p53 Suppressor Gene PDF
Preview p53 Suppressor Gene
MoLECUlAR 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 PuBLISHER's NotE R.G. Landes Company publishes five book series: Medical Intelligence Unit, Molecular Biology Intelligence Unit, Neuroscience Intelligence Unit, Tissue Engineering Intelligence Unit and Biotech- nology Intelligence Unit. The authors of our books are acknowl- edged leaders in their fields and the topics are unique. Almost without exception, no other similar books exist on these topics. Our goal is to publish books in important and rapidly changing areas of medicine for sophisticated researchers and clinicians. To achieve this goal, we have accelerated our publish- ing program to conform to the fast pace in which information grows in biomedical science. Most of our books are published within 90 to 120 days of receipt of the manuscript. We would like to thank our readers for their continuing interest and wel- come any comments or suggestions they may have for future books. Deborah Muir Molsberry Publications Director R.G. Landes Company 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.
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