Mutant p53 and MDM2 in Cancer

376 Pages·2014·6.29 MB·English

by  Swati Palit Deb, Sumitra Deb (eds.)

Subcellular Biochemistry 85
Swati Palit Deb
Sumitra Deb E ditors
Mutant p53
and MDM2
in Cancer
Mutant p53 and MDM2 in Cancer
Subcellular Biochemistry
Volume 85
Series editor
Robin Harris, Northumberland, UK
For further volumes:
http://www.springer.com/series/6515
Swati Palit Deb (cid:129) Sumitra Deb
Editors
Mutant p53 and MDM2
in Cancer
Editors
Swati Palit Deb
Sumitra Deb
Department of Biochemistry and Molecular
Biology, and the Massey Cancer Center
Virginia Commonwealth University
Richmond , VA , USA
ISSN 0306-0225
ISBN 978-94-017-9210-3 ISBN 978-94-017-9211-0 (eBook)
DOI 10.1007/978-94-017-9211-0
Springer Dordrecht Heidelberg New York London
Library of Congress Control Number: 2014946109
© Springer Science+Business Media Dordrecht 2014
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Prefa ce
Since its discovery, p53 research has been the highlight of understanding the crucial
role of oncogenes and tumor suppressors in regulated or deregulated cell growth.
In the last decade, special attention was focused on gain of function mutations of
p53 that can turn the tumor suppressor to an oncoprotein, as well as on abnormal
expression of oncogenes such as MDM2 and MDMX that could inactivate the tumor
suppressor function of p53 in the hope of devising cancer treatment. A wealth of
information has emerged regarding what genes the gain-of-function mutants of p53
activate and how they induce oncogenesis, how these mutants are stabilized in can-
cer cells, how they respond to chemotherapy, and how interaction of p53 mutants
with p53 family members may induce oncogenesis. Similarly there are exciting
reports on how the oncoprotein MDM2, known to exist to control p53, can activate
signaling pathways independent of p53 when overexpressed, and how MDMX is
involved in the regulation of p53 by MDM2.
Mutant p53 and MDM2 in Cancer includes 19 chapters that discuss the activation
of diverse oncogenic pathways consequent to p53 mutation and overexpression of
MDM2 and MDMX and their splice variants. This book also includes chapters
that discuss p53 mutation in hereditary cancer, response of cancers with p53
mutation to chemotherapy and radiation, structural aspects of mutant p53 that make
it an oncoprotein and targeting of these structures for cancer therapy. The function
of wild type p53 in response to stress and regulation of this function by MDM2 has
also been included. Overall, this book provides an insight into the primary molecu-
lar events leading to oncogenesis consequent to p53 mutation and overexpression
of MDM2. The information should be invaluable for beginning or experienced
researchers, and even for future researchers opting to commit to cancer biology.
To dissect the oncogenic functions of mutant p53 and MDM2, the book focuses
primarily on human systems. Since a large volume of literature is available for the
mouse models, perhaps it calls for a separate volume.
We thank Dr. Thijs van Vlijmen for giving us the opportunity of designing and
editing the book. We also owe thanks to the staff of Springer Science and Business
Media for their work in the completion of the book. We convey our sincerest thanks
v
vi Preface
to the scientists who contributed the chapters for their insightful discussion. We are
indebted to our graduate students for their untiring effort in every step of this work.
We are particularly thankful to Isabella Pearsall for her help in communicating with
authors during initiation and completion of the book. We also thank Catherine
Vaughan for grammatical editing of chapters and Shilpa Singh for her support.
Richmond, VA, USA Swati Palit Deb
Sumitra Deb
Contents
1 p53 and Hereditary Cancer .................................................................... 1
Diana Merino and David Malkin
2 Alterations of p63 and p73 in Human Cancers .................................... 17
Kazushi Inoue and Elizabeth A. Fry
3 Cooperation of p53 Mutations with Other Oncogenic
Alterations in Cancer .............................................................................. 41
Javier E. Girardini , Dawid Walerych , and Giannino Del Sal
4 p53: Its Mutations and Their Impact on Transcription ...................... 71
Catherine Vaughan , Isabella Pearsall , Andrew Yeudall ,
Swati Palit Deb , and Sumitra Deb
5 Transcriptional Regulation by Mutant p53 and Oncogenesis ............ 91
Raffaela Santoro , Sabrina Strano , and Giovanni Blandino
6 p53 Mutation in the Genesis of Metastasis ........................................... 105
W. A. Yeudall
7 Structural Studies on Mechanisms to Activate Mutant p53 ............... 119
Hector Viadiu , Gilberto Fronza , and Alberto Inga
8 Mutant p53 and the Response to Chemotherapy and Radiation ....... 133
Leila Tchelebi , Hani Ashamalla , and Paul R. Graves
9 The p53-Mdm2 Loop: A Critical Juncture of Stress Response .......... 161
Yaara Levav-Cohen , Zehavit Goldberg , Kah Hin Tan ,
Osnat Alsheich-Bartok , Valentina Zuckerman ,
Sue Haupt , and Ygal Haupt
10 Mechanisms of Mutant p53 Stabilization in Cancer ........................... 187
Rebecca A. Frum and Steven R. Grossman
vii
viii Contents
11 Crosstalk Between Mdm2, p53 and HIF1-α: Distinct Responses
to Oxygen Stress and Implications for Tumour Hypoxia .................... 199
E. Douglas Robertson , Kostyantyn Semenchenko ,
and Bohdan Wasylyk
12 MDM2 Overexpression, Activation of Signaling Networks,
and Cell Proliferation ............................................................................. 215
Swati Palit Deb , Shilpa Singh , and Sumitra Deb
13 p53-Independent Effects of Mdm2 ........................................................ 235
Stephen Bohlman and James J. Manfredi
14 Splice Variants of MDM2 in Oncogenesis ............................................. 247
Melissa Rosso , Danielle E. Okoro , and Jill Bargonetti
15 Mdm2 and MdmX Involvement in Human Cancer ............................. 263
Steven J. Berberich
16 Targeting p53-MDM2-MDMX Loop for Cancer Therapy.................. 281
Qi Zhang , Shelya X. Zeng , and Hua Lu
17 Involvement of p53 in the Repair of DNA Double Strand
Breaks: Multifaceted Roles of p53 in Homologous Recombination
Repair (HRR) and Non-Homologous End Joining (NHEJ) ................ 321
Vijay Menon and Lawrence Povirk
18 The Role of Tumor Suppressor p53 in the Antioxidant
Defense and Metabolism ......................................................................... 337
Andrei V. Budanov
19 Lung Cancer Stem Cells, p53 Mutations and MDM2 ......................... 359
Venkat Sundar Gadepalli , Swati Palit Deb , Sumitra Deb ,
and Raj R. Rao
Index ................................................................................................................. 371
Chapter 1
p53 and Hereditary Cancer
Diana Merino and David Malkin
Abstract T he roles of p53 as “guardian of the genome” are extensive, encompassing
regulation of the cell cycle, DNA repair, apoptosis, cellular metabolism, and
senescence - ultimately steering cells through a balance of death and proliferation.
The majority of sporadic cancers exhibit loss of p53 activity due to mutations or
deletions of TP53, and alterations in its signaling pathway. Germline T P53
mutations have been identifi ed in a group of families exhibiting a rare but highly
penetrant familial cancer syndrome, called the Li-Fraumeni syndrome (LFS).
Between 60–80% of ‘classic’ LFS families carry mutant T rp53 . The most frequent
cancers observed are premenopausal breast cancer, bone and soft-tissue sarcomas,
adrenal cortical carcinomas, and brain tumors. Penetrance is nearly 100% by age
70. Although T P53 is currently the only validated susceptibility locus recognized
for LFS, recent studies have focused on the identifi cation of genetic modifi ers that
may explain the wide phenotypic variability observed in LFS patients. Analyses of
single nucleotide polymorphisms (SNPs), genome-wide copy number and telomere
length have provided greater insight into the potential genetic modifi ers of LFS.
Moreover, the study of T rp53 mutant heterozygous mouse models has elucidated
novel functions of p53, and offers insight into the mechanisms governing tumori-
genesis in LFS. The key fi ndings outlined in this chapter provide an overview of the
molecular basis of LFS and the role of p53 in this unique heritable cancer
syndrome.
T his work is supported in part by a grant from the Canadian Institutes of Health Research (DM).
Ms. Merino is supported in part by a Vanier Scholarship of the Canadian Institutes of Health Research.
D. Merino , M.Sc. (cid:129) D. Malkin , M.D. (*)
Division of Hematology/Oncology, Program in Genetics and Genome Biology , The Hospital
for Sick Children, 555 University Avenue , M5G 1X8 Toronto , ON , Canada
Departments of Pediatrics and Medical Biophysics , University of Toronto , Toronto , ON ,
Canada
e-mail: [email protected]
S.P. Deb and S. Deb (eds.), Mutant p53 and MDM2 in Cancer, 1
Subcellular Biochemistry 85, DOI 10.1007/978-94-017-9211-0_1,
© Springer Science+Business Media Dordrecht 2014