Cell Death: Mechanism and Disease

280 Pages·2014·4.856 MB·English

by  David L. Vaux (auth.), Hao Wu (eds.)

Hao Wu Editor
Cell Death
Mechanism and Disease
Cell Death

Hao Wu
Editor
Cell Death
Mechanism and Disease
Editor
Hao Wu
Department of Biological Chemistry
and Molecular Pharmacology
Harvard Medical School
Boston , MA , USA
Program in Cellular and Molecular
Medicine, Boston Children’s Hospital
Boston, MA, USA
ISBN 978-1-4614-9301-3 ISBN 978-1-4614-9302-0 (eBook)
DOI 10.1007/978-1-4614-9302-0
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2013952922
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Foreword
The concept of “apoptosis” as a regulated cell death pathway in mammalian cells
was fi rst proposed by Andrew Wyllie based on an intriguing observation made dur-
ing his Ph.D. study that showed dying cancer cells having DNA fragmentation.
While Wyllie’s work could had been easily dismissed as a “descriptive” study by
today’s standard and rejected outright, it laid the foundation for the subsequent
decades of studies that led to the understanding of the molecular mechanisms of
apoptosis. Now the concept of cellular “suicide” is no longer a strange or a novel
idea. It has been generally accepted that regulation of cell death is important for
development as well as for the maintenance of the normal tissue homeostasis.
The studies on apoptosis led to many conceptual advances that helped us to
understand the disease mechanisms. The molecular mechanism that protects mam-
malian cells from apoptosis were fi rst illustrated by the ground-breaking work from
the group of David Vaux and colleagues who showed the ability of Bcl-2 when
overexpressed to prolong the survival of cancer cells. Vaux’s work provided the
second most important principle in oncogenesis, after the uncontrolled and exces-
sive proliferation, that tumor cells must develop mechanisms to evade apoptosis.
The two decades of research on Bcl-2 family provided the molecular understanding
as how pro- and anti-apoptotic members of Bcl-2 family interact and control the
cellular survival. This understanding provided the crucial insights as how such
interactions may be manipulated pharmacologically. The exclusive dependence of
cancer cell survival on the apoptosis inhibitory effect of Bcl-2 family is now being
explored for therapeutic benefi ts in the treatment of cancers.
The execution of apoptosis in mammalian cells is mediated by the evolution-
arily conserved caspase family, a principle fi rst illustrated by the works from my
own group. Mammalian caspase family is rather large with at least 12 members
which is almost certain due to the complicated tasks that these caspases are
involved in. These caspases are arranged into amplifi cation cascades that control
either the “intrinsic apoptosis” pathway regulated by the mitochondrial pathway
which leads to the activation of “apoptosome” or the “extrinsic apoptosis” path-
way which is activated by the ligands of death receptor family. Caspases can be
activated to mediate apoptosis by a wide range of physiological and pathological
v
vi Foreword
signaling in different cell types: from DNA damage in cancer cells to tropic factor
deprivation in neurons. The consequence of caspase activation, however, is not
always lethal: in neurons, limited and localized caspase activation has now been
implicated in modulating synaptic plasticity or mediating neurite pruning in fi ne
tuning of neuronal circuitry.
The two decades of research on cell death broke some of the historical dogma
such as necrosis can only be passive cell death. It turns out that when apoptosis fails
to occur, cells may undergo a form of regulated necrosis, termed “necroptosis” or
“programmed necrosis.” Necroptosis activated by TNFα is the most understood
necrotic cell death pathway. Stimulation of type I TNF receptor by TNFα leads to
the transient formation of a membrane complex associated with the intracellular
death domain of TNFR1, called “complex I” which includes adaptor protein
TRADD, RIP1, and E3 ubiquitin ligases TRAF2 and cIAP1/2. The complex I is
then transitioned into one of the two alternative intracellular signaling complexes,
“complex IIa” or “complex IIb.” The complex IIa, which includes FADD, caspase-8,
and RIP1, leads to the activation of caspase-8 and apoptosis. On the other hand,
under certain conditions when apoptosis fails to be activated, an alternative complex
that includes RIP1 and RIP3 kinases is formed. The kinase activity of RIP1 is
required for the formation of complex IIb to mediate necroptosis and sometimes is
also involved in mediating the activation of caspases with complex IIa in the absence
of cIAP1/2. Interestingly, as shown by Hao Wu’s group, the complex IIb formed by
RIP1 and RIP3 involves the formation of amyloid-like structure. Given the wide
association of amyloid-like structures in neurodegenerative diseases, the formation
of amyloid structure in a regulated necrotic cell death pathway is very intriguing.
The involvement of RIP1 kinase in mediating acute neurological injuries has already
been suggested by the ability of necrostatin-1, a highly specifi c inhibitor of RIP1
kinase, to protect a wide range of animal models induced by ischemia. It will be
interesting to examine the involvement of RIP1–RIP3 amyloid complexes in human
neurodegenerative diseases in future.
The history of cell death research argues strongly for the important value of
investigators initiated and curiosity-driven research. While there are certainly val-
ues for “-omics” approaches where we may get to systematically understand the
physical nature of our cells, our body, and our genetic compositions, the mecha-
nisms that control cell death certainly would not had been understood without the
hypothesis-driven researches as that had occurred. The researches on cell death
mechanisms also provide an excellent example where excellence in basic scientifi c
research not only led to molecular insights to our living world in general but also
can be translated into medicines that can treat diseases to improve our lives.
A cell that dies is never in vain.
Boston , MA , USA Junying Yuan
Pref ace
As editor of this book, I wish to thank several important people, without whose
assistance a successful outcome would not have been possible. I was originally
approached by Dr. Portia E. Formento, an Editor of Springer Science + Business
Media, during the Biophysical Society Meeting in Baltimore, Maryland, in March,
2011, about editing a book on cell death. I hesitated at fi rst. While scientists are
always busy, it was an extra busy time for me as my son Alex was preparing to go
to college and I was contemplating fresh job opportunities. Portia was convincing
enough to persuade me that such a book would be both valuable and timely and that
Springer would assist me in accomplishing this at my own pace. I am deeply
indebted to her for her support and encouragement.
Although I signed up for the job of putting such a book together then, I did not
begin to contact potential contributors until more than a year later, a couple of
months before my lab’s move from Weill Cornell Medical College to Boston
Children’s Hospital and Harvard Medical School. Fortunately, the theme of the
book, titled “Cell Death: Mechanism and Disease,” is exactly as intended and cov-
ers the molecular basis of cell death—apoptotic and necrotic—as well as the rele-
vance of cell death mechanisms to understanding, preventing, and treating human
disease. I have had the pleasure of working in this highly exciting and competitive
fi eld for the past 16 years and have seen its rapid evolution, with one surprising fi nd-
ing after another. The book strives to present a balanced and comprehensive view of
the current state of the art.
I am particularly grateful to all the wonderful contributors who truly made the
book possible. They are not only amazing scientists but also good friends whom I
have come to know over the years. I am especially indebted to David Vaux, a pio-
neering fi gure in cell death research, for his commitment to and enthusiasm about
the book. Earlier this year, I had the honor of visiting “Davo” (short for Dave Vaux)
and his family in Melbourne, where I experienced his hospitality fi rsthand. I would
also like to praise my dear colleague and friend Junying Yuan for writing such a
beautiful forward for the book. I am extraordinarily thankful to Daniel L. Dominguez,
vii
viii Preface
the Developmental Editor of the book, who pushed and shoved and made sure that
things got done on time. Finally, I take this opportunity to express my appreciation
for the boundless love around me, my children Alex and Michael who are my joy
and pride, and my current and former lab members who are the heroes behind every
research accomplishment from my laboratory.
It is my wish that you will enjoy reading the book as much as I have enjoyed edit-
ing it, regardless of whether you are an amateur or an expert in the cell death fi eld.
Boston , MA , USA Hao Wu
Contents
1 Historical Perspective: The Seven Ages of Cell Death Research ........ 1
David L. Vaux
2 The Intrinsic Apoptotic Pathway ........................................................... 15
Xuejun Jiang
3 Molecular Basis of Cell Death Programs
in Mature T Cell Homeostasis................................................................ 41
Carrie L. Lucas and Michael J. Lenardo
4 Bcl-2 Family and Their Therapeutic Potential ..................................... 61
Qian Liu, Xiaoke Chi, Brian Leber, and David W. Andrews
5 IAP Proteins and Their Therapeutic Potential .................................... 97
Domagoj Vucic
6 Cell Death and Cancer ............................................................................ 121
David L. Vaux
7 The DNA Damage Response Mediates Apoptosis
and Tumor Suppression .......................................................................... 135
Katherine Baran, Diego Rodriguez, and Douglas Green
8 Neuronal Death Mechanisms in Development and Disease ................ 167
Corey L. Cusack, Ryan P. Annis, Adam J. Kole,
and Mohanish Deshmukh
9 The Complex Interplay Between Metabolism and Apoptosis ............. 189
Kelly Lindblom and Sally Kornbluth
10 Programmed Necrosis/Necroptosis: An Infl ammatory Form
of Cell Death ............................................................................................ 211
Francis Ka-Ming Chan
ix