Oncogene (1998) 17, 3207 3213

1998 Stockton Press All rights reserved 0950 9232/98 $12.00

http://www.stockton-press.co.uk/onc

Signal transduction pathways that regulate cell survival and cell death
Tomislav Dragovich3, Charles M Rudin3 and Craig B Thompson*,1,2,3
1

Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, Illinois 60637, USA; 2Howard
Hughes Medical Institute, The University of Chicago, Chicago, Illinois 60637, USA and 3Department of Medicine, The University
of Chicago, Chicago, Illinois 60637, USA

Apoptosis or programmed cell death (PCD) is a

physiological process critical for organ development,
tissue homeostasis and elimination of defective or
potentially dangerous cells in complex organisms.
Apoptosis permits cell death without a concomitant
inammatory response in the surrounding tissues. The
process of apoptosis depends on the reception of multiple
extracellular and intracellular signals, integration and
amplication of these signals by second messengers and
nally, activation of the death eector proteases. Defects
in control of apoptotic pathways may contribute to a
variety of diseases including cancer, autoimmune and
neurodegenerative conditions and AIDS. While many
components of the regulatory network controlling
apoptosis have been dened, the mechanisms of action
and patterns of interaction of these factors remain
controversial. This article summarizes some of the known
aspects of signaling pathways involved in apoptosis.
Keywords: signal transduction; bcl-2 proteins; caspases;
death receptors

Events that activate the central pathway of cell death

Programmed cell death or apoptosis can be initiated
by a wide variety of stimuli, including developmental
signals, cellular stress and disruption of cell cycle. In
contrast, execution of apoptosis is remarkably uniform, involving characteristic morphologic and biochemical changes. The morphologic hallmarks of
apoptosis include membrane blebbing, volume loss,
nuclear condensation and DNA fragmentation (Kerr
et al., 1972). A number of the key factors involved in
the regulation, coordination and execution of these
events have been identied. Genetic studies of the
nematode Caenorhabditis elegans led to identication
of three genes essential for control and execution of
apoptosis in developing worms (Hengartner and
Horvitz, 1994). Mammalian homologs of all three of
these genes have been identied. The regulation and
execution of apoptosis in C. elegans seems deceptively
simple. Apoptotic cell death in the worm requires
CED-3, a cousin of mammalian caspases and its
activator CED-4 that is homologous to mammalian
Apaf-1. Additional control of cell death/survival is
provided by the anti-apoptotic factor CED-9 which is

*Correspondence: CB Thompson

a counterpart of mammalian Bcl-2 protein (Yuan et

al., 1993). Recently, a novel C. elegans protein, Egl-1,
has been found to bind to and inhibit the antiapoptotic function of CED-9 (Conradt and Horvitz,
1998). The molecular basis of apoptotic signaling
appears to be more complex in mammalian cells. In
mammalian cells, Bcl-2 is one of a large family of
CED-9 related proteins that function as either positive
or negative regulators of apoptosis. Mammalian
counterparts of the nematode protein CED-3 comprise a large family of cysteine proteases, called
caspases, which are critical in generation of apoptotic
morphology. The multiple members of these gene
families may allow for the independent regulation of
apoptotic signaling pathways.
Based on the established interactions among the
known mediators of apoptosis three classic pathways
of apoptotic signaling in mammalian cell have
emerged (Figure 1). The rst one is initiated by the
withdrawal of growth factors and is regulated by Bcl2 family of proteins. This pathway results in
cytochrome c release from mitochondria, activation
of Apaf-1 and triggering of a caspase cascade. The
other well-established apoptosis pathway involves
signaling by cell surface death receptors such as
TNF or Fas, which through adapter molecules can
recruit and activate caspases. The third and least well
characterized pathway is initiated by DNA damage.
Although in part regulated by proteins such as p53
and ATM, how this pathway results in caspase
activation is not known. In all three of these
pathways of cell death, caspases and Bcl-2 protein
family play a key role in regulation and execution of
apoptosis.

Caspases
Multiple mammalian homologs of CED-3 have been
identied (1 13). They all cleave peptide substrates
after aspartic acid residues (Alnemri et al., 1996).
Caspase activation initiates a proteolytic degradation
that results in apoptotic morphology (Casiano et al.,
1996). Specic inhibitors of caspases prevent cell death,
or at least apoptotic morphology, in response to many
of the known signals that trigger apoptosis (Miura et
al., 1993; Rabizadeh et al., 1993). Overexpression of
most of the known caspases triggers apoptosis in cell
lines, although only a subset of caspases appears to be
involved in physiological apoptosis. Caspase-9 has been
most clearly linked to central pathway of apoptotic
induction. Apaf-1 in response to cytochrome c binding
can form a complex with caspase-9 that initiates
apoptotic events in cell free system (Li et al., 1997).

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Figure 1 Multiple apoptotic signals converge on caspase activation. Pathways discussed in this review include (1) those derived from cell
surface receptor engagement, represented here by Fas receptor signaling, (2) those derived from growth factor withdrawal, represented here
by the IL-3 receptor, and (3) those derived from nuclear DNA damage

Caspase-9 is a critical regulator of at least some forms

of apoptosis. Homozygous inactivation of the caspase9 gene resulted in embryonic lethality manifested by
severe perturbations of the cerebral cortex and
forebrain (Hakem et al., 1998; Kuida et al., 1998).
Caspase-9 decient cells were resistant to cell death
induced by gamma-irradiation or cytotoxic drugs
although the death response to other apoptotic
stimuli, including Fas receptor engagement, was
preserved.
Caspase activation requires proteolytic processing
from inactive proenzymes. The processing sites for procaspases are themselves caspase consensus sequences.
Thus caspases may cleave and activate their own as
well as other caspase pro-enzymes. This may serve as
an important mechanism for amplifying caspasedependent apoptotic pathways. For example, active
caspase-9 cleaves procaspase-3; active caspase-3 in turn
appears to be required for many of the characteristic
apoptotic nuclear changes. Downstream caspases
cleave and inactivate proteins crucial for the maintenance of cellular cytoskeleton, DNA repair, signal
transduction and cell cycle control (Fraser and Evan,
1996; Nagata 1997).
Recent studies have uncovered a possible link
between cytosolic caspase activation and apoptotic
nuclear changes (Enari et al., 1998; Sakahira et al.,

1998). A caspase-dependent deoxyribonuclease, CAD,

is inactive and localized in the cytosol when bound to
the inhibitor ICAD. Caspase-3 can cleave and
inactivate ICAD thus releasing CAD that then
translocates to the nucleus and initiates chromosomal
degradation.
While caspase activation typically results in apoptotic morphology, not all programmed cell death
pathways are caspase-dependent. Cells which sustain
traumatic damage or are deprived of growth-factors
can die even in the presence of caspase inhibitors
(Rathmell and Thompson, 1998). However, in the
presence of such inhibitors the morphology of dying
cell lacks many morphologic features of apoptosis,
including typical nuclear changes (Hirsch et al., 1997).
Outside of such experimental systems, it appears that
caspase activation and cellular autodigestion may
invariably accompany apoptosis in vivo.
The Bcl-2 family
A mammalian homolog of the C. elegans ced-9 gene,
bcl-2, was identied as one of the genes at
chromosomal breakpoint of t(14 : 18) in B-cell lymphomas. Overexpression of Bcl-2 protects cells from a
variety of apoptotic stimuli, such as growth-factor
withdrawal, exposure to chemotherapy agents or

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T Dragovich et al

toxins, viral infection and inappropriate oncogene

expression. A number of Bcl-2 related proteins have
been subsequently identied (Reed, 1997). Although
they all share domains of structural homology, some
Bcl-2 family proteins promote apoptosis while the
others have anti-apoptotic function. The relative levels
of pro- and anti-apoptotic Bcl-2 family proteins have
been suggested to function as a `rheostat' regulating
the apoptotic threshold of the cell (Yang and
Korsmeyer, 1996). The antagonistic function of some
of the members of the family is at least in part
explained by their ability to form heterodimers. The
anti-apoptotic proteins Bcl-xL and Bcl-2 form heterodimers with pro-apoptotic Bax (Oltvai and Korsmeyer,
1994). An excess of Bax promotes cell death, but coexpression of Bcl-xL or Bcl-2 can neutralize this eect.
An alpha-helical domain known as BH3 and shared by
multiple members of the Bcl-2 family is critical for the
formation of homo- and heterodimers (Kelekar and
Thompson, 1998). Some of pro-apoptotic Bcl-2 family
members, such as Bad and Bid, only share homology
within the BH3 domains (so-called BH3 proteins).
Most Bcl-2 family proteins have a conserved Cterminal hydrophobic domain, which is necessary for
insertion into the outer mitochondrial, endoplasmic
reticular and outer nuclear membranes. Based on this
unusual subcellular localization and homology to
bacterial pore forming molecules, such as the poreforming subunit of diphteria toxin, it is suspected that
some members of Bcl-2 protein family function as
membrane pores or channels (Muchmore et al., 1996).
Indeed, both Bcl-xL and Bcl-2 as well as the proapoptotic Bax were found to have pore-forming
capacity in vitro (Minn et al., 1997; Schendel et al.,
1997; Antonsson et al., 1997).
Recent studies support the central role of Bcl-2
family proteins in the regulation of mitochondrial
membrane integrity and cytochrome c release (Yang et
al., 1995; Vander Heiden et al., 1997). Overexpression
of either Bcl-2 or Bcl-xL inhibits cytochrome c release
from mitochondria. In contrast, when transfected in
mammalian or yeast cells, Bax overexpression results in
dissipation of mitochondrial membrane potential and
release of cytochrome c (Rosse et al., 1998; Manon et
al., 1997). The molecular mechanism of this regulation
has not been determined. Some investigators suggest
that Bcl-2 like proteins regulate the opening of what
has been referred to as mitochondrial permeability
transition pore (PTP) or megachannel. The hypothetical PTP would consist of the adenine nucleotide
translocator in the inner mitochondrial membrane,
voltage-dependent anion channel in the outer membrane as well as other components (Marzo et al., 1998).
Physical association between Bcl-2 family proteins and
components of PTP remains speculative although both
Bcl-xL and Bcl-2 localize to contact points between the
inner and outer mitochondrial membrane and Bax was
recently co-puried with other components of the pore
(Marzo et al., 1998). In addition, some of the antiapoptotic Bcl-2 proteins may function by complexing
with and inactivating factors that trigger caspase
activation. Both cytochrome c and Apaf-1 have been
dened as co-factors that are critical for the activation
of caspase-9 and the subsequent apoptotic cascade. As
mentioned before, in C. elegans CED-9 directly
interacts with CED-4 preventing it from activating

caspase CED-3. In mammalian cells, Bcl-xL has been

reported to interact with the mammalian CED-4
homolog Apaf-1 and by that mechanism might
prevent Apaf-1 from activating downstream caspases
(Hu et al., 1998).
These several lines of evidence suggest that Bcl-2
family members function at a critical decision point
immediate upstream of an irreversible commitment to
cell death. The Bcl-2 family proteins, Apaf-1, and
caspases together comprise mammalian equivalent of
the C. elegans `apoptosome' consisting of Ced-9, Ced-4
and Ced-3. Loss of mitochondrial transmembrane
potential and activation of caspases represent molecular hallmarks of mammalian central apoptotic
pathway. Bcl-2 family proteins appear to be critical
in regulation of both events. Nevertheless, signicant
gaps in this model remain. For example, although the
model integrates the three critical apoptotic regulators
dened in C. elegans, it fails to explain how
extramitochondrial Bcl-2 inhibits apoptosis and why
it can do so even after cytochrome c is released (Rosse
et al., 1998; Li et al., 1997). It does not explain the
nding that caspase inhibitors do not inhibit Bax
toxicity in mammalian cells suggesting that Bax may
induce apoptotic changes independently of the
mammalian `apoptosome' (Xiang et al., 1996). Further
analysis of the molecular basis of programmed cell
death execution will be required to answer these and
other important questions.
Receptors and second messengers that regulate cell death
and survival
Homeostasis in mammalian cells is dependent on the
continuous integration of survival and death signals
from the extracellular environment (Ra, 1992).
Extracellular signals that activate apoptotic or survival
pathways include peptide growth factors, cytokines and
interleukins. Signaling pathways can be triggered by
both soluble factors and by direct cell to cell contact.
One of the most intensively studied families of
receptors involved in apoptotic signaling is that of
tumor necrosis factor receptor (TNFR) family (Bazzoni
and Beutler, 1996). This is a family of multimeric
receptors that upon activation by their respective
ligands may initiate either cell death or survival
signals. Extracellular domains of the TNFR family
members are related, while intracellular domains dier
widely both in sequence and in their anity for various
adapter molecules and second messengers. The
subfamily of receptors most closely linked to induction
of cell death (e.g. Fas, TNFR1 and DR3) do contain a
conserved intracellular sequence known as a `death
domain'. Through these domains, receptors associate
with a number of intracellular signal transduction
molecules that themselves contain the `death domain'.
For example, the intracellular domain of activated Fas
receptor interacts with that of a linker molecule called
FADD (Fas-associated death domain-containing protein) (Chinnaiyan et al., 1995). Subsequent transduction of the apoptotic signal is dependent on another
domain of FADD, the `death eector domain', which
interacts with additional downstream molecules. One
of them is caspase-8, which after activation by FADD
can initiate a cascade of caspase activation leading to

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degradation of intracellular substrates and cell death

(Muzio et al., 1996). TNFR1 similarly induces cell
death through interaction with a related but dierent
adapter molecule called TRADD (TNFR-associated
death domain protein) (Hsu et al., 1996).
While activation of Fas, TNFR1 and DR3 receptors
induces apoptosis by associating with cytoplasmic
factors such as FADD, TRADD and RIP, other
receptors such as CD40, TNFR2 and CD30 promote
cell survival by interacting with a distinct group of
second messengers, including the TNF receptorassociated factors or TRAFs (Arch et al., 1998). To
date six mammalian TRAF proteins have been
identied. Some members of the TRAF family
negatively regulate apoptosis through induction of
survival pathways. For example, recruitment of
TRAF2 protein to TNF receptors has been reported
to promote survival and activates JNK (c-Jun Nterminal kinase) and NF-kB (nuclear factor-kB) (Yeh
et al., 1997). A number of recent studies have linked
NF-kB activation to the induction of cell survival
pathway (Liu et al., 1996; Beg and Baltimore, 1996).
Additional regulatory proteins further modify
signaling pathways downstream from TRAF recruitment. These include adapter proteins like A20, cellular
inhibitor of apoptosis (c-IAP), TRAF-interacting
protein (TRIP) and TRAF family member associated
NF-kB activator (I-TRAF/TANK) (Cheng and Baltimore, 1996; Lee and Choi, 1997; Rothe et al., 1996;
Roy et al., 1997). TRIP inhibits NF-kB activation by
TRAFs while I-TRAF/TANK augments it depending
on the specic cellular context. c-IAP1 and c-IAP2
interact with TRAFs and have been reported to
interfere with the activation of caspases even downstream of cytochrome c release (Roy et al., 1997).
FLICE inhibitory protein or FLIP, which contains two
death eector domains and an inactive caspase
domain, binds to FADD and caspase-8 and inhibits
death receptor-induced apoptosis (Hu et al., 1997;
Thome et al., 1997).
This web of interacting proteins leads to very
dierent responses in dierent cells and at dierent
times. Interaction of CD30 and CD40 receptors with
TRAF proteins, depending on cellular context can
promote either cell death or cell survival (Arch et al.,
1998). It is interesting that signaling through CD30 and
CD40 can promote survival of naive lymphocytes, but
subsequently increases their sensitivity to death
inducing signals from Fas or TNFR1 (Rathmell et
al., 1996; Duckett and Thompson, 1997). This may
serve as an internal control mechanism to prevent
unlimited proliferation of cells that might otherwise
result in development of autoimmune disease or
neoplasia.
Another extracellular signal for induction of
apoptosis is deprivation of cells of their anchorage to
extracellular matrix or from cell to cell contacts. The
induction of apoptotic pathway through disruption of
cell anchorage to the substratum is termed anoikis
(Aplin et al., 1998). The exact signaling pathway
responsible for the induction of apoptosis after cell
anchorage deprivation is unknown. One of the two
pathways proposed includes tyrosine kinase FAK, PI-3
kinase and Akt. The other, parallel pathway may
involve the stress induced kinases including MEKK-1
and JNK (Frisch and Rouslahti, 1997). Overexpression

of Bcl-2 in epithelial cells can protect the cells from

anoikis. The physiological role of anoikis is unclear
although disregulation of this process may be
important for the ability of malignant cells to invade
and metastasize elsewhere.
Nuclear factors ivolved in apoptosis
In addition to extracellular signals, cells can undergo
apoptosis in response to internal signals including
genetic abnormality. Defective or inappropriate cell
cycle progression caused by a variety of genotoxic
injuries can result in cell cycle arrest, and subsequent
induction of apoptosis. The tumor suppressor gene p53
has been clearly linked to these pathways leading to its
designation as the `guardian of the genome'. DNA
strand breaks induce rapid p53 upregulation but the
exact mechanism of this triggering event remains
unknown. The upregulation of p53 is mostly posttranscriptional, involving both, an increase in translation and prolonged half-life. p53 is a sequence-specic
DNA-binding protein, which activates transcription of
genes including Gadd45, mdm2, p21 and bax (Cox and
Lane, 1995; Wyllie, 1997). Increase in bax transcription
may be in part responsible for p53-induced apoptosis
following DNA damage (Miyashita and Reed, 1995).
However, p53 can also activate apoptosis by transcription-independent mechanisms (Caelles et al., 1994).
What is more, there are p53-independent pathways that
result in cellular apoptosis following DNA damage. T
cell lymphoma lines derived from p53 knockout mice
died rapidly after exposure to irradiation or to drugs
that promote DNA strand breaks (Strasser et al.,
1994). Death occurred by apoptosis and was inhibitable by Bcl-2 suggesting that Bcl-2 acts downstream of
p53 signal and pointing out that there are additional,
parallel and p53-independent pathways regulating
DNA damage induced apoptosis in mammalian cells.
Another gene implicated in DNA damage induced
apoptosis is ATM (Morgan and Kastan, 1997). This
gene is defective in patients with ataxia-telangiectasia
disorder, who are prone to lymphoid malignancies,
cerebellar degeneration and are extremely sensitive to
ionizing radiation. Cells decient in ATM do not
upregulate p53 following irradiation damage, suggesting that ATM plays a role in the induction of p53. The
downstream p53-dependent apoptotic pathway, however appears to be intact in ATM-decient cells.
Interactions between the molecules that sense DNA
damage and molecules involved in cytosolic activation
of caspases have not been established. Such connections must exist as cytosol-nuclear translocation of the
nuclease CAD requires cytosolic, caspase-dependent
inactivation of ICAD. How `inside-out' or nuclearcytoplasmic signal transduction is achieved remains to
be elucidated.
Cross-talk between the pathways
Dierent pathways involved in regulation of cell
proliferation and cell death may have dierent
signicance in various cells or within the same cell at
dierent stages of development. We now have some
evidence of the cross-talk between the components of

Signal transduction in apoptosis

T Dragovich et al

dierent signaling pathways within the cell (Figure 2).

Bid, a pro-apoptotic Bcl-2 family protein, is cleaved by
caspase-8 in response to Fas signaling (Li et al., 1998;
Luo et al., 1998). Following cleavage, the C-terminal
fragment of Bid binds to mitochondria inducing the
release of cytochrome c, which in turn activates Apaf-1
and initiates procaspase-9 processing. Thus, this crosstalk connects two of the classic apoptotic pathways
depicted in Figure 1; that of Fas receptor mediated
activation of caspase-8 with that of IL-3 withdrawalinduced mitochondrial release of cytochrome c and
activation of caspase-9.
Another example of the cross-talk between dierent
signaling pathways that regulate cell proliferation and
cell death involves Bad, a pro-apoptotic Bcl-2 family
protein. Bad executes its pro-apoptotic function by
binding to anti-apoptotic proteins Bcl-2 and Bcl-xL.
Following growth factor receptor engagement, the
growth factor dependent serine/threonine kinase Akt
phosphorylates Bad (Figure 2). The phosphorylated
Bad is sequestered by cytosolic protein 14-3-3 thus
increasing the levels of free Bcl-2 and Bcl-xL (Zha et al.,
1996). In this example, a growth factor initiated,
survival-promoting signal interferes with a Bcl-2/BclxL-dependent regulation of the cellular apoptotic

threshold (Gajewski and Thompson, 1996). It is

expected that more such examples of cross-talk will
be uncovered as we continue to untangle the web of
apoptotic signaling pathways.
Conclusion
Our understanding of the complex processes that
determine cell fate has advanced over the past decade
yet many unanswered questions remain. The complexity and redundancy involved in regulation of apoptosis
reects its central importance for the growth and
development of complex organisms. The signal
transduction of apoptotic stimuli resembles a complex
information network which includes systems for
reception, processing of information, amplication,
feedback, and response integration. The apoptotic
threshold varies widely with the cell type and its stage
of development and dierentiation. As the cells exist in
a dynamic equilibrium, their threshold for apoptosis
may be constantly changing. Alterations in external
milieu are sensed through the cell surface receptors as
well as multiple cytoplasmic and nuclear factors. These
multiple signals are integrated through a complex

Figure 2 Cross-talk between positive and negative apoptotic signaling pathways. Positive and negative apoptotic signals can be integrated at
the level of the mitochondrial outer membrane by interactions involving the Bcl-2 family of apoptotic regulators

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network of positive and negative regulators of

apoptosis that ultimately determine cell fate. Bcl-2
family members, both by their ability to interact with
other mediators of apoptosis and their subcellular
localization, appear to function at the point of
convergence of multiple apoptotic signals. Disturbances in cellular metabolism, whether imposed by
starvation, infection, toxins or by DNA damage
ultimately result in mitochondrial membrane release
of cytochrome c and activation of downstream
caspases. Based on recent studies, mitochondrial
membrane disruption appears to be a `point of no
return' for the cell, an ultimate commitment to cell
death. Bcl-2 family members and caspases appear to be
critical factors involved in regulating the outcome of
these events.
Recent advances in apoptosis research have identied
new molecular players that regulate this fundamental

and complex biological process. However, there are

large gaps in our ability to understand the intricate
network of apoptotic signal transduction. While there is
considerable information concerning apoptotic signaling pathways that involve cell surface receptors that can
induce caspase activation, much less is known about
Bcl-2 family proteins and their promiscuous interactions
among themselves, with caspases and with components
of the mitochondria. A deeper understanding of the
physiological importance of numerous molecules
involved in apoptotic signaling pathways requires
further investigation. In addition, we need to learn
more about how DNA damage initiates and regulates
the execution of programmed cell death. There is every
reason to believe that new and exciting advances in
apoptosis research will continue to come at a rapid
pace, constantly changing the eld and making reviews
like this outdated by the time they reach the press.

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