BCL2 Protein Family: Essential Regulators of Cell Death

156 Pages·2010·3.326 MB·English

by  Claudio Hetz

BCL-2 Protein Family
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
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NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research
JOHN D. LAMBRIS, University of Pennsylvania
RODOLFO PAOLETTI, University of Milan
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BCL-2 PROTEIN FAMILY: ESSENTIAL REGULATORS OF CELL DEATH
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BCL-2 Protein Family
Essential Regulators of Cell Death
Edited by
Claudio Hetz, PhD
Institute of Biomedical Sciences, FONDAP Center for Molecular Studies of the Cell (CEMC)
Millennium Nucleus for Neural Morphogenesis (NEMO), University of Chile
Santiago, Chile
and
Department of Immunology and Infectious Diseases, Harvard School of Public Health,
Boston, Massachusetts, USA
Springer Science+Business Media, LLC
Landes Bioscience
Springer Science+Business Media, LLC
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BCL-2 Protein Family: Essential Regulators of Cell Death, edited by Claudio Hetz. Landes Bioscience
/ Springer Science+Business Media, LLC dual imprint / Springer series: Advances in Experimental
Medicine and Biology.
ISBN: 978-1-4419-6705-3
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Library of Congress Cataloging-in-Publication Data
BCL-2 protein family : essential regulators of cell death / edited by Claudio Hetz.
p. ; cm. -- (Advances in experimental medicine and biology ; v. 687)
Includes bibliographical references and index.
ISBN 978-1-4419-6705-3
1. Apoptosis. 2. Tumor proteins. I. Hetz, Claudio. II. Series: Advances in experimental medicine and
biology, v. 687. 0065-2598 ;
[DNLM: 1. Proto-Oncogene Proteins c-bcl-2--metabolism. 2. Proto-Oncogene Proteins c-bcl-2--
physiology. 3. Apoptosis--physiology. 4. Neoplasms--metabolism. 5. Neoplasms--pathology. W1
AD559 v.687 2010 / QU 55.2 B363 2010]
QH671.B45 2010
571.9’36--dc22
2010017334
FOREWORD
The BCL-2 family proteins, which have either pro- or anti-apoptotic activities,
have been studied intensively for the past decade owing to their importance in the
regulation of apoptosis, tumorigenesis and cellular responses to anti-cancer therapy.
They control the point of no return for clonogenic cell survival and thereby affect
tumorigenesis and host-pathogen interactions and regulate animal development. In
this informative volume, Claudio Hetz has brought together experts in the apoptosis
field to provide an overview of the emerging roles of BCL-2 family members in dif-
ferent physiological and pathological conditions. Several chapters focus on the role
of the BCL-2 family in mitochondrial-dependent apoptosis as well as physiological
processes in healthy cells such as metabolism, organelle morphogenesis and organ-
elle stress; other chapters discuss biochemical and genetic mechanisms related to
deregulation of apoptosis such as cancer. Authors include Anthony Letai and Owen
O’Connor, expert in apoptosis and cancer; Luca Scorrano and Mariusz Karbowski,
pioneers in identifying the crosstalk between the apoptosis machinery and mito-
chondrial dynamics; and Nika Danial, Hamsa Puthalakath, and Claudio Hetz, who
have contributed to identifying novel functions of the BCL-2 family in different
organelles ranging from metabolism to protein folding stress. An important focus of
the book is considering the potential THERAPEUTIC benefits of targeting apoptosis
pathways in the context of human disease. Readers interested in understanding how
a cell handles stress and the consequences of dysregulation of this process for human
disease will find this volume very valuable.
Richard J. Youle
Senior Investigator
National Institute of Neurological Disorders and Stroke
The National Institutes of Health
Bethesda, Maryland, USA
v
PREFACE
Apoptosis is a conserved cell death mechanism essential for normal development
and tissue homeostasis. Although it presumably participates in the development of all
cell lineages, aberrations in the expression of apoptosis-related proteins have been
implicated in the initiation of a variety of human diseases including autoimmunity,
immunodeficiency, cancer, neurodegenerative diseases and many others. Signaling
pathways regulate the initiation of apoptosis through death receptors and the
intrinsic mitochondrial pathway. The BCL-2 family of proteins represents a critical
intracellular checkpoint in the apoptotic pathway where, notably, the founding
member was first identified at the chromosomal breakpoint of the translocation
(14;18) in human follicular B cell lymphoma. BCL-2 expression increases the
resistance of cells to many different death stimuli, including cytokine withdrawal,
DNA damage, endoplasmic reticulum stress and oxidative stress, among others.
The BCL-2 family of proteins is comprised of both pro- and anti-apoptotic
members that are defined by the presence of up to four conserved (cid:2)-helical BCL-2
homology domains. Each member of the BCL-2 family has distinct patterns of
developmental expression, subcellular localization and differential responsive-
ness to specific death stimuli. The functional balance of pro- versus anti-apoptotic
members at the mitochondrial membrane determines whether a cell will live or die.
In addition, different BCL-2-related proteins are located in multiprotein complexes
within other organelles such as the endoplasmic reticulum and nucleus, helping
control diverse cellular processes beyond apoptosis. Recent evidence indicates that
BCL-2 family proteins control glucose metabolism at the mitochondria in addition
to mitochondrial dynamics and morphogenesis. These new findings highlight the
physiologic relevance of the BCL-2 family in the integration of apoptosis with other
homeostatic pathways.
In this book, scientists pioneering the field have compiled a series of focused
chapters to highlight the relevance of the BCL-2 family of proteins in apoptosis,
physiology and disease. Dr. Anthony Letai gives a comprehensive overview on the
molecular regulation of apoptosis at the mitochondria and the hierarchical organi-
zation of the pathway. Together with Dr. Owen O’Connor, this basic knowledge is
applied to discuss recent advances on targeting the core apoptosis pathway for the
vii
viii Preface
treatment of cancer. Drs. Lucca Scorrano and Mariusz Karbowski discuss molecular
pathways emerging as regulators of mitochondrial dynamics and the contributions
of such tightly controlled processes to disease conditions. To address alternative
functions of BCL-2 family proteins, Dr. Nika Danial, Hamsa Puthalakath and my-
self describe novel functions beyond apoptosis at different organelles, including
DNA damage, autophagy, glucose metabolism, protein folding and many others.
Finally, Dr. Marie Hardwick summarizes alternative functions of the BCL-2 family
in the brain, an emerging area of research with pathological relevance. In summary,
this book constitutes an attempt to describe a fascinating area of research where
physiology and biomedicine converge at different levels, revealing a trip from the
molecular regulation of apoptosis to the impact of this process to the physiology of
a whole organism.
Claudio Hetz, PhD
Institute of Biomedical Sciences,
FONDAP Center for Molecular Studies of the Cell (CEMC)
and
Millennium Nucleus for Neural Morphogenesis (NEMO)
University of Chile, Santiago, Chile
and
Department of Immunology and Infectious Diseases,
Harvard School of Public Health,
Boston, Massachusetts, USA
ABOUT THE EDITOR...
CLAUDIO HETZ received his BA in Biotechnology Engineering from
the University of Chile in 2000. In his PhD work with Claudio Soto at Serono
Pharmaceutical Research Institute, Geneva, he showed that Prion pathogenesis
involves endoplasmic reticulum stress responses and apoptosis. In 2004 he joined
as a postdoctoral fellow Stanley Korsmeyer’s lab at Dana-Farber Cancer Institute, a
pioneer in the apoptosis field. Together they discovered new functions of the BCL-2
family in organelle physiology. Dr. Hetz followed his projects in Laurie Glimcher’s
lab at Harvard. During this period he expanded his studies on neurodegeneration,
addressing the connection between apoptosis and the unfolded protein response in
vivo. Since 2007 he is an Assistant Professor at the University of Chile and adjunct
professor at Harvard. His lab uses animal models to investigate the signaling responses
involved in protein misfolding disorders and the role of the BCL-2 protein family in
stress conditions. He was recently awarded with the TWAS-ROLAC Young Scientist
Prize, also as finalist with the Eppendorf and Science Award in Neurobiology, and
other important recognitions.
ix
PARTICIPANTS
Benjamin Caballero J. Marie Hardwick
Institute of Biomedical Sciences Department of Molecular Microbiology
FONDAP Center for Molecular Studies and Immunology
of the Cell (CEMC) Johns Hopkins University
and Baltimore, Maryland
Millennium Nucleus for Neural USA
Morphogenesis (NEMO)
University of Chile Claudio Hetz
Santiago Institute of Biomedical Sciences
FONDAP Center for Molecular Studies
Chile
of the Cell (CEMC)
and
Nika N. Danial
Millennium Nucleus for Neural
Department of Pathology
Morphogenesis (NEMO)
Harvard Medical School
University of Chile
and
Santiago
Department of Cancer Biology
Chile
Dana-Farber Cancer Institute
and
Boston, Massachusetts
Department of Immunology
USA
and Infectious Diseases
Harvard School of Public Health
Alfredo Gimenez-Cassina Boston, Massachusetts
Department of Pathology USA
Harvard Medical School
and Mariusz Karbowski
Department of Cancer Biology Biotechnology Institute
Dana-Farber Cancer Institute Medical Biotechnology Center
Boston, Massachusetts University of Maryland
USA Baltimore, Maryland
USA
xi