factor receptor signaling. Alternatively, it may well be
that BH3-only proteins, often the most dynamic partici-
pants in BCL-2 family interactions, play the determining
role in other cell types (Datta et al., 1997).
Is GSK-3 more generally a participant in cell survival
and apoptosis decision making? The authors point out
that GSK-3 has been shown to promote apoptosis in
neuronal cells and that GSK-3 inhibitors can prevent
death of cerebellar granule neurons (Cross et al.,
2001). If GSK-3 can be linked so directly to life and death
decisions in hematopoietic and neuronal cells, this is
potentially of practical interest, as small molecule inhib-
itors of GSK-3 kinase exist, and there is ample evidence
that selective kinase inhibitors can be made into effec-
tive drugs. Therefore, it is theoretically possible that
GSK-3 inhibitors might promote survival of neurons,
and other cells, in important clinical contexts. This is in
contrast to the kinase inhibitors used clinically today,
all of which function by promoting cell death. This opti-
mistic conjecture obviously requires considerable test-
ing in vivo.
In a specific setting, Maurer et al. (2006) extend our
understanding of apoptosis following growth factor
withdrawal. IL-3 signaling alone, however, influences,
and is influenced by, myriad other downstream path-
ways. As a consequence, initial conditions are critical
in determining cell fate following cytokine signalling
(Janes et al., 2005). Therefore, this work may well pro-
vide only a small view of the panorama that is IL-3 sur-
vival signaling. Given the large number of cytokines,
the complex, almost chaotic, web of downstream sig-
naling, and the universe of varied initial conditions pos-
sible, can we ever hope to have a complete understand-
ing of how cytokine signaling determines cell fate?
Perhaps not, but advances like those in Maurer et al.
(2006) provide us with important principles that can be
tested in other systems and perhaps allow us to predict
and control cell behavior. As in chess, we may not al-
ways be able to predict a priori all the moves, but the
guidance of sound strategic principles may allow us
nonetheless to construct a winning game.
1Department of Medical Oncology
Dana-Farber Cancer Institute
44 Binney Street
Boston, Massachusetts 02115
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Molecular Cell 21, March 17, 2006 ª2006 Elsevier Inc. DOI 10.1016/j.molcel.2006.03.003
CED-9 and EGL-1: A Duo
Also Regulating Mitochondrial
In both Caenorhabditis elegans and mammals, Bcl-2
family members control apoptosis. In this issue of Mo-
on a new role of Bcl-2 family members as regulators of
mitochondrial network morphology.
In mammalian cells, Bcl-2 family members play a pivotal
role in apoptosis by regulating mitochondrial outer
membrane permeabilization (MOMP) and subsequent
release of apoptogenic factors (Green and Kroemer,
2004). Proapoptotic Bcl-2 family proteins such as Bax
trigger cytochrome c release and mitochondrial frag-
mentation, whereas antiapoptotic proteins (Bcl-2 and
Bcl-xL) can inhibit these events (Karbowski and Youle,
2003). In the nematode C. elegans, CED-9, the Bcl-2-re-
tion of CED-4, a caspase-activating protein. EGL-1,
a nematode ‘‘BH3-only’’ protein (a proapoptotic subset
of the Bcl-2 family members with only a Bcl-2 homology
domain 3) binds to CED-9 and displaces its interaction
with CED-4, thereby allowing CED-4 to recruit and acti-
vate the caspase CED-3 (Lettre and Hengartner, 2006)
(Figure 1). Although CED-9 is anchored to the mitochon-
dria outer membrane, it had not been reported whether
CED-9 regulates MOMP and/or mitochondrial morphol-
ogy during apoptosis.
Although CED-9 and Bcl-2 share only 23% homology,
Bcl-2 expression inhibits apoptosis in C. elegans (Lettre
observed that, unlike Bcl-xL, CED-9 expression fails to
prevent Bax-mediated MOMP, cytochrome c release,
and apoptosis in mammalian cells. Therefore, CED-9
is unable to modulate MOMP and cytochrome c release.
Mitochondria form a highly dynamic network whose
morphology is regulated by frequent fission and fusion
events (Okamoto and Shaw, 2005). Most of the effectors
ofthefusion andfission machinery werefirstdiscovered
optosis, a morphological change occurs with the frag-
mentation of the reticular mitochondrial network. This
event requires the activity of physiological mediators of
the fission/fusion machinery (Karbowski and Youle,
2003). Although it has been proposed that Bcl-2 family
members directly regulate mitochondrial fragmentation
during apoptosis (Youle and Karbowski, 2005), the mo-
lecular mechanisms remained unknown. In their study,
Delivani et al. (2006) observed that CED-9 expression in
mammalian cells promotes mitochondrial fusion, and
consistent with this finding, CED-9 immunoprecipitates
with Mfn-2 (a mediator of mitochondrial fusion, Table 1),
but not with other effectors of the mitochondrial fis-
sion/fusion machinery such as Mfn-1, Drp1, or OPA1
(Table 1). Interestingly, an interaction of Bcl-2 and Bcl-
xL with Mfn-2 was also observed. Nevertheless, those
results must be handled with caution because interac-
tions between endogenous Mfn-2 and Bcl-2 or Bcl-xL,
and between FzoRP-1 (the worm homolog of Mfn-2)
and CED-9 have not yet been demonstrated. Finally, De-
livani et al. (2006) also reported that Bcl-xL, like CED-9,
promotes mitochondrial fusion, consistent with the find-
ing that Bcl-xL may bind to Mfn-2.
Inthemitochondrial pathwayofapoptosis, ithasbeen
the activation of the molecular machinery involved in
fission, leading to mitochondrial fragmentation (Frank
et al., 2001; Youle and Karbowski, 2005). However,
whether mitochondrial fragmentation is strictly re-
quired in MOMP and cytochrome c release remains
Figure 1. Molecular Model of Caspase Activation and Mitochondrial Fragmentation in C. elegans Apoptosis
In living cells, CED-9 sequesters a CED-4 dimer on the outer surface of the mitochondria and maintains it in an inactive conformation. CED-9
also binds to Mfn/FzoRP-1, a mitochondrial outer membrane protein with a cytosolic GTPase domain and two coiled coil regions. The coiled
coil domain mediates oligomerization between Mfn/FzoRP-1 molecules, allowing Mfn/FzoRP-1 oligomers to coordinate mitochondrial fusion.
After a cell death signal, the BH3-only protein EGL-1 is produced and the binding of EGL-1 to CED-9 induces a conformational change of CED-9,
leading to the release of the CED-4 dimer from the CED-9/CED-4 complex. In parallel, the conformational change of CED-9 may disrupt Mfn/
FzoRP-1 oligomers, triggering a mitochondrial fragmentation as a consequence of an inhibition of the mitochondrial fusion. Once freed from
the inhibitory interaction with CED-9, two CED-4 dimers associate and recruit pro-CED3 to form the ‘‘apoptosome.’’ Next, CED-3 is activated
to trigger apoptosis. This model was adapted from Lettre and Hengartner (2006).
Table 1. Conservation of the Proteins Involved in the Mitochondrial Fusion/Fission Machinery
Human Protein Yeast ProteinC. elegans Protein LocalizationStructure Function
Fuzzy onions 1 (Fzo1)FzoRP-1 OM, integrated Large transmembrane
GTPase, crossing OM twice
Mgm1Not characterized IMSFusion, Cristae
Dnm1 Drp1Cytosol, OM Dynamin-related GTPase
Fis1 Not characterizedOM, integrated Integral membrane proteinFission
Abbreviations: OM, outer membrane; IMS, inner membrane space.
controversial (Arnoult et al., 2005). Delivani et al. (2006)
showed that CED-9 expression prevents apoptosis-
associated mitochondrial fragmentation, although it has
no effects on MOMP and cytochrome c release, sug-
uisite for apoptosis.
In the nematode, EGL-1 inhibits the ability of CED-9 to
suppress apoptosis (Lettre and Hengartner, 2006) (Fig-
ure 1), and a recent study suggests that EGL-1 induces
fragmentation of the mitochondrial network during apo-
ptosis in C. elegans (Jagasia et al., 2005). Delivani et al.
(2006) studied whether EGL-1 could antagonize the abil-
ity of CED-9 to induce mitochondrial fusion. As ex-
pected, EGL-1 is capable of suppressing CED-9-medi-
ated mitochondrial fusion, and coexpression of EGL-1
withCED-9 promotesamassivemitochondrial fragmen-
tation that is not associated with cytochrome c release
and apoptosis, suggesting that mitochondrial fragmen-
tation can be dissociated from apoptosis. Thus, it ap-
pears that EGL-1 can simultaneously antagonize the
ability of CED-9 to sequester CED-4 on the outer mem-
moting mitochondrial fusion (Figure 1). However, further
studies will be required to determine whether in the
sequence of a transcriptional process and/or posttrans-
lational changes such as conformational changes as
described in mammals (Willis and Adams, 2005). In
mammalian cells, given that Bcl-xL induces mitochon-
drial fusion likely via interaction with Mfn-2, it will be of
interest to examine whether the mammalian BH3-only
antagonists of Bcl-xL, such as Bid, Bim, and Puma (Wil-
lis and Adams, 2005), prevent the fusion-promoting
function of Bcl-xL. Thus, a putative inhibition of the fu-
sion-promoting activity of Bcl-xL by the BH3-only may
participate in the fragmentation of the mitochondrial
network observed during apoptosis.
Based on the results reported by Delivani et al. (2006),
it appears that Bcl-2 family members have two distinct
conserved functions: a role as regulators of apoptosis
that has been intensively studied and a newly discov-
ered role as regulators of the mitochondrial fusion and
fission dynamic. In yeast, the continuous cycles of fis-
sion and fusion normally occur although no Bcl-2 family
members are found. Therefore, it remains to be investi-
gated why and how in multicellular organisms, Bcl-2
family members are required in addition of the classical
effectors of the fission/fusion machinery to determine
the morphology of the mitochondrial network. It is
tempting to speculate that the fusion-promoting func-
tion of the antiapoptotic Bcl-2 family members may
have a role in respiration, maintenance of mitochondrial
DNA, and prevention of oxidative damage. Finally, fur-
ther studies are required to determine whether both
roles of Bcl-2 family members are separable and un-
related, as suggested by Delivani et al. (2006). If so,
although mitochondrial fragmentation is a common fea-
ture of apoptosis, it does not seem to be essential for
MOMP and cytochrome c release. An interesting ques-
tion remains: what is the role of mitochondrial fragmen-
tation during apoptosis?
Je ´ro ˆme Estaquier1and Damien Arnoult1
1Unite ´ de Physiopathologie des Infections Lentivirales
28 rue du Dr. Roux
75724 Paris cedex 15
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Molecular Cell 21, March 17, 2006 ª2006 Elsevier Inc. DOI 10.1016/j.molcel.2006.03.004
The Double-Edged Sword of Nrf2:
Subversion of Redox Homeostasis
during the Evolution of Cancer
Low levels of Nrf2 activity predispose cells to chem-
ical carcinogenesis. Surprisingly, Padmanabhan et al.
(2006) provide evidence in a recent issue of Molecular
Cell to support the notion that elevated Nrf2 activity
may also play a role in the evolution of cancer.
Maintenance of the correct homeostatic reduction po-
tential (i.e., the appropriate balance between oxidants
but is perpetually threatened by extrinsic factors, such
as increases in the levels of reactive oxygen species
chemicals that are metabolised to antioxidant-depleting