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(Received for publication, November 7, 1995; and in revised form, February 15, 1996) From the
Bcl-2 and Bax are members of a family of cytoplasmic proteins
that regulate apoptosis. The two proteins have highly similar amino
acid sequences but are functionally opposed: Bcl-2 acts to inhibit
apoptosis, whereas Bax counteracts this effect. The antagonism appears
to depend upon dimerization between Bcl-2 and Bax, but its mechanism is
otherwise unknown. Here we report that overexpressing Bax induces
apoptosis in a mammalian fibroblast cell line, and we identify a novel,
short ``suicide domain'' in Bax that is required for this
effect. Inserting this domain in place of the corresponding, divergent
sequence in Bcl-2 converts Bcl-2 from an inhibitor into an activator of
cell death. These findings imply that a specific region in Bax confers
an active propensity for apoptosis in mammalian cells and support the
view that Bcl-2 may block death primarily by suppressing Bax activity.
The form of programmed cell death known as apoptosis is
controlled in part by a family of cytoplasmic proteins whose prototype
is Bcl-2 (reviewed in (1) ). Members of this family share
highly conserved amino acid sequences and the ability to dimerize with
themselves and with one another but, despite these similarities, can
have widely divergent biological
effects(1, 2, 3, 4, 5, 6, 7, 8) .
Overexpression of Bcl-2, for example, potently inhibits the apoptotic
response induced by many different stimuli and in many different
species and cell types. By contrast, the Bax protein, whose sequence is
52% similar to and 28% identical with that of Bcl-2, acts as a
functional antagonist that can counteract the protective effects of
Bcl-2. The reciprocal antagonism between Bcl-2 and Bax appears to
depend upon their ability to form heterodimers, giving rise to the
hypothesis that the relative abundance of homo- or heterodimers of
these proteins regulates activity of a critical, distal step in the
apoptotic pathway(8) . However, the mechanism by which this
interaction controls apoptosis is unknown, and, in particular, it has
not been determined whether Bax plays an active role or merely
functions as an inhibitor of Bcl-2. Here we demonstrate that
overexpression of Bax induces rapid apoptosis in the human fibroblast
cell line GM701. By making a series of Bax/Bcl-2 chimeric proteins and
testing their effect on these cells, we were able to isolate a region
of Bax that is responsible for this effect. Furthermore, transfer of
this region into a functional mutant of Bcl-2 converts Bcl-2 from an
apoptotic antagonist into an apoptotic agonist. This region of Bax,
which we term the ``suicide domain,'' appears to mediate an
active function in the induction of apoptosis.
Stable expression of Bax is permissive for apoptosis, but
does not necessarily induce death in vertebrate cells(2) . In
yeast, however, expression of human Bax triggers acute cell death which
can be prevented by Bcl-2(6, 7) . We have observed a
similar phenomenon in certain mammalian cell lines, including the human
fibroblast line GM701, after transient transfection with an active bax gene. For these studies, GM701 cells were transfected with
a
Figure 1:
Overexpression of Bax induces apoptosis
in GM701 fibroblasts. A, X-gal staining of GM701 cells 24 h
after transfection with a vector encoding
Figure 2:
Induction of apoptosis in GM701 cells by
chimeric Bcl-2/Bax proteins. A, schematic of the constructs
tested. The Bax residues (black rectangles) in each construct
are listed at left; numbers at right denote
boundaries of Bcl-2 sequences (white rectangles). B,
frequency of apoptosis in GM701 cells transfected with these
constructs. Each was tested in two triplicate assays, both performed in
a blind fashion. Data shown indicate the mean ± S.D. (n = 6). C, Western blot of constructs containing the
Bcl-2 epitope. Bcl2
This phenomenon was
exploited as an assay to map the peptide sequences responsible for the
divergent effects of Bax and Bcl-2. Although the two proteins have
closely related sequences, Bax lacks sequences corresponding to a
highly conserved region at the N terminus of Bcl-2 (2) . This
region (residues 1-29) is absolutely required for Bcl-2
function(11) , and its deletion results in a mutant which can
dimerize with, and dominantly inhibit the activity of, wild-type
Bcl-2(12) . When we tested this dominant negative Bcl-2 mutant
(construct Bcl2 We therefore asked whether sequences from Bax could
alter the activity of Bcl-2. Using the GM701 assay, we tested six
vectors encoding chimeric proteins in which various regions throughout
Bcl-2 were replaced by their approximate counterparts from Bax (Fig. 2A, constructs C1-C10). The results
demonstrate that a specific subset of Bax sequences can confer
death-agonist activity when substituted into Bcl-2: chimeras C2 and C4
gave only background levels of cell killing, whereas C1, C3, C8, and
C10 each induced death at or near the frequency seen with Bax (Fig. 2B). Western blots with anti-Bcl-2 antibody
confirmed that constructs C2, C4, and Bcl2 The most
informative construct in this series was C8, which contained only 23
residues of Bax sequence but killed almost as efficiently as
full-length Bax. All three of the other chimeras that induced cell
death also included this sequence (Bax residues 55-77), which
corresponds to a region that is minimally conserved between Bax and
Bcl-2 (Fig. 3A). To determine whether this region is
essential for the death-promoting effect of Bax, we tested the
properties of a Bax mutant lacking residues 53-74 in the GM701
assay. As shown in Fig. 3B, this mutant, termed
Bax
Figure 3:
The suicide domain of Bax is necessary for
function. a, comparison of the C8 region in Bax with the
corresponding region in Bcl-2, based on the Genetics Computer Group
``Gap'' program. b, a Bax mutant lacking residues
53-74 failed to induce apoptosis in GM701 cells (column
1) and also failed to inhibit function of full-length Bax in trans (column 3). pSffvBax
We extended these results by
inserting the active Bax sequences into a fully functional variant of
Bcl-2. For this purpose, we utilized the deletion mutant Bcl2 The family of proteins
structurally related to Bcl-2 includes some members that inhibit, and
others that promote, apoptotic death. The overall propensity of a cell
to undergo apoptosis reflects the relative expression levels of these
two protein classes(2, 5) , whose functional
antagonism appears to depend upon their ability to bind one
another(4, 5) . Because most previous studies have
focused on the ability of Bax to counteract the protective effects of
Bcl-2, it has not been clear whether Bax-like proteins have intrinsic
death-promoting activity or simply function by blocking Bcl-2-like
activity. Here we have demonstrated that Bax can induce killing of at
least one vertebrate cell line directly; this killing does not result
simply from inhibition of endogenous Bcl-2, since expression of a
dominant negative Bcl-2 mutant fails to kill these cells (Fig. 2, construct Bcl2 In another recent report, Chittenden et al.(16) show that a homologous region in the pro-apoptotic
protein Bak (17, 18, 19) mediates the
induction of programmed cell death in Rat-1 cells. The authors
demonstrate that this region of Bak, as well as similar regions in Bax
and Bik(20) , are necessary for their ability to both bind
other Bcl-2 family members and promote apoptosis. Of particular
interest in this region is the BH3 domain, which is the only peptide
sequence within Bik which shares high homology with that of Bax and
Bak(20) . Although Bcl-2 residues 97-105 resemble the BH3
domain closely enough to suggest a common function (see Fig. 3A), our finding that the activity of Bcl-2
variants containing residues 97-105 can be reversed by inserting
the Bax domain (Fig. 4) suggests that the two sequences are not
biologically equivalent.
Figure 4:
Fragments of Bax cloned into a fully
functional Bcl-2 mutant convert it into an apoptotic agonist. a, selected regions of Bax were cloned into Bcl2
Although the molecular function of the
suicide domain remains to be determined, one possibility is that it
serves to mediate the functional interaction of Bax, Bak, Bik, and
perhaps other agonist proteins with a common distal factor in the
apoptotic pathway. Moreover, our data are consistent with the proposal (2, 6) that Bcl-2 could promote survival simply by
inhibiting Bax function, and they further suggest specific mechanisms
by which this might occur. For example, if homodimerization of Bax (2, 4, 5) is necessary for activity of the
suicide domain, Bcl-2 might inactivate this domain by competitively
inhibiting Bax dimerization. Alternatively, this domain may be active
in monomeric form but masked or inactivated when dimerized with
Bcl-2(16) . In either case, our results suggest a molecular
basis for the observation (14, 15) that apoptosis is
the default state of many cell types, and that such cells survive by
holding in check an active proclivity for suicide.
Volume 271,
Number 15,
Issue of April 12, 1996 pp. 8521-8524
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
Cell Lines and Plasmids
Human GM701 fibroblasts
were maintained in Dulbecco's modified Eagle's medium with
10% fetal calf serum. For light microscopy, 2 
10
cells were plated onto glass coverslips in 35-mm plates and
transfected with 10 µg of a plasmid encoding 
-gal (
)under control of the SV40 early promoter and either Bcl-2
(pSffvBcl2--gal) or Bax (pSffvBax--gal) under control of the
spleen focus-forming virus (Sffv) long terminal repeat, in a Bluescript
KS+ (Pharmacia Biotech Inc.) backbone. Cells were transfected by
the calcium phosphate method for 6 h, washed twice with PBS containing
25 mM HEPES, then fed with fresh medium. At 24 h
post-transfection, cells were fixed and stained as
described(9) , washed 3 times with PBS and once with distilled
water, mounted with Aquamount, and photographed with Nomarski optics.
For quantitation of apoptosis, 2 10 cells were
plated in 2 ml of media on Nunc 35-mm gridded plates and transfected in
triplicate as above. After staining with X-gal, 200 blue cells per
plate were counted and scored as normal or apoptotic (small with
conspicuous blebbing). Plasmids encoding chimeric proteins were made
using variants of pSffvBcl2--gal that encoded the constructs
shown. These were prepared from a series of bcl2 deletion
mutants (12) in which deleted residues had been replaced by a
unique in-frame BglII site encoding the dipeptide Arg-Ser; the bax fragments were generated by PCR using primers that
introduced flanking BglII ends, which were then ligated into
the deletants. Bax
C8 was created by PCR mutagenesis and contains
an in-frame BglII site (encoding Arg-Ser) in place of the
deletion. In some cases, an oligonucleotide encoding the epitope for
anti-hemagglutinin monoclonal antibody 12CA5 (Boehringer Mannheim) was
ligated onto the 3` ends of these constructs to facilitate Western
blotting(12) . BaxC8 was created by PCR mutagenesis and
contains an in-frame BglII site (encoding Arg-Ser) in place of
the deletion. All constructs were confirmed by DNA sequencing.Western Blot Analysis
For Western blot analysis,
20 µg of plasmid was transfected into the quail QT6 fibrosarcoma
line, which lacks endogenous immunoreactive Bcl-2, and extracts were
prepared 40 h later and blotted as described(10) , with all
samples on a given gel containing extract from an equivalent number of
cells. Blots were probed for 3 h at room temperature with either
anti-Bcl-2 (Dako; specific for residues 41-54) at 1:200, or the
anti-HA antibody 12CA5 at 1:2,000, in PBS, 0.1% Tween 20 + 2.5%
dry milk. After washing 3 10 min in PBS, 0.1% Tween-20, filters
were incubated with anti-mouse immunoglobin G conjugated to horseradish
peroxidase (Amersham) at a dilution of 1:10,000 for 1 h, then washed as
before and developed with ECL (Amersham)
-galactosidase (-gal) reporter gene together with either bax or bcl-2 on a single expression plasmid; 24 h
after transfection, plates were stained for -gal activity in order
to identify transfected cells, which were then examined under light
microscopy. In repeated experiments, we found that 40-50% of
-gal positive cells in Bax-transfected plates showed the typical
morphologic features of apoptosis, including cell shrinkage, distinct
membrane blebbing, and nuclear condensation (Fig. 1A and 2B). By contrast, these features were seen in only
3-5% of cells transfected with wild-type Bcl-2 (data not shown)
or with Bcl217, a severely truncated, nonfunctional Bcl-2 mutant (Fig. 2, A and B). This effect of Bax was
greatly reduced by co-transfection of Bcl-2 (Fig. 1B).
Thus, transient, high-level Bax expression in these cells specifically
induces apoptosis that can be blocked by Bcl-2.
-gal along with either
Bcl-2 (left) or Bax (right). Cells transfected with
Bax show changes characteristic of apoptosis, including cell shrinkage
and membrane blebbing. B, this effect of Bax is specifically
inhibited by co-transfection with Bcl-2. 1 µg of pSffvBax--gal
was co-transfected with 7 µg of pUC118 and 2 µg of either
pSV40-Neo (left) or pSV40-Bcl2 (right). pSV40-Bcl2
encodes full-length human Bcl-2; the pSV40-Neo plasmid was used to
control for promoter competition between the SV40 ori and the
Sffv long terminal repeat. The data indicate the mean percentage of
cell death ± S.D. for triplicate
determinations.
1, C2, and C4 are expressed at levels
comparable to C8, demonstrating that their lack of effect on GM701
cells is not due to protein instability. None =
untransfected QT6 cells. D, Western blot of HA-epitope-tagged
derivatives of chimeras that lacked the Bcl-2 epitope, with C8-HA
included for comparison. The ability of these constructs to kill cells
was not affected by addition of the HA tag (data not shown) and likely
accounts for their apparently low expression. The most potent apoptotic
agonist, C3-HA, is not detectable. QT6 = untransfected
QT6 cells.
1) in the GM701 assay, we found that it failed to
induce death (Fig. 2), suggesting that cell killing did not
result simply from inhibition of any endogenous Bcl-2-like proteins.
Moreover, fusion of Bcl-2 residues 1-29 onto the N terminus of
Bax (construct Bcl2/Bax) did not eliminate its cytotoxicity (Fig. 2).1 were expressed at
levels comparable to that of C8 (Fig. 2C). Expression
of C1, C3, and C10 was more difficult to compare directly, since they
lacked the Bcl-2 epitope and killed the cells that expressed them, but
a Western blot of epitope-tagged derivatives of these proteins
suggested that none was expressed more strongly than C8 (Fig. 2D). Thus, the differences in activity among
constructs were not due to differences in protein stability. Nor could
the activity of C1, C3, C8, and C10 be attributed to the deletion of
Bcl-2 sequences alone, since the Bcl-2 deletion mutants from which they
were made did not induce death appreciably in the GM701 assay (Fig. 2B, construct Bcl217, and data not shown).
Hence, the death-promoting activity of these chimeras is attributable,
at least in part, to the Bax sequences they contain.C8, completely lacked Bax activity. When co-transfected along
with full-length Bax, however, BaxC8 did not prevent cell killing,
indicating that it is an inactive, recessive mutant and not a
functional equivalent of Bcl-2.
C8--gal was
transfected at 10 µg/plate (column 1). For the trans-inhibition assay, 1 µg of pSffvBax--gal was
co-transfected with 7 µg of pUC118 and 2 µg of pSV40 (column 2), pSV40-BaxC8 (column 3), or
pSV40-Bcl2 (column 4). Data indicate mean percentage of cell
death ± S.D. for triplicate
determinations.
2,
which lacks the nonconserved residues 30-79 but inhibits
apoptosis as potently as wild-type Bcl-2 in two well-characterized
model systems, including staurosporine-treated GM701
cells(12, 13) . As shown in Fig. 3, we found
that Bcl22 did not cause cell death in our assay, but that
insertion of the Bax sequences from C3, C7, or C10 in place of the
deletion conferred potent death-promoting activity. Interestingly, the
23-residue Bax sequence from C8 did not confer death-agonist function
onto Bcl22, implying that its activity is somewhat
context-dependent. However, the C7 and C10 sequences, which each
comprise C8 along with 22-23 additional Bax residues downstream
or upstream, respectively, each produced chimeras that induced
significant levels of cell death. Thus, inserting as few as 45 amino
acid residues from Bax into a fully functional Bcl-2 completely
reversed its effect on cell survival.1). Using this assay system, we have
identified a short region within Bax that is essential for its killing
activity and which, when substituted into an antiapoptotic or
nonfunctional Bcl-2 mutant, converts these proteins into potent
apoptotic agonists. These observations strongly indicate that this
domain subserves an active function that is permissive for apoptosis in
many cellular systems, and which may be required for Bax-dependent
induction of apoptosis in yeast(6, 7) , as well as in
the GM701 cells studied here. We designate this region, which may span
as few as 23 amino acids (residues 55-77), as the suicide domain
of Bax.
2, a
48-amino acid deletion mutant of Bcl-2 which blocks
staurosporine-induced apoptosis of GM701 cells as efficiently as
wild-type Bcl-2(12) . b, death-promoting activity of
the resulting chimeras, and of the parental Bcl22, assayed in
GM701 cells as described for Fig. 1. Data indicate mean
percentage of cell death ± S.D. for triplicate determinations. c, Western blot of HA-tagged variants of these chimeras,
expressed in QT6 cells and detected with anti-HA antibody. Because some
of these constructs induce apoptosis, expression appears inversely
related to activity, and the most potent apoptotic agonist
(2C3-HA) is not detectable.
)-gal, -galactosidase; Sffv, spleen
focus-forming virus; PBS, phosphate-buffered saline; X-gal,
5-bromo-4-chloro-3-indolyl -D-galactopyranoside; PCR,
polymerase chain reaction; HA, influenza hemagglutinin epitope.
We thank B. L. Bond for expert technical assistance,
C.-M. Chang and M. Fitch for reagents and advice, A. L. DeFranco, N.
Killeen, and X. C. Liao for comments on the manuscript, and I.
Fariñas for photography.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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