Table Of ContentMoLECUlAR
BIOLOGY
INTELLIGENCE
UNIT
P53 SuPPRESSOR GENE
MoLECUlAR
BIOLOGY
INTELLIGENCE
UNIT
P53 SUPPRESSOR GENE
Tapas Mukhopadhyay, Ph.D.
Steven A. Maxwell, Ph.D.
Jack A. Roth, M.D.
University ofTexas
M. D. Anderson Cancer Center
Houston, Texas, U.S.A.
Springer-Verlag
RG. LANDEs CoMPANY
Berlin Heidelberg GmbH
AUSTIN
MoLEcULAR BIOLOGY lNTELLIGENCE UNIT
P53 SUPPRESSOR GENE
R.G. LANDES COMPANY
Austin, Texas, U.S.A.
Submitted: December 1994
Published: March 1995
U.S. and Canada Copyright © 1995 R.G. Landes Company
All rights reserved.
International Copyright © 1995 Springer-Verlag Berlin Heidelberg
Originally published by Springer-Verlag Berlin Heidelberg in 1995
Softcover reprint of the hardcover 1s t edition 1995
All rights reserved.
International ISBN 978-3-662-22277-5
While the authors, editors and publisher believe that drug selection and dosage and the specifications and
usage of equipment and devices, as set forth in this book, are in accord with current recommendations and
practice at the rime of publication, they make no warranty, expressed or implied, with respect to material
described in this book. In view of the ongoing research, equipment development, changes in governmental
regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is
urged to carefully review and evaluate the information provided herein.
Library ofCongress Cataloging-in-Publication Data
Mukhopadhyay, Tapas.
p53 suppressor gene 1 Tapas Mukhopadhyay, Steven A. Maxwell, Jack A. Roth
p. cm.--(Molecular biology intelligence unit)
Includes bibliographical references and index.
ISBN 978-3-662-22277-5 ISBN 978-3-662-22275-1 (eBook)
DOI 10.1007/978-3-662-22275-1
1. p53 antioncogene. 1. Maxwell, Steven A. II. Roth, Jack A. III. Title. IV. Series.
RC268. 44.P16M85 1995
616.99'4042--dc20
95-4045
CIP
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rr===================== CONTENTS ===================:::::::::;-]
1. The Role ofp 53 in Cancer .......................................................... 1
From Oncogene to Tumor Suppressor Gene ......................................... 1
Interactions with DNA Tumor Virus-Transforming Proteins ............... 2
2. Gene Structure .......................................................................... 13
Introduction ....................................................................................... 13
Structure ofp 53 Gene ......................................................................... 13
3. Wild-Type versus Mutant p53 .................................................. 19
Introduction ....................................................................................... 19
Structure and Function ofWild-Type p53 Protein .............................. 20
Mutational Inactivation ofp 53 ........................................................... 24
Methods of Assayingp53 Gene Mutation in Human Cancers ............. 30
Mutant p53 Proteins ........................................................................... 33
p53 Mutations in Human Cancer .......................... , ............................ 36
4. Biophysical and Biochemical Properties of the p53 Protein ...... 55
Introduction ....................................................................................... 55
Missense Mutations within a Conserved Region ofp 53
Alter Its Biological Activity ............................................................ 59
The Central Conserved Region is a Conformational
Domain ofp 53 .............................................................................. 60
The Conformation ofp 53 Determines Its Biological Activity .............. 61
Conclusion .......................................................................................... 64
5. Regulation and Modulation of the Function ofp 53 .................. 73
Introduction ....................................................................................... 73
Protein Interactions Can Regulate p53 ................................................ 73
Regulation ofp 53 by Phosphorylation ................................................ 79
Redox Mechanisms ............................................................................. 81
Allosteric Regulation Model ................................................................ 81
Regulation oflntracellular p53 Levels ................................................. 84
Regulation of Subcellular Localization ofp 53 ..................................... 86
Control Over the Potential Role ofp 53 in DNA Replication .............. 87
Cell Cycle Regulation ofp 53 Function ............................................... 89
Tissue- and Cell Type-Specific Regulation ofp 53 Activity .................. 90
Conclusions ........................................................................................ 93
6. Potential Clinical Significance
of the p53 Tumor Suppressor Gene in Cancer Patients .......... 113
Second Primary Cancers ................................................................... 114
The Role ofp 53 in Premalignancy .................................................... 115
Prognostic Studies in Cancer Patients ............................................... 116
Gene Replacement Clinical Trials ..................................................... 116
Retroviral Vectors for Gene Delivery ................................................. 118
Adenoviral Vectors for Gene Delivery ............................................... 120
Clinical Applications ......................................................................... 122
Index .............................................................................................. 127
======PREFACE======
he p53 field has been growing at a rapid pace, with more than 2500 articles
T
published since 1989. Publications onp53 will probably exceed 600 in 1994.
The recognition of multiple roles for p53 in biological processes of growth,
apoptosis, differentiation and transformation awarded it the distinction of"Mol-
ecule of the Year" by the journal Science. The p53 protein is the most commonly
mutated gene product identified to date in human cancers. The recent identifi-
cation of alterations in p53 regulatory proteins, such as mdm-2, indicate that the
p53 biochemical pathway of growth control may be a more frequent origin for
human cancer than previously realized.
We reluctantly undertook the task of assembling the vast wealth of informa-
tion on the p53 gene and its product. It was unfeasible to include all articles
written on p53, and we selected those that would provide a source for additional
information on the specific topics concerning p53 discussed in this book. Our
main goal was to provide an overview of the p53 gene, its product, regulatory
mechanisms, action and clinical implications that could be used by investigators
interested in the field. We hope that this book will be a useful tool for those who
are just beginning in the p53 field, as well as for researchers well established in the
field.
We would like to thank Carol Torrence and Marie Bunker for their assis-
tance in typing and editing this manuscript.
Author's Note: In this book the authors' use of p53 was used to denote the gene
and p53 was used to denote the protein
AcKNOWLEDGMENTS
This study was partially supported by grants (R29 CA45187
[S.A.M.] and ROl CA45187 [J.A.R.]) from the National Cancer
Institute; by gifts to the Division of Surgery from Tenneco and
Exxon for the Core Lab Facility; by the Cancer Core Center
Support Grant (CA16672); and by a grant from the Mathers
Foundation.
