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
Cheng, E.H., Wei, M.C., Weiler, S., Flavell, R.A., Mak, T.W., Linds-
ten, T., and Korsmeyer, S.J. (2001). Mol. Cell 8, 705–711.
Cross, D.A., Culbert, A.A., Chalmers, K.A., Facci, L., Skaper, S.D.,
and Reith, A.D. (2001). J. Neurochem. 77, 94–102.
Datta, S.R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., and
Greenberg, M.E. (1997). Cell 91, 231–241.
Janes, K.A., Albeck, J.G., Gaudet, S., Sorger, P.K., Lauffenburger,
D.A., and Yaffe, M.B. (2005). Science 310, 1646–1653.
Kennedy, S.G., Wagner, A.J., Conzen, S.D., Jordan, J., Bellacosa,
A., Tsichlis, P.N., and Hay, N. (1997). Genes Dev. 11, 701–713.
Kuo, M.L., Chuang, S.E., Lin, M.T., and Yang, S.Y. (2001). Oncogene
Maurer, U., Charvet, C., Wagman, A.S., Dejardin, E., and Green,
D.R. (2006). Mol. Cell 21, this issue, 749–760.
Opferman, J.T., Iwasaki, H., Ong, C.C., Suh, H., Mizuno, S., Akashi,
K., and Korsmeyer, S.J. (2005). Science 307, 1101–1104.
Songyang, Z., Baltimore, D., Cantley, L.C., Kaplan, D.R., and
Franke, T.F. (1997). Proc. Natl. Acad. Sci. USA 94, 11345–11350.
Vaux, D.L., Cory, S., and Adams, J.M. (1988). Nature 335, 440–442.
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.