The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
e-mail: bouillet{at}wehi.edu.au or strasser{at}wehi.edu.au
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Summary |
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Key words: Apoptosis, Cell death, Bcl-2, BH3-only proteins, Signal transduction
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Introduction |
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Genetic and biochemical studies have identified two major pathways to
programmed cell death that are largely independent
(Strasser et al., 1995). On
the one hand, apoptosis can be triggered by ligation of a subgroup of the
tumour necrosis factor receptor (TNF-R) family of cell surface receptors,
`death receptors' (e.g. CD95/Fas/APO-1 or TNF-R1). This apoptosis signalling
pathway is sometimes called the `extrinsic pathway'. On the other hand,
apoptosis can also be initiated by a diverse range of stress conditions. The
central pathway activated by these apoptotic stimuli is sometimes called the
`intrinsic pathway' or the `mitochondrial pathway'. We believe that these
names are not ideally suited, firstly, because this pathway can be initiated
by extrinsic signals, such as cytokine withdrawal or
-irradiation, and
secondly, because mitochondria, although affected by this process, are not
required for cell execution in all cell types and in response to all stress
stimuli (see below). We propose to call this the `Bcl-2 regulated pathway',
because the Bcl-2 family of proteins are critical regulators of this process
(Adams and Cory, 2001
). Amongst
the members of the Bcl-2 family, the BH3-only proteins have now been
recognised as essential initiators of programmed cell death and stress-induced
apoptosis (Huang and Strasser,
2000
). This review focuses on the `Bcl-2-regulated pathway',
particularly on the role of the BH3-only proteins in the apoptosis signalling
cascade.
Apoptotic cell death is characterised by a series of morphological and
biochemical changes such as plasma membrane blebbing, chromatin condensation,
internucleosamal DNA cleavage and exposure of phospatidyl serine on the
extracellular side of the plasma membrane. Genetic and biochemical studies in
Caenorhabditis elegans, Drosophila melanogaster and mammals have led
to the identification of the main players of the cell death machinery and have
shown that this process has been conserved throughout evolution
(Strasser et al., 2000;
Vaux and Strasser, 1996
). The
collapse of the cell is brought about by the action of aspartate-specific
cysteine proteases termed caspases
(Thornberry and Lazebnik,
1998
). Caspases are normally present in healthy cells as zymogens
with low enzymatic activity. They become activated through proteolysis by
already active caspases or through autocatalytic processing, which is mediated
by aggregation of zymogens in a complex containing adapter proteins (e.g.
Apaf-1, C. elegans CED-4 and FADD) and co-factors (e.g. ATP and
cytochrome c) (Thornberry and Lazebnik,
1998
).
Proteins of the Bcl-2 family are critical regulators of caspase activation
and apoptosis (Adams and Cory,
1998; Gross et al.,
1999
). The anti-apoptotic members of the Bcl-2 family (Bcl-2,
Bcl-xL, Bcl-w, Mcl-1, A1, Boo/Diva/Bcl-2-L10, Bcl-B and C.
elegans CED-9) all contain three or four characteristic regions of
homology (BH1-4; Bcl-2 Homology domains). According to
their structure and biochemical function (see below), the pro-apoptotic Bcl-2
family members can be divided into two subgroups. Bax, Bak, Bcl-xS,
Bok/Mtd and Bcl-GL contain two or three BH domains, whereas Bad,
Bik/Nbk, Blk, Bid, Hrk/DP5, Bim/Bod, Bmf, Noxa, Puma/Bbc-3 and C.
elegans Egl-1 share with each other and the rest of the family only the
short (9-16 amino acid) BH3 domain (Fig.
1) (Huang et al.,
2000
). The BH3 domain is essential for the binding of these
BH3-only proteins to the anti-apoptotic members of the family and for their
ability to kill cells (Huang et al.,
2000
). Hetero-dimerisation is mediated by the insertion of the BH3
domain of the pro-apoptotic molecules into a hydrophobic cleft formed by the
BH1, BH2 and BH3 domains on the surface of the anti-apoptotic proteins
(Sattler et al., 1997
). Many
pro- as well as anti-apoptotic members of the Bcl-2 family also have a
C-terminal transmembrane domain, which can target these proteins to the
cytoplasmic side of intracellular membranes of the nucleus, endoplasmic
reticulum and mitochondria (Chen-Levy and
Cleary, 1990
; Lithgow et al.,
1994
). How the Bcl-2 family of proteins regulates apoptosis is
still controversial (Adams and Cory,
1998
; Green and Reed,
1998
; Gross et al.,
1999
; Strasser et al.,
2000
) and possible mechanisms of the biochemical action of these
molecules are discussed below.
|
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The essential roles of the various BH3-only proteins |
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Regulation of BH3-only proteins |
---|
Evolution has led to the existence of many different BH3-only proteins in
mammals and other vertebrates (e.g. frogs, fish and birds), and several
mechanisms have been put in place to keep these killer proteins in check
(Huang and Strasser, 2000). As
is the case for C. elegans EGL-1, the activity of some mammalian
BH3-only proteins is also regulated at the transcriptional level.
Noxa and puma/Bbc3 have both been identified as
p53-inducible genes (Han et al.,
2001
; Nakano and Wousden,
2001
; Oda et al.,
2000
; Yu et al.,
2001
) and are therefore thought to be critical for DNA
damage-induced apoptosis. A different stress stimulus, growth factor
deprivation, causes increased hrk/dp5 and bim mRNA
expression in neurons by a JNK-dependent mechanism
(Harris and Johnson, 2001
;
Imaizumi et al., 1997
;
Inohara et al., 1997
;
Putcha et al., 2001
;
Whitfield et al., 2001
). In
contrast, in haematopoietic cells cytokine withdrawal has been reported to
augment bim expression through activation of the forkhead
transcription factor FKHR-L1 (Dijkers et
al., 2000
).
Pro-apoptotic activity of BH3-only proteins can also be regulated
post-transcriptionally. For example, BimEL and BimL, the
two most abundantly expressed isoforms of the Bim gene
(O'Connor et al., 1998;
O'Reilly et al., 2000
), are
sequestered to the microtubular dynein motor complex by binding to the dynein
light chain DLC-1/LC8 (Puthalakath et al.,
1999
). Certain apoptotic stimuli cause the release of Bim (still
associated with DLC-1) from the cytoskeleton and allow it to translocate to
mitochondria and the nuclear envelope, where it can bind to and antagonise the
function of pro-survival Bcl-2 molecules
(Puthalakath et al., 1999
).
Interestingly, Bmf is regulated in a similar way by binding to another dynein
light chain molecule, DLC-2, and sequestration to myosin V motors on the actin
cytoskeleton (Puthalakath et al.,
2001
). This difference in subcellular localization may account for
the fact that Bmf is activated by cellular detachment (anoikis), whereas Bim
senses the effects of cytokine deprivation, abnormal calcium flux and
treatment with taxol.
Bid can be cleaved by caspase-8 and certain other caspases
(Li et al., 1998;
Luo et al., 1998
). The
truncated p15 tBid polypeptide is thought to trigger apoptosis more
efficiently than full-length Bid because the proteolytic fragment can be
myristoylated, which promotes its translocation to intracellular membranes
(e.g. on mitochondria) where anti-apoptotic Bcl-2 relatives reside
(Zha et al., 2000
). Moreover,
the cleavage of Bid by caspase-8 has been reported to be attenuated by
phosphorylation by casein kinase I and casein kinase II
(Desagher et al., 2001
). Bad,
on the other hand, is phosphorylated in response to cytokine signalling by
Akt/PKB (Datta et al., 1997
;
del Peso et al., 1997
) or by
the mitochondrial kinase PKA (Harada et
al., 1999
). Phosphorylated Bad is sequestered in the cytosol by
binding to 14-3-3
scaffold proteins, and cytokine withdrawal causes
de-phosphorylation of Bad, thereby allowing it to break away from 14-3-3
proteins and to translocate and bind to pro-survival Bcl-2 molecules
(Zha et al., 1996
). Bik has
recently also been shown to be regulated by phosphorylation, but, unlike in
the case of Bid and Bad, phosphorylation of Bik somehow increases its
pro-apoptotic activity (Verma et al.,
2001
). Collectively, these data indicate that the subcellular
localisation of BH3-only proteins plays a critical role in cell death control,
enabling the cell to react rapidly and efficiently to external and internal
death signals, but keeping pro- and anti-apoptotic Bcl-2 molecules apart in
healthy cells.
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Functional interactions between BH3-only proteins and anti-apoptotic Bcl-2 family members |
---|
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Functional interactions between BH3-only proteins and Bax/Bak-like multi-domain pro-apoptotic Bcl-2 family members |
---|
Collectively, these results demonstrate that BH3-only proteins and Bax/Bak-like proteins have distinct but interdependent functions that are both essential for initiation of apoptosis. Whether the two types of pro-apoptotic proteins are part of the same linear pathway or act in parallel, both impinging on the Bcl-2-like pro-survival proteins, is presently not clear (Fig. 2).
|
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Regulation of Bax/Bak-like pro-apoptotic Bcl-2 family members |
---|
![]() |
Possible models for the biochemical function of the Bcl-2 family members |
---|
The studies in the bax-/-bak-/- and
bim-/- mice strongly suggest that Bax/Bax-like multi-BH
domain and the BH3-only pro-apoptotic proteins function at different levels of
a linear pathway to death. It is commonly accepted that some mechanism of
Bax/Bak aggregation is critical for cell killing, but how this signal is
translated into cell destruction is still hotly debated. According to one
model, the principal function of multi-BH domain pro-apoptotic proteins is to
disrupt mitochondrial membrane integrity and allow the release of cytochrome c
(and other pro-apoptotic molecules). It has been proposed that Bax/Bak-like
proteins mediate this process either by binding to and modifying mitochondrial
channel proteins (VDAC or ANT) (Marzo et
al., 1998; Narita et al.,
1998
) or by direct pore formation
(Antonsson et al., 1997
;
Eskes et al., 1998
;
Nechushtan et al., 2001
;
Pavlov et al., 2001
). How
Bcl-2-like pro-survival molecules would block this activity of the
Bax/Bak-like proteins is unclear. Inhibition may happen by direct binding of
Bcl-2 to Bax (Oltvai and Korsmeyer,
1994
), but several reports suggest that such an interaction does
not occur physiologically within cells but may only be detected as a
by-product of cell lysis when certain detergents are used
(Antonsson et al., 2001
;
Hsu and Youle, 1998
;
Nechushtan et al., 2001
). In
this regard, it is also noteworthy that certain mutants of Bcl-xL
that are unable to bind to Bax/Bak (even in detergent lysates) can protect
cells against apoptotic stimuli that were shown to be Bax/Bak-dependent
(Cheng et al., 1996
). Although
Bcl-2 is unable to prevent dimerisation of Bax or its translocation to the
mitochondrial surface, it appears to block integration and aggregation of
Bax/Bak in the outer mitochondrial membrane
(Antonsson et al., 2001
;
Nechushtan et al., 2001
). The
following scenario appears plausible. Upon an apoptotic signal, cohorts of
BH3-only proteins, transcriptionally induced or waiting in different places in
the cytoplasm, are unleashed and move to the surface of the mitochondria and
probably also to other intracellular membranes. These BH3-only proteins will
bind to the prosurvival members of the Bcl-2 family, and this will somehow
facilitate membrane integration and aggregation of Bax/Bak-like proteins
(Fig. 3). It has been proposed
that Bax/Bak aggregation is induced by their binding to some of the BH3-only
proteins, as has been reported for Bid
(Eskes et al., 2000
). However,
there is no evidence so far that binding of any of the BH3-only proteins to
Bax or Bak occurs with an affinity that is biologically meaningful.
Collectively, these observations indicate that Bcl-2-like pro-survival
molecules can prevent membrane integration and aggregation of Bax/Bak-like
proteins until they are antagonised by BH3-only proteins.
|
Several experimental observations challenge the idea that outer
mitochondrial membrane disruption and release of cytochrome c are absolutely
required for apoptosis initiation (Huang
and Strasser, 2000; Strasser
et al., 2000
). Indeed, a number of developmental processes, such
as cavitation or organ morphogenesis, which require cell death for their
completion, still occur normally in embryos lacking either Apaf-1
(Cecconi et al., 1998
;
Yoshida et al., 1998
),
caspase-9 (Hakem et al., 1998
;
Kuida et al., 1998
),
cytochrome c (Li et al.,
2000
), caspase-3 (Kuida et
al., 1996
) or Bax/Bak
(Lindsten et al., 2000
).
Moreover, we have shown that apoptosis occurs normally in a number of
haematopoietic cell types lacking either Apaf-1 or caspase 9 (V. Marsden and
A.S., unpublished). We have therefore postulated that cell death is initiated
by one or several CED-4-like caspase adapters that are directly regulated by
interaction with members of the Bcl-2 family
(Strasser et al., 2000
)
(Fig. 3). According to this
model, cytochrome c and Apaf-1-mediated caspase-9 activation form part of an
amplification loop in apoptosis that is essential in some cell types (e.g.
developing neurons) but dispensable in others (e.g. haematopoietic cells).
Further genetic and biochemical experiments are needed to determine which of
these two mechanisms is the critical initiator of programmed cell death and
whether they act in parallel or in a linear pathway.
Another puzzling conundrum is that C. elegans has only a
pro-survival Bcl-2 homologue, CED-9, and a BH3-only protein, EGL-1, but, in
contrast to mammals and flies, apparently lacks Bax/Bak-like multi-BH domain
pro-apoptotic Bcl-2 family members. CED-9 is not only essential for cell
survival but has also been reported to promote apoptosis in nematodes with a
certain genetic make-up (hypomorphic ced-3 mutation)
(Hengartner and Horvitz,
1994). It is therefore interesting to consider the possibility
that CED-9 has features of both pro-survival Bcl-2-like and pro-apoptotic
Bax/Bak-like molecules. Because the structure of Bax
(Suzuki et al., 2000
) is
remarkably similar to that of Bcl-xL
(Muchmore et al., 1996
), it is
possible that they represent the two different conformational states that
CED-9 can assume, one when it is free and the other when it is bound to EGL-1.
If one accepts this idea, it is possible that mammalian CED-4 homologues may
interact with Bax/Bak-like molecules rather than with the pro-survival members
of the Bcl-2 family. We therefore believe that it may be informative to solve
the structures of free CED-9, EGL-1-CED-9 and CED-9-CED-4 complexes and
compare them to those of free Bcl-2, free Bax and Bcl-2 bound to a BH3-only
protein.
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Conclusions |
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Acknowledgments |
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