongjak-gu, Seoul 156-707, Korea; [email protected] (J.K.); [email protected] (Y.J.C.) 2 Department of Pathology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 156-707, Korea; [email protected] (Y.A.K.); [email protected] (J.H.P.) 3 Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 156-707, Korea; [email protected] (I.S.C.); [email protected] (J.H.P.) 4 Department of Obstetrics & Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 156-707, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-2-870-2275; Fax: +82-2-831-2826 These authors contributed equally to this work. y Received: 28 February 2020; Accepted: 8 April 2020; Published: 10 April 2020 Abstract: We investigated the prognostic influence of androgen receptor (AR) on breast cancer. AR status was assessed using immunohistochemistry with tissue microarrays from 395 operable primary breast cancer patients who received curative surgery. The Kaplan–Meier estimator was used to analyze the survival rates and a log-rank test was used to determine the significance of the differences in survival. The Cox proportional hazards model was used to calculate the hazard ratio (HR) and the 95% confidence interval (CI) of survival.
    [Show full text]
  • Immunohistochemical Study of Androgen, Estrogen and Progesterone Receptors in Salivary Gland Tumors
    Oral Pathology Oral Pathology Immunohistochemical study of androgen, estrogen and progesterone receptors in salivary gland tumors Fabio Augusto Ito(a) Abstract: The aim of this work was to study the immunohistochemi- (b) Kazuhiro Ito cal expression of androgen receptor, estrogen receptor and progesterone Ricardo Della Coletta(c) Pablo Agustín Vargas(c) receptor in pleomorphic adenomas, Warthin’s tumors, mucoepidermoid Márcio Ajudarte Lopes(c) carcinomas and adenoid cystic carcinomas of salivary glands. A total of 41 pleomorphic adenomas, 30 Warthin’s tumors, 30 mucoepidermoid carcinomas and 30 adenoid cystic carcinomas were analyzed, and the im- (a) DDS, PhD; (b)MD, Professor – Department of Pathology, Londrina State University, munohistochemical expression of these hormone receptors were assessed. Londrina, PR, Brazil. It was observed that all cases were negative for estrogen and progesterone (c) DDS, PhD, Professor, Department of Oral receptors. Androgen receptor was positive in 2 cases each of pleomorphic Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), adenoma, mucoepidermoid carcinoma and adenoid cystic carcinoma. In Piracicaba, SP, Brazil. conclusion, the results do not support a role of estrogen and progesterone in the tumorigenesis of pleomorphic adenomas, Warthin’s tumors, muco- epidermoid carcinomas and adenoid cystic carcinomas. However, andro- gen receptors can play a role in a small set of salivary gland tumors, and this would deserve further studies. Descriptors: Receptors, androgen; Receptors, estrogen; Receptors, progesterone; Salivary gland neoplasms. Corresponding author: Márcio Ajudarte Lopes Semiologia, Faculdade de Odontologia de Piracicaba, UNICAMP Av. Limeira, 901 Caixa Postal: 52 CEP: 13414-903 Piracicaba - SP - Brazil E-mail: [email protected] Received for publication on Oct 01, 2008 Accepted for publication on Sep 22, 2009 Braz Oral Res.
    [Show full text]
  • Androgen Receptor Is Targeted to Distinct Subcellular Compartments in Response to Different Therapeutic Antiandrogens
    7392 Vol. 10, 7392–7401, November 1, 2004 Clinical Cancer Research Androgen Receptor Is Targeted to Distinct Subcellular Compartments in Response to Different Therapeutic Antiandrogens Hayley C. Whitaker,1 Sarah Hanrahan,3 informed sequential treatment regime may benefit prostate Nick Totty,3 Simon C. Gamble,1 cancer patients. The observed subnuclear and subcytoplas- Jonathan Waxman,1 Andrew C. B. Cato,4 mic associations of the AR suggest new areas of study to 2 1 investigate the role of the AR in the response and resistance Helen C. Hurst, and Charlotte L. Bevan of prostate cancer to antiandrogen therapy. 1Prostate Cancer Research Group and 2Cancer Research UK Molecular Oncology Unit, Department of Cancer Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom; INTRODUCTION 3Protein Analysis, Cancer Research UK, London Research Institute, Prostate cancer is the most commonly diagnosed male London, United Kingdom; and 4Forschungszentrum Karlsruhe, cancer in the United States and the second leading cause of male Institute of Toxicology and Genetics, Karlsruhe, Germany cancer death (1). Prostate growth is initially androgen depend- ent; thus, treatment involves reducing circulating androgen lev- ABSTRACT els using leuteinizing hormone-releasing hormone analogs and opposing androgen action using antiandrogens. Little is known Purpose: Antiandrogens are routinely used in the treat- about how antiandrogens elicit their effects, although they act at ment of prostate cancer. Although they are known to pre- the level of the androgen receptor (AR), which mediates the vent activation of the androgen receptor (AR), little is effects of all androgens including the major circulating androgen known about the mechanisms involved. This report repre- testosterone and the more potent dihydrotestosterone (DHT).
    [Show full text]
  • The Role of the Androgen Receptor Signaling in Breast Malignancies PANAGIOTIS F
    ANTICANCER RESEARCH 37 : 6533-6540 (2017) doi:10.21873/anticanres.12109 Review The Role of the Androgen Receptor Signaling in Breast Malignancies PANAGIOTIS F. CHRISTOPOULOS*, NIKOLAOS I. VLACHOGIANNIS*, CHRISTIANA T. VOGKOU and MICHAEL KOUTSILIERIS Department of Experimental Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece Abstract. Breast cancer (BrCa) is the most common decades, BrCa still has a poor prognosis with 5-year survival malignancy among women worldwide, and one of the leading rates of metastatic disease reaching to 26% only. BrCa is the causes of cancer-related deaths in females. Despite the second leading cause of death among female cancers with development of novel therapeutic modalities, triple-negative 40,610 estimated deaths in the U.S. expected in 2017 (1). breast cancer (TNBC) remains an incurable disease. Androgen Breast cancer comprises a heterogeneous group of diseases receptor (AR) is widely expressed in BrCa and its role in the with variable course and outcome. Currently, BrCa is sub- disease may differ depending on the molecular subtype and the classified into distinct molecular subtypes named: normal stage. Interestingly, AR has been suggested as a potential target breast like, luminal A/B, HER-2 related, basal-like and claudin- candidate in TNBC, while sex hormone levels may regulate the low (2, 3). Estrogen receptor (ER), progesterone receptor (PR) role of AR in BrCa subtypes. In the presence of estrogen and HER2 have long been established as useful prognostic and receptor α ( ERa ), AR may antagonize the ER α- induced effects, predictive biomarkers. Hormonal therapy in ER and PR whereas in the absence of estrogens, AR may act as an ER α- positive tumors (4), as well as the use of monoclonal antibodies mimic, promoting tumor.
    [Show full text]
  • Estrogen Receptor Β, a Regulator of Androgen Receptor Signaling in The
    Estrogen receptor β, a regulator of androgen receptor PNAS PLUS signaling in the mouse ventral prostate Wan-fu Wua, Laure Maneixa, Jose Insunzab, Ivan Nalvarteb, Per Antonsonb, Juha Kereb, Nancy Yiu-Lin Yub, Virpi Tohonenb, Shintaro Katayamab, Elisabet Einarsdottirb, Kaarel Krjutskovb, Yu-bing Daia, Bo Huanga, Wen Sua,c, Margaret Warnera, and Jan-Åke Gustafssona,b,1 aCenter for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204; bCenter for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, 14186 Stockholm, Sweden; and cAstraZeneca-Shenzhen University Joint Institute of Nephrology, Centre for Nephrology & Urology, Shenzhen University Health Science Center, Shenzhen 518060, China Contributed by Jan-Åke Gustafsson, March 31, 2017 (sent for review February 8, 2017; reviewed by Gustavo E. Ayala and David R. Rowley) − − − − As estrogen receptor β / (ERβ / ) mice age, the ventral prostate (13). Several ERβ-selective agonists have been synthesized (14– (VP) develops increased numbers of hyperplastic, fibroplastic le- 20), and they have been found to be antiinflammatory in the brain sions and inflammatory cells. To identify genes involved in these and the gastrointestinal tract (21, 22) and antiproliferative in cell changes, we used RNA sequencing and immunohistochemistry to lines (23–27) and cancer models (23, 28). We have previously − − compare gene expression profiles in the VP of young (2-mo-old) shown that there is an increase in p63-positive cells in ERβ / − − and aging (18-mo-old) ERβ / mice and their WT littermates. We mouse VP but that these cells were not confined to the basal layer also treated young and old WT mice with an ERβ-selective agonist but were interdispersed with the basal and luminal layer (13).
    [Show full text]
  • A Dissertation Entitled the Androgen Receptor
    A Dissertation entitled The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit Submitted to the Graduate Faculty as partial fulfillment of the requirements for the PhD Degree in Biomedical science Dr. Manohar Ratnam, Committee Chair Dr. Lirim Shemshedini, Committee Member Dr. Robert Trumbly, Committee Member Dr. Edwin Sanchez, Committee Member Dr. Beata Lecka -Czernik, Committee Member Dr. Patricia R. Komuniecki, Dean College of Graduate Studies The University of Toledo August 2011 Copyright 2011, Mesfin Gonit This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit As partial fulfillment of the requirements for the PhD Degree in Biomedical science The University of Toledo August 2011 Prostate cancer depends on the androgen receptor (AR) for growth and survival even in the absence of androgen. In the classical models of gene activation by AR, ligand activated AR signals through binding to the androgen response elements (AREs) in the target gene promoter/enhancer. In the present study the role of AREs in the androgen- independent transcriptional signaling was investigated using LP50 cells, derived from parental LNCaP cells through extended passage in vitro. LP50 cells reflected the signature gene overexpression profile of advanced clinical prostate tumors. The growth of LP50 cells was profoundly dependent on nuclear localized AR but was independent of androgen. Nevertheless, in these cells AR was unable to bind to AREs in the absence of androgen.
    [Show full text]
  • Phosphorylation-Induced Conformational Dynamics in an Intrinsically Disordered Protein and Potential Role in Phenotypic Heterogeneity
    Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity Prakash Kulkarnia,1, Mohit Kumar Jollyb, Dongya Jiab,c, Steven M. Mooneyd, Ajay Bhargavae, Luciane T. Kagoharaf, Yihong Chena, Pengyu Haog, Yanan Hea, Robert W. Veltrif, Alexander Grishaeva, Keith Weningerg, Herbert Levineb,h,i,1, and John Orbana,j,1 aInstitute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850; bCenter for Theoretical Biological Physics, Rice University, Houston, TX 77005; cGraduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX 77005; dDepartment of Biology, University of Waterloo, Waterloo, ON Canada N2L 3G1; eShakti BioResearch, Woodbridge, CT 06525; fDepartment of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287; gDepartment of Physics, North Carolina State University, Raleigh, NC 27695; hDepartment of Physics and Astronomy, Rice University, Houston, TX 77005; iDepartment of Bioengineering, Rice University, Houston, TX 77005; and jDepartment of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742 Contributed by Herbert Levine, February 15, 2017 (sent for review January 3, 2017; reviewed by Takahiro Inoue and Vladimir N. Uversky) Intrinsically disordered proteins (IDPs) that lack a unique 3D and inheritance of biological traits (17), further emphasizing their structure and comprise a large fraction of the human proteome importance in state (or phenotype) switching. Moreover, if overex- play important roles in numerous cellular functions. Prostate- pressed, IDPs have the potential to engage in multiple “promiscuous” Associated Gene 4 (PAGE4) is an IDP that acts as a potentiator of interactions with other proteins, which can lead to changes in phe- the Activator Protein-1 (AP-1) transcription factor.
    [Show full text]
  • 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
    [Show full text]
  • Estrogen, Androgen, Glucocorticoid, and Progesterone Receptors in Progestin-Induced Regression of Human Breast Cancer1
    [CANCER RESEARCH 40, 2557-2561, July 1980] 0008-5472/80/0040-OOOOS02.00 Estrogen, Androgen, Glucocorticoid, and Progesterone Receptors in Progestin-induced Regression of Human Breast Cancer1 F. A. G. Teulings,2 H. A. van Gilse, M. S. Henkelman, H. Portengen, and J. Alexieva-Figusch Departments of Biochemistry [F. T., M. S. H., H. P.] and Internal Medicine [H. van G., J. A-F.], Rotterdamsch Radio-Therapeutisch Instituât, Dr. Daniel den Hoed Kliniek, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands ABSTRACT negative ER values responded favorably (12). There is some clinical evidence, however, that breast cancer patients who A study was made of basic mechanisms involved in regres respond to progestin therapy do not belong to exactly the same sion of breast cancer exposed to high levels of synthetic group as do those who respond to the conventional androgenic progestins. The possibility that progestins act on breast cancer or estrogenic hormones (15). Furthermore, patients whose by way of the progesterone receptor mechanism and subse tumors were unresponsive to prior therapy with estrogens quent increase of estradiol 17/8-dehydrogenase activity could alone subsequently responded to a combination of estrogen not be confirmed in this investigation. It is demonstrated that and progesterone (5, 14). the progestins megestrol acetate and medroxyprogesterone In addition to ER, many breast cancer specimens contain acetate are strong competitors for steroids which bind specifi AR, GR, and PR (7, 18, 19). The role of the various receptor cally to androgen, glucocorticoid, and progesterone receptors, sites in progestin therapy has not been established yet, and indicating that the progestins are able to bind to these receptors the mechanisms of action by which additive endocrine thera with high affinity.
    [Show full text]