Genomic Instability and Immortality in Cancer

249 Pages·1997·16.17 MB·English

by  Giovanni Cenci

GENOMIC INSTABILITY
AND IMMORTALITY
IN CANCER
PEZCOLLER FOUNDATION SYMPOSIA
SERIES EDITOR:
Enrico Mihich, Roswell Park Cancer Institute, Buffalo, New York
STANDING PEZCOLLER SYMPOSIA COMMITTEE:
Enrico Mihich (Chairman), Roswell Park Cancer Institute, Buffalo, New York
David M. Livingston (Vice-Chairman), Dana-Farber Cancer Institute, Boston, Massachusetts
Giuseppe Bernardi, Pezcoller Foundation, Trento, Italy
Bruce Chabner, Massachusetts General Hospital Cancer Center, Boston, Massachusetts
Carlo M. Croce, Jefferson Medical College, Philadelphia, Pennsylvania
Riccardo Dalla Favera, College of Physicians & Surgeons of Columbia University,
New York, New York
Giuseppe Della Porta, European Institute of Oncology, Milan, Italy
Thomas Graf, European Molecular Biology Lab, Heidelberg, Germany
Giorgio Lenaz, University of Bologna, Bologna, Italy
Paolo Schlechter, Pezcoller Foundation, Trento, Italy
Claudio Schneider, LNCIB Area Science Park, Trieste, Italy
Tadatsugu Taniguchi, University of Tokyo, Tokyo, Japan
Fulvio Zuelli, University of Trento, Trento, Italy
PROGRAM COMMITTEE:
Enrico Mihich (Chair), Roswell Park Cancer Institute, Buffalo, New York
Leland Hartwell (Co-Chair), University of Washington, Seattle, Washington
Carol Greider (Co-Chair), Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
Garth Anderson, Roswell Park Cancer Institute, Buffalo, New York
Margherita Bignami, Istituto Superiore Sanita, Rome, Italy
David M. Livingston, Dana-Farber Cancer Institute, Boston, Massachusetts
Recent volumes published by Plenum Press:
Volume 4 • CELL ADHESION MOLECULES: Cellular Recognition Mechanisms
Edited by Martin E. Hemler and Enrico Mihich
Volume 5 • APOPTOSIS
Edited by Enrico Mihich and Robert T. Schimke
Volume 6 • NORMAL AND MALIGNANT HEMATOPOIESIS: New Advances
Edited by Enrico Mihich and Donald Metcalf
Volume 7 • CANCER GENES: Functional Aspects
Edited by Enrico Mihich and David Housman
Volume 8 • GENOMIC INSTABILITY AND IMMORTALITY IN CANCER
Edited by Enrico Mihich and Leland Hartwell
A Continuation Order Plan is available for this series. A continuation order will bring delivery of each
new volume immediately upon publication. Volumes are billed only upon actual shipment. For further
information please contact the publisher.
GENOMIC INST ABILITY
AND IMMORTALITY
IN CANCER
Edited by
Enrico Mihich
Roswell Park Cancer Institute
Buffalo, New York
and
Leland Hartwell
University of Washington
Seattle, Washington
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Llbrary of Congress Catalaglng-In-Publlcatlan Dati
Gena.lc lnstabl11ty and lmmartallty In cancer I edlted by Enrlca
Mlhlch and Leland Hartwell.
p. cm. -- (Pezcaller Faundatlan sympasia ; 8)
"Praceedlngs of 'ha Eighth Annual Pezcoller Sympo~tu. en Genamie
Instabl11ty and Inartality In Cancer, held June 17-19', 1996, In
Trenta, Italy"--T.p. versa.
Includes blbliagraphlcal references and index.
ISBN 978-1-4613-7448-0 ISBN 978-1-4615-5365-6 (eBook)
DOI 10.1007/978-1-4615-5365-6
1. Cancer--Genetlc aspects--Cangresses. 2_ Cancer cel1s-
-Congresses. 3_ Apaptasis--Cangresses. 1. Mihlch, Enrlca.
II. Hartwell, Leland. III. Pezcaller Sy.paslum an Gena.lc
Instablllty and Immartality In Cancer (1997 Trenta. Italy)
IV. Serles.
[ONLM: 1. Neoplasms--genatlcs--cangrasses. 2. Cell
Transformatlon. Neaplastic--genetlcs--cangresses. 3. Cell Cycle
-genetlcs--congresses. 4. Gene Expresslon--genetics--cangresses.
Wl PE995 v.8 1997 I OZ 202 G3328 19971
RC288.4.G478 1997
818.99'4042--dc21
ONLM/DLC
for Llbrary of Congress 97-29987
CIP
Proceedings of the Eighth Annual Pezcoller Symposium on Genomic Instability and Immortality in
Cancer, held June 17-19, 1996, in Trento, Italy
ISBN 978-1-4613-7448-0
o
1997 Springer Science+Business Media New York
Origina\ly published by Plenwn Press, New York in 1997
Softcover reprint of the hardcover 1st edition 1997
http://www.plenum.com
1098765432 1
AU rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by
any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written
permission from the Publisher
THE PEZCOLLER FOUNDATION
The Pezcoller Foundation was created in 1979 by Professor Alessio Pezcoller
(1896-1993) who was the chief surgeon of the S. Chiara Hospital in Trento from 1937 to
1966 and who gave a substantial portion of his estate to support its activities; the F ounda
tion also benefits from the cooperation of the Savings Bank Cassa di Risparmio di Trento
e Rovereto.
The main goal of this non-profit foundation is to provide and recognize scientific
progress on life-threatening diseases, currently focusing on cancer. Towards this goal, the
Pezcoller Foundation awards, every two years, the Pezcoller Prize, recognizing highly
meritorious contributions to medical research; it also sponsors a series of annual symposia
promoting interactions among scientists working at the cutting edge of basic oncological
sciences.
The symposia are held in the Trentino Region of Northern Italy and their scientific
focus is selected by Enrico Mihich with the collaboration of an international Standing
Symposia Committee. A Program Committee determines the content of each symposium.
The first symposium focused on Drug Resistance: Mechanisms and Reversal (E. Mi
hich, Chairman, 1989); the second on The Therapeutic Implications of the Molecular Biol
ogy of Breast Cancer (M.E. Lippman and E. Mihich, Co-Chairmen, 1990); the third on
Tumor Suppressor Genes (D.M. Livingston and E. Mihich, Co-Chairmen, 1991); the
fourth on Cell Adhesion Molecules: Cellular Recognition Mechanisms (M.E. Hemler and
E. Mihich, Co-Chairmen, 1992); the fifth on Apoptosis (E. Mihich and R.T. Schimke, Co
Chairmen, 1993); the sixth on Normal and Malignant Hematopoiesis: New Advances (E.
Mihich and D. Metcalf, Co-Chairmen, 1994); the seventh on Cancer Genes: Functional
Aspects (E. Mihich and D. Housman, Co-Chairmen, 1995); the ninth on The Biology of
Tumors (E. Mihich and C. Croce, Co-Chairmen, 1997).
v
PREFACE
The eighth Annual Pezcoller Symposium, entitled Genomic Instability and Immor
tality in Cancer, was held in Trento, Italy, June 17-19, 1996 and was focused on the clari
fication of the mechanisms of genetic instability, a characteristic of neoplastic cells which
also determines tumor progression, and immortality consequent to the lack of susceptibil
ity to mechanisms of maturations, senescence and/or apoptosis.
With presentations at the cutting edge of progress and stimulating discussions, this
symposium addressed issues related to mutational lability, changes in DNA repair capa
bilities, gene recombination processes, cell cycle checkpoints and apoptosis, the signifi
cance of telomerases in cell immortalization and senescence, and the clinical relevance
and exploitation of the phenomena considered.
We wish to thank the participants in the symposium for their substantial contribu
tions and their participation in the spirited discussions that followed. We would also like
to thank Drs. Carol Greider, Garth Anderson, Margherita Bignami, and David Livingston,
for their essential input as members of the Program Committee, and Ms. A. Toscani for her
invaluable assistance. The aid of the Savings Bank Cassa di Risparmio di Trento e Ro
vereto, and the Municipal, Provincial, and Regional Administrations in supporting this
Symposium through the Pezcoller Foundation are also acknowledged with deep apprecia
tion. Finally, we wish to thank the staff of Plenum Publishing Corporation for their effi
cient cooperation in the production of these proceedings.
Enrico Mihich
Leland Hartwell
vii
CONTENTS
1. Telomeres and Cell Division in Drosophila melanogaster
Giovanni Cenci and Maurizio Gatti
2. A Molecular Cytogenetic View of Chromosomal Heterogeneity in Solid Tumors 13
Joe W. Gray, Koei Chin, and Fredric Waldman
3. Cell Cycle Control of Genetic Stability ................................. 33
Geoffrey M. Wahl, Steven P. Linke, Thomas G. Paulson, and Li-chun Huang
4. Aneuploidy and Heterogeneity Mechanisms in Human Colorectal Tumor
Progression .................................................. 53
Walter Giaretti
5. p53-Dependent Signaling in Response to DNA Damage or Arrest of DNA
Synthesis and Its Role in Cell Cycle Control ........................ 69
Munna L. Agarwal, William R. Taylor, and George R. Stark
6. Recombining DNA Damage Repair, Basal Transcription, and Human Syndromes 83
Jan H. 1. Hoeijmakers, Gijsbertus T. 1. van der Horst, Geert Weeda,
Wim Vermeulen, G. Sebastiaan Winkler, Jan de Boer, Wouter L. de Laat,
Anneke M. Sijbers, Elizabetta Citterio, Nicolaas G. 1. Jaspers,
Jean-Marc Egly, and Dirk Bootsma
7. Telomere Length Regulation by the Pin DNA Helicase . . . . . . . . . . . . . . . . . . . . 97
Ellen K. Monson, Vincent P. Schulz, and Virginia A. Zakian
8. Consequences of Mutations that Alter Telomeres in the Yeast K. lactis 111
Michael 1. McEachern and Elizabeth H. Blackburn
9. Regulation of Telomere Length in Mammalian Cells ...................... 133
Brenda R. Grimes, David Kipling, Niolette I. McGill, Claudia Teschke,
Sally H. Cross, Patricia Malloy, Helen E. Wilson, Christine 1. Farr, and
Howard 1. Cooke
10. The DNA Damage Checkpoint. .. ... . . .. .. ... . . . . .. . . . .. . . . . . .. . .. . .. . 149
Leland Hartwell, Amanda Paulovich, and David Tocyzki
ix
x Contents
11. A Eukaryotic Cell Cycle ........................... . . . . . . . . . . . . . . . . . . 159
Kim Nasmyth
12. The Integration of Signalling Pathways in Mammalian Cells. . . . . . . . . . . . . . . . 171
Gerard I. Evan, Andrea Kauffmann-Zeh, Eugen Ulrich, Trevor Littlewood,
David Hancock, and Elizabeth Harrington
13. Antitumor Drugs and Yeast Cell Cycle Checkpoints. . . . . . . . . . . . . . . . . . . . . . . 189
Martin Weinberger, Lisa Black, Terry A. Beerman, Joel A. Huberman, and
William C. Burhans
14. Neoplastic Progression in Barrett's Esophagus ........................... 195
Michael T. Barrett, Carissa A. Sanchez, Patricia C. Galipeau,
Katayoun Neshat, David S. Cowan, Douglas S. Levine, and Brian J. Reid
15. E2F-1 Degradation by the Ubiquitin-Proteasome Pathway. . . . . . . . . . . . . . . . . . 215
Francesco Hofmann and David M. Livingston
16. Cdk4-Cyclin D 1 and Cdk2-Cyclin EI A Phosphorylate Different Sites in the RB
Protein ...................................................... 229
Yoichi Taya, Hai-Kwan Jung, Masako Ikeda, Katsuyuki Tarnai,
Hideaki Higashi, and Masatoshi Kitagawa
17. Cell Cycle Regulatory Proteins as Targets of Oncogenic Events 233
Francesca Fiore and Giulio F. Draetta
Index.......... .............................. ...... .. ....... .. ... . .... 247
1
TELOMERES AND CELL DIVISION IN
Drosophila melanogaster
Giovanni Cenci and Maurizio Gatti
Dipartimento di Genetica e Biologia Molecolare
Universita di Roma "La Sapienza"
P.le Aldo Moro 5, 00185 Roma, Italy
INTRODUCTION
Telomeres are specialized DNA-protein complexes that protect the ends of linear
eukaryotic chromosomes from degradation and incomplete DNA replication. In most
organisms telomeres contain arrays of tandem G-rich repeats that are added to the chromo
somal termini by a specialized polymerase, called telomerase, which contains an integral
RNA template (reviewed by Zakian, 1989). In Drosophila melanogaster telomeric DNA is
comprised of two LINE-like retrotransposable elements, called HeT-A and TART, which
are specifically added to chromosome ends to compensate for replicative DNA loss (for
reviews, see Mason and Biessman, 1995; Pardue, 1995). Apart from this difference in the
DNA content, Drosophila telomeres behave like those of other organisms and are likely to
bind similar, evolutionary conserved proteins (Biessman and Mason, 1992). For example,
both Drosophila and yeast telomeres have heterochromatic properties and share the ability
of modulating the expression of adjacent genes, a phenomenon called telomere position
effect (Levis et aI., 1985; Shore, 1995).
Telomeres are also believed to help organize the architecture of interphase nucleus
by interacting with the nuclear envelope (reviewed by Dernburg et aI., 1995). A non ran
dom organization of the chromosomes within the nucleus was first described by Rabl
(1885). Rabl noticed that the telomeres of prophase chromosomes were located at one side
of the nucleus, while the centromeres were lying at the opposite side. Because this polar
ized chromosomal arrangement was similar to that of the preceding anaphase, Rabl sug
gested that chromosomes maintain their anaphase configuration throughout interphase.
Since these early studies, a Rabl orientation of chromosomes has been observed in a wide
range of animals and plants; in many cases telomeres were found near the nuclear periph
ery, suggesting an interaction between these structures and the nuclear envelope (reviewed
by Dernburg et aI., 1995). However, no clear evidence of a Rabl orientation was found in
mouse and human interphase nuclei. Moreover, in these cells telomeres do not appear to
be associated with the nuclear envelope (Manuelidis and Borden, 1988; Billia and de
Boni, 1991; Vourc'h et aI., 1993).
Genomic Instability and Immortality in Cancer
edited by Mihich and Hartwell, Plenum Press, New York, 1997
2 G. Cenci and M. Gatti
TELOMERE-TELOMERE ASSOCIATIONS
A number of studies has shown that telomeres not only interact with the nuclear
envelope but also with each other (reviewed by Dernburg et ai., 1995). Examination of
interphase nuclei has shown that in many cases telomeres are tightly clustered at the peri
phery of the nucleus. Most interestingly, physical connections between homologous and
heterologous telomeres of prophase chromosomes have been documented in several or
ganisms (for reviews see Avivi and Feldman, 1980; Dernburg et ai., 1995). For example,
in favorable preparations from onion and other plant cells, and from the coccid Chysom
phalus ficus, all the chromosomes are linked through their telomeres to form a continuous
chain or "spireme" (Hughes-Schrader, 1957; Wagenaar, 1969; Stack and Clarke, 1973).
The telomere-telomere connections observed in onion cells are already present during
interphase; they persist in prophase, tend to disappear in metaphase and are no longer
detectable during anaphase (Stack and Clarke, 1973). This suggests that the telomeric
attachments seen in prophase are a relic of the interphase chromosome organization, and
implies that such attachments must form de novo during each cell cycle. The biological
meaning of these telomeric associations and the mechanisms underlying this phenomenon
are not understood.
Normal mammalian cells do not exhibit telomere-telomere associations (TAs).
However such associations have been observed in senescent human fibroblast (Benn,
1976), in cells from patients with ataxia telangiectasia (Hayshi and Schimd, 1975; Taylor
et ai., 1981), in lymphocytes of one patient suffering from Thiberg-Weissenbach syndrome
(Dutrillaux et ai., 1978) and in a wide variety of human tumors (for reviews see Hastie
and Allshire, 1989; de Lange, 1995). In most of these tumors 20-30% of metaphases
showed clear telomeric associations resulting in the formation or either ring or dicentric
chromosomes. These aberrant chromosome configurations were generally caused by ran
dom association of chromosomes and no tumor-specific patterns of telomeric associations
have been described (for reviews see Hastie and ABshire, 1989; de Lange, 1995).
In many cases telomeric associations observed in cancer cells appear to persist dur
ing anaphase; they can form anaphase bridges that result in either chromosome breakage
or non disjunction (Hastie and Allshire, 1989; de Lange, 1995). Telomeric associations can
therefore promote loss of heterozygosity, contributing to tumor development. Moreover, it
has been speculated that the frequency of TAs may be particularly high in early stages of
carcinogenesis, before telomerase activation has counterbalanced replicative telomere
shortening (de Lange, 1995). Despite the potential involvement of TAs in human tu
morigenesis, little is known about the molecular mechanisms underlying telomere
telomere attachments. It is generally accepted that the occurrence of TAs is correlated with
the short telomere length in cancer cells. However, the finding that some tumor cell lines
with particularly short telomeres do not exhibit TAs, indicates that telomeric lenght is not
the only determinant oftelomeric fusions (Saltman et aI., 1993; de Lange, 1995). It is thus
likely that specific transacting factors can contribute to the genesis of TAs in tumor cells.
Two transacting functions required to prevent telomeric fusions in normal Drosophila
cells are described in the next section.
Drosophila MUTANTS AFFECTING TELOMERE BEHAVIOR
In the course of genetic screens for mutations affecting the fidelity of chromosome
segregation we have identified two genes [UbcDI and pendolino (pen)] required for