DOCSLIB.ORG

Telomere Erosion and Chromosomal Instability in Cells Expressing the HPV Oncogene 16E6

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Telomere Erosion and Chromosomal Instability in Cells Expressing the HPV Oncogene 16E6 Oncogene (2004) 23, 3561–3571 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $25.00 www.nature.com/onc Telomere erosion and chromosomal instability in cells expressing the HPV oncogene 16E6 Annemieke W Plug-DeMaggio*,1, Terri Sundsvold1, Michelle A Wurscher1, Jennifer I Koop1, Aloysius J Klingelhutz1,3 and James K McDougall1,2,4 1Cancer Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA; 2Departmentof Pathology, University of Washington, Seattle, WA 98195, USA Progression to advanced-stage cervical carcinomas is Introduction characterized by a recurrent pattern of chromosomal rearrangements. Structural chromosome rearrangements Human cancers are subject to ongoing chromosomal are generated through the fusion of broken chromosome changes as a result of defects in the checkpoints that ends. These chromosome breaks may be induced by normally ensure stability of the genome. Two types of mutagenic agents such as ionizing radiation, or chromo- chromosomal instability are recognized: (1) aneuploidy, some ends may be exposed through extensive telomere or change in chromosome copy number and (2) shortening. The human papilloma virus oncogene 16E6 structural aberrations of chromosomes. Chromosomal induces telomerase activity in human keratinocytes, a instability is an early event in the development of human model system for cervical tumor formation. The present (Heselmeyer et al., 1996, 1997; Kirchhoff et al., 1999; study explores the relationship between 16E6 expression, Matthews et al., 2000) papillomavirus (HPV) associated telomerase activity, and chromosomal instability. We anogenital carcinoma. Epidemiological studies have show that the frequency of anaphase bridges is dependent determined that high-risk type HPVs are the main on the level of telomerase activity in 16E6/E7-expressing etiological factors for cervical cancer (Zur Hausen, clones, and is the result of telomere shortening. High 2002). Immortalization of human keratinocytes, which frequencies of anaphase bridges, associated with low are the natural host cells of HPV infection, is dependent telomerase activity, correlate with increased chromosome on expression of the HPV oncogenes E6 and E7 instability. Anaphase bridge formation is also associated (Hawley-Nelson et al., 1989; Mu¨ nger et al., 1989). The with the presence of micronuclei, which are shown to E7 oncoprotein inactivates the retinoblastoma tumor contain unstable chromosomes frequently involved in suppressor (Rb) and the cyclin-dependent kinase (CDK) rearrangements. As anaphase bridges are observed in inhibitor p21 (Dyson et al., 1989; Helt et al., 2002). both high and low telomerase 16E6/E7 clones, but not Inactivation of Rb and p21 overrides cellular senescence in hTERT-expressing control clones, expression of 16E6 by allowing expression of genes required for entry and in these immortalized clones is not sufficient to stabilize transit through the S phase (Demers et al., 1996; Jones shortened telomeres completely. We suggest a model in et al., 1997). The E6 oncoprotein targets tumor which HPV-induced tumorigenesis may be dependent on suppressor p53 for degradation (Scheffner et al., 1990; persistent bridge–breakage–fusion cycles that allow for Werness et al., 1990). Lack of p53, a transcription factor continued genomic rearrangements. which mediates the expression of a variety of genes that Oncogene (2004) 23, 3561–3571. doi:10.1038/sj.onc.1207388 induce a growth arrest or apoptosis, abrogates the cellular Published online 12 April 2004 response to DNA damage (Lakin and Jackson, 1999). Structural chromosome rearrangements are generated Keywords: human papillomavirus; telomere erosion; through the fusion of broken chromosome ends. When HPV 16E6; chromosomal instability; tumorigenesis; both chromosome fragments include a centromere, the anaphase bridges resulting dicentric chromosome is broken again when the two centromeres are pulled in opposite directions by the mitotic spindle apparatus. Unless the resulting chromosome fragments are stabilized, this process will repeat itself in a breakage–fusion–bridge (BFB) cycle (McClintock, 1941). Chromosome breaks may be *Correspondence: AW Plug-DeMaggio, Fred Hutchinson Cancer induced by mutagenic agents such as ionizing radiation, Research Center, Cancer Biology Program, 1100 Fairview Avenue or chromosome ends may be exposed through extensive N, Seattle, WA 98109-1024, USA; E-mail: [email protected] telomere shortening (reviewed in Lundblad, 2000). 3Current address: Department of Microbiology, University of Iowa, Telomere dysfunction as a result of telomere erosion 3-403 BSB, Iowa City, IA 52242, USA 4In memory of Jim McDougall, our mentor and our friend has been shown to trigger extensive DNA fragmentation Received 28 July 2003; revised 9 October 2003; accepted 20 November and evolution of complex chromosome abnormalities in 2003; Published online 12 April 2004 human malignant tumors (Gisselsson et al., 2001a, b). In Chromosomal instability in the development of HPV AW Plug-DeMaggio et al 3562 addition, telomeric erosion induced BFB cycles, which genomic rearrangements, in addition to a failure in the were shown to play an important role in epithelial mitotic spindle checkpoint, which results in aneuploidy. carcinogenesis in mice (Chang et al., 2001). Stabilization of telomere length is a critical event in the immortalization of human cells and is associated Results with telomerase activity (McEachern et al., 2000). Regulation of telomerase activity is dependent on the Anaphase bridges and nuclear abnormalities in human reverse-transcriptase component of telomerase, hTERT keratinocytes expressing the HPV oncogenes 16E6 (Meyerson et al., 1997; Nakamura et al., 1997). and E7 Previously, it has been demonstrated that HPV 16E6 can upregulate hTERT transcription (Veldman et al., To study the role of HPV oncogenes in the induction of 2001). The present study explores the relationship genomic instability, human foreskin keratinocyte cul- between expression of HPV 16E6, telomerase activity, tures were infected with retroviral constructs that and genomic instability. We show that the frequency of expressed either HPV 16E6 alone, 16E7 alone, or 16E6 anaphase bridges is dependent on the level of telomerase and E7 together. Following selection, both pooled activity in 16E6/E7-expressing clones, and is a result of populations and clones were passaged in culture. HPV telomere shortening. High frequencies of anaphase 16E6-, 16E7- and 16E6/E7-expressing clones growing in bridges, associated with low telomerase activity, corre- plates were fixed, stained with DAPI to visualize DNA, late with increased chromosome instability. Anaphase and examined using an inverted fluorescent microscope. bridge formation is associated with the presence of Previously described mitotic abnormalities in 16E6/E7 micronuclei, which are shown to contain unstable cells include multipolar metaphases and metaphases chromosomes frequently involved in rearrangements. with lagging chromosomes (Duensing et al., 2000; Plug- As anaphase bridges were observed in both high and low deMaggio and McDougall, 2002). Cytological observa- telomerase 16E6/E7 clones, but not in hTERT-expres- tions also indicate the frequent presence of anaphase sing control clones, expression of 16E6 in these bridges in cells expressing HPV oncogenes. Anaphase immortalized clones is not sufficient to stabilize shor- bridges form between daughter nuclei when the cen- tened telomeres completely. We suggest a model in tromeres of a dicentric chromosome are pulled in which HPV-induced tumorigenesis may be dependent opposite directions by the mitotic spindle (Figure on persistent BFB cycles that allow for continued 1a, b). These chromatin bridges are usually resolved Figure 1 Abnormalities in HPV 16E6/E7-expressing keratinocytes. Fixed cells were stained with DAPI and examined using an inverted fluorescent microscope. (a, b) Anaphase bridge. (c) Micronuclei in interphase. (d) Chromatin string between interphase nuclei Oncogene Chromosomal instability in the development of HPV AW Plug-DeMaggio et al 3563 through chromosome breaks; however, they may also crisis; (2) high telomerase activity precrisis, reduced or remain as chromatin strings between two interphase low activity postcrisis; (3) low telomerase activity pre- cells (Figure 1d). Anaphase bridges are present at varying frequencies in cells expressing both 16E6 and E7 together, and become prominent around passage 15 a (Figure 2a). Cells expressing 16E7 alone have a 20 significantly higher frequency of anaphase bridges than 18 cells expressing 16E6 alone at passage 15 (Figure 2b). 16 Following selection, the frequency of anaphase bridges 14 varies between 0 and 3.5% at passage 4, similar to 12 control HFKs (Figure 2a). This suggests that the 10 * * expression of 16E6 may not have a direct effect on the 8 formation of anaphase bridges. If anaphase bridge 6 4 frequencies would have been equally high at this early % anaphase bridges 2 passage as compared to later passages, a direct effect of 0 HPV 16E6 on the formation of these bridges, for 24579262728381739 example by inducing chromosome breaks, could have HPV 16E6/E7-clones been suspected. However, our data clearly indicate that p4 (*p8) p15 this is not the case. b Cytological analysis of 16E6- and/or 16E7-expressing 30 clones also revealed the occurrence of micronuclei in interphase cells. Micronuclei are formed by nuclear 25 membrane formation around either a lagging chromo- 20 some or chromosomal
Load more

Recommended publications
  • Aneuploidy and Aneusomy of Chromosome 7 Detected by Fluorescence in Situ Hybridization Are Markers of Poor Prognosis in Prostate Cancer'
    [CANCERRESEARCH54,3998-4002,August1, 19941 Advances in Brief Aneuploidy and Aneusomy of Chromosome 7 Detected by Fluorescence in Situ Hybridization Are Markers of Poor Prognosis in Prostate Cancer' Antonio Alcaraz, Satoru Takahashi, James A. Brown, John F. Herath, Erik J- Bergstralh, Jeffrey J. Larson-Keller, Michael M Lieber, and Robert B. Jenkins2 Depart,nent of Urology [A. A., S. T., J. A. B., M. M. U, Laboratory Medicine and Pathology (J. F. H., R. B. fl, and Section of Biostatistics (E. J. B., J. J. L-JCJ, Mayo Clinic and Foundation@ Rochester, Minnesota 55905 Abstract studies on prostate carcinoma samples. Interphase cytogenetic analy sis using FISH to enumerate chromosomes has the potential to over Fluorescence in situ hybridization is a new methodologj@which can be come many of the difficulties associated with traditional cytogenetic used to detect cytogenetic anomalies within interphase tumor cells. We studies. Previous studies from this institution have demonstrated that used this technique to identify nonrandom numeric chromosomal alter ations in tumor specimens from the poorest prognosis patients with path FISH analysis with chromosome enumeration probes is more sensitive ological stages T2N@M,Jand T3NOMOprostate carcinomas. Among 1368 than FCM for detecting aneuploid prostate cancers (4, 5, 7). patients treated by radical prostatectomy, 25 study patients were ascer We designed a case-control study to test the hypothesis that spe tamed who died most quickly from progressive prostate carcinoma within cific, nonrandom cytogenetic changes are present in tumors removed 3 years of diagnosis and surgery. Tumors from 25 control patients who from patients with prostate carcinomas with poorest prognoses .
    [Show full text]
  • 7Q Deletions Proximal Interstitial FTNP
    Support and Information Rare Chromosome Disorder Support Group, G1, The Stables, Station Road West, Oxted, Surrey RH8 9EE, United Kingdom Tel/Fax: +44(0)1883 723356 [email protected] III www.rarechromo.org Join Unique for family links, information and support. 7q deletions Unique is a charity without government funding, existing entirely on donations and grants. If you can, please make a donation via our website at www.rarechromo.org Please help us to help you! proximal interstitial Facebook group for 7q deletions and duplications: www.facebook.com/groups/493223084038489 Unique lists external message boards and websites in order to be helpful to families looking for information and support. This does not imply that we endorse their content or have any responsibility for it. This information guide is not a substitute for personal medical advice. Families should consult a medically qualified clinician in all matters relating to genetic diagnosis, management and health. Information on genetic changes is a very fast-moving field and while the information in this guide is believed to be the best available at the time of publication, some facts may later change. Unique does its best to keep abreast of changing information and to review its published guides as needed. The guide was compiled by Unique and reviewed by Dr Steve Scherer, Centre for Applied Genomics, Hospital for Sick Children, Toronto, Canada and by Professor Maj Hultén, BSc, PhD, MD, FRCPath, Professor of Medical Genetics, University of Warwick, 2009. Copyright © Unique 2009 Rare Chromosome Disorder Support Group Charity Number 1110661 Registered in England and Wales Company Number 5460413 rrraraaarrrreeeecccchhhhrrrroooommmmoooo....oooorrrrgggg 24 A 7q deletion the development of an embryo.
    [Show full text]
  • Ongoing Human Chromosome End Extension Revealed by Analysis of Bionano and Nanopore Data Received: 4 May 2018 Haojing Shao , Chenxi Zhou , Minh Duc Cao & Lachlan J
    www.nature.com/scientificreports OPEN Ongoing human chromosome end extension revealed by analysis of BioNano and nanopore data Received: 4 May 2018 Haojing Shao , Chenxi Zhou , Minh Duc Cao & Lachlan J. M. Coin Accepted: 22 October 2018 The majority of human chromosome ends remain incompletely assembled due to their highly repetitive Published: xx xx xxxx structure. In this study, we use BioNano data to anchor and extend chromosome ends from two European trios as well as two unrelated Asian genomes. At least 11 BioNano assembled chromosome ends are structurally divergent from the reference genome, including both missing sequence and extensions. These extensions are heritable and in some cases divergent between Asian and European samples. Six out of nine predicted extension sequences from NA12878 can be confrmed and flled by nanopore data. We identify two multi-kilobase sequence families both enriched more than 100- fold in extension sequence (p-values < 1e-5) whose origins can be traced to interstitial sequence on ancestral primate chromosome 7. Extensive sub-telomeric duplication of these families has occurred in the human lineage subsequent to divergence from chimpanzees. Te genome sequence of chromosome ends in the reference human genome remains incompletely assembled. In the latest draf of the human genome1 21 out of 48 chromosome ends were incomplete; amongst which fve chromosome ends (13p, 14p, 15p, 21p, 22p) are completely unknown and the remaining chromosome ends are capped with 10–110 kb of unknown sequence. Tere are many interesting observations in the chromosome end regions which remain unexplained, such as the observed increase in genetic divergence between Chimpanzee and Humans towards the chromosome ends2.
    [Show full text]
  • Familial Bone Marrow Monosomy 7 Evidence That the Predisposing Locus Is Not on the Long Arm of Chromosome 7 Kevin M
    Familial Bone Marrow Monosomy 7 Evidence That the Predisposing Locus Is Not on the Long Arm of Chromosome 7 Kevin M. Shannon,* All G. Turhan,*$ Sharon S. Y. Chang,"1 Anne M. Bowcock,' Paul C. J. Rogers,** William L. Carroll,# Morton J. Cowan,* Bertil E. Glader,* Connie J. Eaves, *1111 Allen C. Eaves,t1111 and Yuet Wai Kan1ltl Departments of*Pediatrics and "'Medicine and 1lHoward Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143; Departments of Pathology, **Pediatrics, and 111IMedicine, University ofBritish Columbia, and the §Terry Fox Laboratory, British Columbia Cancer Centre, Vancouver, British Columbia, Canada; Departments of'Genetics and "Pediatrics, Stanford University Medical School, Stanford, California 94303; and t*Department ofPediatrics, Washington University School of Medicine, St. Louis, Missouri 63110 Abstract cinogen exposure (3, 6). The age distribution of these de novo cases shows peaks in the first and fifth decades (6). Overall, Loss of expression of a tumor-suppressing gene is an attractive monosomy 7 or 7q- is identified in - 5% of de novo and in model to explain the cytogenetic and epidemiologic features of 40% of secondary cases of AML (1, 3-5). Although childhood cases of myelodysplasia and acute myelogenous leukemia bone marrow monosomy 7 is an uncommon disorder, it has (AML) associated with bone marrow monosomy 7 or partial been observed in two or more siblings at least seven times deletion of the long arm (7q-). We used probes from within the (7-10, Lange, B. J., personal communication, and our unpub- breakpoint region on 7q- chromosomes (7q22-34) that detect lished data).
    [Show full text]
  • A Physical Map of Chromosome 7 of Candida Albicans
    Copyright 1998 by the Genetics Society of America A Physical Map of Chromosome 7 of Candida albicans Hiroji Chibana,* B. B. Magee,* Suzanne Grindle,* Ye Ran,*,1 Stewart Scherer²,2 and P. T. Magee* *Department of Genetics and Cell Biology, University of Minnesota, St. Paul, Minnesota 55108 and ²Department of Microbiology, University of Minnesota, Minneapolis, Minnesota 55455 Manuscript received February 2, 1998 Accepted for publication May 20, 1998 ABSTRACT As part of the ongoing Candida albicans Genome Project, we have constructed a complete sequence- tagged site contig map of chromosome 7, using a library of 3840 clones made in fosmids to promote the stability of repeated DNA. The map was constructed by hybridizing markers to the library, to a blot of the electrophoretic karyotype, and to a blot of the pulsed-®eld separation of the S®I restriction fragments of the genome. The map includes 149 fosmids and was constructed using 79 markers, of which 34 were shown to be genes via determination of function or comparison of the DNA sequence to the public databases. Twenty-®ve of these genes were identi®ed for the ®rst time. The absolute position of several markers was determined using random breakage mapping. Each of the homologues of chromosome 7 is approximately 1 Mb long; the two differ by about 20 kb. Each contains two major repeat sequences, oriented so that they form an inverted repeat separated by 370 kb of unique DNA. The repeated sequence CARE2/Rel2 is a subtelomeric repeat on chromosome 7 and possibly on the other chromosomes as well. Genes located on chromosome 7 in Candida are found on 12 different chromosomes in Saccharomyces cerevisiae.
    [Show full text]
  • Cloning Human Telomeric DNA Fragments Into Saccharomyces
    Proc. Nadl. Acad. Sci. USA Vol. 86, pp. 6240-6244, August 1989 Genetics Cloning human telomeric DNA fragments into Saccharomyces cerevisiae using a yeast-artificial-chromosome vector (genome mapping/in situ hybridization/human repetitive DNA) HAROLD C. RIETHMAN*, ROBERT K. MOYZISt, JULIANNE MEYNEt, DAVID T. BURKE**, AND MAYNARD V. OLSON* *Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110; and tGenetics Group, LS-3, Los Alamos National Laboratory, University of California, Los Alamos, NM 87545 Communicated by John Carbon, May 15, 1989 (received for review April 1, 1989) ABSTRACT Telomeric fragments of human DNA ranging characterized, X and Y'. X is present at most ofthe telomeres in size from 50 to 250 kilobases were cloned into Saccharomyces in a single copy. Y' is present on about half of the telomeres, cerevisiae using a yeast-artificial-chromosome (YAC) vector. is sometimes present in multiple copies on a single telomere, Six human-telomeric YAC (HTY) strains were selected by and is always distal to X (refs. 11 and 12; A. Link and virtue of the specific hybridization of their DNA with the M.V.O., unpublished). S. cerevisiae has a strain-specific human telomeric terminal-repeat sequence (TTAGGG),, and distribution of these subtelomeric repeats among its 32 telo- the telomeric localization ofthis sequence within each YAC was meres; they are probably responsible in part for the chromo- demonstrated by its sensitivity to nuclease BAL-31. In situ some-length polymorphisms that have been noted among hybridization of DNA from three of these HTY strains with strains (ref. 13; A.
    [Show full text]
  • Centromeric Copy Number of Chromosome 7 Is Strongly Correlated with Tumor Grade and Labeling Index in Human Bladder Cancer1
    (CANCER RESEARCH 51, 3807-3813. July 15, 1991] Centromeric Copy Number of Chromosome 7 Is Strongly Correlated with Tumor Grade and Labeling Index in Human Bladder Cancer1 Frederic M. Waldman,2 Peter R. Carroll, Russell Kerschmann, Michael B. Cohen,3 Frederick G. Field, and Brian H. Mayall Departments of Laboratory Medicine [F. M. W., F. G. F., B. H. M.], Pathology [R. K., M. B. C.¡,and Urology ¡P.R. C.J, University of California San Francisco, San Francisco, California 94143-0808 BrdUrd4 into tumor DNA5 or by immunohistochemical staining ABSTRACT of cell cycle-specific antigens such as Ki67 (21) or PCNA (22) The relationship between interphase cytogenetics and tumor grade, expressed only in proliferating cells. The present study was stage, and proliferative activity was investigated in 27 transitional cell undertaken in order to study the relationships in bladder cancer carcinomas of the urinary bladder. Using fluorescence in situ hybridiza between genotypic and phenotypic abnormalities. Tumor grade, tion with chromosome-specific DNA probes, the copy number of pericen- tumor stage, and tumor labeling index, as measured by BrdUrd tromeric sequences on chromosomes 7, 9, and 11 was detected within incorporation or PCNA labeling, were used to characterize interphase nuclei in touch preparations from tumor biopsies. Monosomy tumor phenotype, while tumor genotype was defined by cyto- of chromosome 9 was detected in 9 of 22 cases (41%), while tetrasomy genetic abnormalities, as detected by FISH with DNA probes for chromosomes 7 and 11 was detected in 10 of 26 (38%) and 6 of 23 specific for chromosomes 7, 9, and 11.
    [Show full text]
  • Cytogenetics and Molecular Genetics of Childhood Brain Tumors 1
    Neuro-Oncology Cytogenetics and molecular genetics of childhood brain tumors 1 Jaclyn A. Biegel 2 Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia and the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 Considerable progress has been made toward improving Introduction survival for children with brain tumors, and yet there is still relatively little known regarding the molecular genetic Combined cytogenetic and molecular genetic approaches, events that contribute to tumor initiation or progression. including preparation of karyotypes, FISH, 3 CGH, and Nonrandom patterns of chromosomal deletions in several loss of heterozygosity studies have led to the identica- types of childhood brain tumors suggest that the loss or tion of regions of the genome that contain a variety of inactivation of tumor suppressor genes are critical events novel tumor suppressor genes and oncogenes. Linkage in tumorigenesis. Deletions of chromosomal regions 10q, analysis in families, which segregate the disease pheno- 11 and 17p, for example, are frequent events in medul- type, and studies of patients with constitutional chromo- loblastoma, whereas loss of a region within 22q11.2, somal abnormalities have resulted in the identication of which contains the INI1 gene, is involved in the develop- many of the disease genes for which affected individuals ment of atypical teratoid and rhabdoid tumors. A review have an inherited predisposition to brain tumors (Table of the cytogenetic and molecular genetic changes identi- 1). The frequency of mutations of these genes in sporadic ed to date in childhood brain tumors will be presented. tumors, however, is still relatively low.
    [Show full text]
  • Mapping of the 7Q31 Subregion Common to the Small
    Oncogene (2000) 19, 754 ± 761 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Mapping of the 7q31 subregion common to the small chromosome 7 derivatives from two sporadic papillary renal cell carcinomas: increased copy number and overexpression of the MET proto-oncogene Liubov Glukhova1, Christian Lavialle2, Didier Fauvet1, Ilse Chudoba3, GiseÁ le Danglot1, Eric Angevin4, Alain Bernheim1 and Anne-FrancËoise Goguel*,1 1Laboratoire de CytogeÂneÂtique et GeÂneÂtique Oncologiques, UMR 1599, PR2, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif cedex, France; 2Laboratoire de GeÂneÂtique Oncologique, Unite Mixte de Recherche 1599 du Centre National de la Recherche Scienti®que, Institut Gustave Roussy, 94805 Villejuif cedex, France; 3Institut fur Humangenetik und Anthropologie, D-07740 Jena, Germany; 4Unite d'ImmunotheÂrapie, Institut Gustave Roussy, 94805 Villejuif cedex, France Molecular cytogenetic analysis of several sporadic throughout tumour progression (Kovacs, 1993b). papillary renal cell carcinomas and of their xenografts Indeed, the most common non papillary subtype, clear in immunode®cient mice had previously allowed us to cell renal carcinoma, is characterized by deletions in delimit a minimal overrepresented region of chromo- chromosome arm 3p, whereas the 3p region is intact in some 7 shared by all of them to band 7q31. We have papillary RCC. In addition, the latter exhibits an re®ned the location of the overlapping region to the increase in chromosome number typically including junction of the subbands 7q31.2 and 7q31.3 by reverse chromosomes 7 and 17. These anomalies are also painting with two dierently labelled probes prepared found in early renal lesions such as adenomas, from the small chromosome 7 derivatives microdissected suggesting that they could be involved in tumour from the cells of two distinct tumours.
    [Show full text]
  • Mapping of Transforming Growth Factor a Gene on Human Chromosome 2 Close to the Breakpoint of the Burkitt's Lymphoma T(2;8) Variant Translocation1
    (CANCER RESEARCH 45, 5593-5597, November 1985] Mapping of Transforming Growth Factor a Gene on Human Chromosome 2 Close to the Breakpoint of the Burkitt's Lymphoma t(2;8) Variant Translocation1 Jane E. Brissenden, Rik Derynck, and Uta Francke Department of Human Genetics, Yale University School of Medicine, New Haven, Connecticut 06510 [J. E. B., U. F.], and Department of Molecular Biology, Genentech, Inc., South San Francisco, California 94080 [R. D.] ABSTRACT or EGF to induce transformation of normal rabbit kidney indicator cells (8, 9) and do not compete with EGF for binding to EGF Transforming growth factors (TGFs) are defined as biologically receptors although they do induce an increase of EGF receptor active polypeptides which reversibly confer the transformed phe- numbers on normal rabbit kidney cells in culture (11). notype onto untransformed cultured cells. TGF-a shows se TGFs-a have been suggested to play a physiological role in quence homology with epidermal growth factor and competes embryonic development (12), and many observations have linked with epidermal growth factor for binding to the epidermal growth their secretion to the malignant transformation of cells. For factor receptor, stimulating the phosphorylation of the receptor. example, cells transformed with a temperature sensitive Kirsten TGF-a is secreted by many transformed cells and may be murine sarcoma virus secrete TGF-a only when phenotypic involved in embryonic development. transformation occurs at the permissive temperature (13). Intro A cloned human TGF-a gene was used to map the locus for duction of the DNA segment coding for middle T-antigen of the TGF-a precursor to the short arm of human chromosome 2, polyoma virus into cells is sufficient to induce both a transformed region 2p11-»2p13, by Southern blotting techniques with DNA phenotype and TGF-a secretion (14).
    [Show full text]
  • Williams Syndrome
    Williams syndrome Description Williams syndrome is a developmental disorder that affects many parts of the body. This condition is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel (cardiovascular) problems. People with Williams syndrome typically have difficulty with visual-spatial tasks such as drawing and assembling puzzles, but they tend to do well on tasks that involve spoken language, music, and learning by repetition (rote memorization). Affected individuals have outgoing, engaging personalities and tend to take an extreme interest in other people. Attention deficit disorder (ADD), problems with anxiety, and phobias are common among people with this disorder. Young children with Williams syndrome have distinctive facial features including a broad forehead, a short nose with a broad tip, full cheeks, and a wide mouth with full lips. Many affected people have dental problems such as teeth that are small, widely spaced, crooked, or missing. In older children and adults, the face appears longer and more gaunt. A form of cardiovascular disease called supravalvular aortic stenosis (SVAS) occurs frequently in people with Williams syndrome. Supravalvular aortic stenosis is a narrowing of the large blood vessel that carries blood from the heart to the rest of the body (the aorta). If this condition is not treated, the aortic narrowing can lead to shortness of breath, chest pain, and heart failure. Other problems with the heart and blood vessels, including high blood pressure (hypertension), have also been reported in people with Williams syndrome. Additional signs and symptoms of Williams syndrome include abnormalities of connective tissue (tissue that supports the body's joints and organs) such as joint problems and soft, loose skin.
    [Show full text]
  • Severe Anomalies Associated with Ring Chromosome 7
    American Journal of Medical Genetics 40429-431 (1991) Severe Anomalies Associated With Ring Chromosome 7 Leslie G. Biesecker, Beth Cox, and Thomas W. Glover Departments of Pediatrics and Communicable Diseases (L.G.B., T.W.G.), Pathology (B.C.) and Human Genetics (T.W.G.), University of Michigan Medical School, Ann Arbor, Michigan A newborn infant with the polyasplenia se- OFC was 29.5 cm (<3rd centile). At birth he was noted to quence, intrauterine growth retardation, cu- have a murmur and multiple congenital anomalies and taneous nevi, and minor anomalieswas found was transferred to a regional center where complex con- to have mosaicism for ring chromosome 7. genital cyanotic heart disease was diagnosed. Pros- This patient’s anomalies are markedly differ- taglandins were administered and he was transferred to ent from those of previous patients reported this institution. with this cytogenetic anomaly. On physical examination he was noted to have large capillary hemangiomata of the forehead, occiput, back, KEY WORDS: chromosomes, asplenia, Ive- and neck. The skin of his neck, back, and scalp was mark “syndrome,” growth redundant. A darkly pigmented nevus was present on retardation, mosaicism, ab- the left thigh (4 cm). His palpebral fissures were wide normalities: multiple, ring (2.3 cm) and his ears were short (3 cm). One earlobe had chromosome, chromosome 7 oblique cutaneous creases. A murmur and a unilateral hydrocele were present. His suck reflex was described as fair and his Moro and deep tendon reflexes were normal. INTRODUCTION An echocardiogram documented situs inversus, d-loop, d-transposition of the great vessels, virtual pul- Seven previous cases of ring chromosome 7 (r(7))have monary atresia, unbalanced atrioventricular septa1 de- been reported in association with minor anomalies with fect, left ventricular hypoplasia, and a common atrio- and without mental retardation [Zackai and Breg, 1973; ventricular valve with 1+ insufficiency.
    [Show full text]