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(Received for publication, June 24, 1997, and in revised form, August 12, 1997)
From the Tumor Immunology Program, German Cancer Research Center,
Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
ABSTRACT Induction of apoptosis by the cell surface
receptor CD95 (APO-1/Fas) has been shown to involve activation of a
family of cysteine proteases (caspases). Recently, a new member of this
family has been identified, designated FLICE (caspase-8/MACH/Mch5).
FLICE is part of the CD95 death-inducing signaling complex and is
therefore the most upstream caspase in the CD95 apoptotic pathway.
A total of eight different isoforms of FLICE (caspase-8/a-h) have been described. To determine which isoforms are expressed in different cells
we have generated a panel of monoclonal antibodies directed against all
functional domains of FLICE. Using these antibodies we could show that
only two of the FLICE isoforms (caspase-8/a and caspase-8/b) were
predominantly expressed in cells of different origin. Both isoforms
were recruited to the CD95 death-inducing signaling complex and were
activated upon CD95 stimulation with similar kinetics. Taken together,
only two of the eight published caspase-8 isoforms could be detected in
significant amounts at the protein level.
INTRODUCTION Apoptosis, or programmed cell death, plays an essential role in
development, homeostasis, and defense in multicellular organisms (1,
2). Several cell surface receptors, such as CD95 (APO-1/Fas), TNF1 receptor 1, DR3
(APO-3/TRAMP/Wsl-1/LARD), and DR4 (TRAILR) (3) belonging to the TNF
receptor/nerve growth factor receptor superfamily, have been shown to
trigger apoptosis upon binding of their cognate ligands or specific
agonistic antibodies. Stimulation of CD95 has been shown to result in
aggregation of its intracellular death domains, leading to the
recruitment of a set of signaling proteins (CAP1-4) and the formation
of the death-inducing signaling complex (DISC) (4, 5). In the DISC,
CAP1 and CAP2 were identified as the adapter molecule FADD (MORT-1) (4,
6, 7) that couples through its C-terminal death domain to the
cross-linked CD95 receptor. The N-terminal death effector domain of
FADD enables recruitment of CAP4, which was identified as FLICE
(MACH FLICE belongs to a family of cysteine proteases (caspases, related to
the Caenorhabditis elegans cell death gene ced-3
that have been shown to play a key role in the induction of most forms of apoptosis (11). Caspases are synthesized as inactive proenzymes that
have to be activated by proteolytic cleavage after specific aspartate
residues (12). Recently, we have shown that FLICE is activated by
association with the CD95 DISC, leading to the release of the active
subunits p18 and p10 into the cytosol (13). There, they can activate
other caspases, in turn resulting in the specific cleavage of a number
of "death substrates." During CD95 triggering all cytosolic FLICE
is activated at the DISC (13). After activation at the DISC a part of
the FLICE prodomain remains bound to the DISC.
A large number of caspases have been identified including caspase-1
(ICE) (14, 15), caspase-2 (ICH-1/Nedd-2) (16, 17), caspase-3
(CPP32/Yama/apopain) (18-20), caspase-4 (ICH-2/TX/ICE-rel-II) (21-23), caspase-5 (ICE-rel-III/TY) (23, 24), caspase-6 (Mch2) (25),
caspase-7 (Mch3/ICE-LAP3/CMH-1) (26-28), caspase-8 (FLICE/MACH/Mch5) (8-10), caspase-9 (Mch6/ICE-LAP6) (29, 30), caspase-10 (Mch4/FLICE2) (10, 31), and caspase-11 (ICH-3) (32). However, the role of these
caspases in different cell death pathways in various tissues remains
elusive. Caspase-3, for example, has been shown to be proteolytically
activated upon CD95-induced cell death. In mice deficient of caspase-3,
however, the CD95 apoptosis pathway was not affected in most tissues
(33).
In addition to the large number of different caspases, various isoforms
of these molecules have been described at the mRNA level. Some of
these isoforms have been found to be inactive splice variants such as
ICE In this study, expression of the different FLICE isoforms on the
protein level in various cell lines was determined by monoclonal antibodies covering the three functional domains of caspase-8. Only two
caspase-8 isoforms were detected on the protein level of all cell lines
tested. Both isoforms were recruited and activated by the CD95 DISC
with identical kinetics.
EXPERIMENTAL PROCEDURES The monocytic cell line MonoMac, the T-cell
lymphoma HUT78, the B-lymphoblastid cell line SKW6.4, the Burkitt
lymphoma Raji, the Burkitt-like lymphoma BJAB, the colon carcinoma cell
line HT-29, the breast carcinoma cell line MCF-7, the cervix carcinoma HeLa, the myorhabdosarcoma cell line KYM-1 (kind gift from M. Grell,
Stuttgart, Germany), the small lung cell carcinoma line SCLC22H (kind
gift from J. Fischer, Heidelberg, Germany), and the neuroblastoma SHEP
(kind gift from M. Schwab, Heidelberg, Germany) were cultured in RPMI + 10% fetal calf serum, 0.05 mg/ml gentamycin, and 0.05 mg/ml HEPES. The
hepatoma cell line HepG2, the gastric cancer line HS746T (both were a
kind gift from M. Müller-Schilling, Heidelberg, Germany), and the
embryonic kidney line 293T were cultured in Dulbecco's modified
Eagle's medium + 10% fetal calf serum, 0.05 mg/ml gentamycin, and
0.05 mg/ml HEPES. All cells were of human origin.
The affinity-purified rabbit
anti-peptide antibodies anti-FLICE-N and anti-FLICE-C against the FLICE
peptides 183-201 and 466-479, respectively, were generated as
described previously (13). For the anti-FLICE mAbs, BALB/c mice were
immunized four times by injection of 300 µg of either purified
GST-N-FLICE or GST-C-FLICE. Spleen cells from immunized animals were
fused with the Ag8 myeloma. 2 weeks after fusion culture supernatants
from wells positive for growth were tested in an enzyme-linked
immunosorbent assay with HIS-FLICE as coated antigen. Hybridomas that
produced anti-FLICE mAbs were cloned several times by limited dilution yielding subclones positive for the desired antibody. The anti-FLICE mAbs used in this study were C5 (IgG2a), C15 (IgG2b), and N2 (IgG1). The mouse mAb anti-APO-1 (IgG3, k) recognizes an epitope on the extracellular part of human APO-1 (CD95/Fas) (35). The horseradish peroxidase-conjugated goat anti-mouse IgG1, IgG2a, and IgG2b were purchased from Dianova (Hamburg, Germany). All chemicals used were of
analytical grade and purchased from Merck (Darmstadt, Germany) or
Sigma.
Using standard
polymerase chain reaction and cloning techniques the following fusion
proteins were generated: HIS-FLICE, GST-N-FLICE (amino acids 1-180),
and GST-C-FLICE (amino acids 181-478). Fusion proteins were purified
as described previously (4). For immunoprecipitation mAbs (10 µg)
were coupled to anti-IgG1 Agarose beads (Sigma) (N2), to protein A
Sepharose beads (Sigma) (C15), or to protein A/G-plus Agarose (Santa
Cruz Biotechnology) (C5). After addition of in vitro
activated [35S]FLICE and incubation for more than 1 h at 4 °C, beads were washed three times with lysis buffer. The
amount of DISC-associated FLICE was determined as follows: 5 × 106 SKW6.4 cells were either first treated with 2 µg/ml
anti-APO-1 for 5 min at 37 °C and then lysed (stimulated condition)
or first lysed and then supplemented with 2 µg/ml anti-APO-1
(unstimulated condition). 35S labeling, cell lysis, and
immunoprecipitation of CD95 were done as described elsewhere (4).
For Western blot detection of cytosolic
proteins postnuclear supernatants equivalent to 1 × 106 cells or 50 µg of total protein as determined by the
BCA method (Pierce) were separated by 12% SDS-PAGE. After
electrophoresis all samples were transferred to Hybond nitrocellulose
membrane (Amersham Corp.), blocked with 2% bovine serum albumin in
PBS/Tween (PBS + 0.05% Tween 20) for at least 1 h, washed with
PBS/Tween, and incubated with supernatant of anti-FLICE hybridomas
diluted 1:5 in PBS/Tween for 16 h at 4 °C. Blots were washed
with PBS/Tween and developed with goat anti-mouse IgG1 (N2), IgG2a
(C5), or IgG2b (C15) (1:20000). After washing with PBS/Tween, the blots
were developed with the chemiluminescence method (ECL) following the manufacturer's protocol (Amersham Corp.).
The CD95 DISC was
immunoprecipitated from 5 × 107 anti-APO-1-treated
SKW6.4 cells (5 min) as described above, and immunoprecipitates were
incubated with in vitro translated 35S-labeled
FLICE (TNT, T7 coupled reticulocyte lysate system, Promega) in FLICE
cleavage buffer (50 mM HEPES, pH 7.4, 100 mM
NaCl, 0.1% CHAPS, 10 mM dithiothreitol, and 10% sucrose)
for 24 h at 4 °C. The cleavage reactions were stopped by
addition of 1% SDS. After boiling for 3 min, samples were diluted 1:10
in lysis buffer and subjected to immunoprecipitation as described
above. The immunoprecipitates were separated on 15% SDS-PAGE, and the
amplified dried gels were subjected to autoradiography.
RESULTS Using either
GST fusion proteins with recombinant FLICE prodomain (GST-N-FLICE,
amino acids 1-180) or the protease domain (GST-C-FLICE, amino acids
181-479) as an immunogen, different mouse anti-FLICE monoclonal
antibodies were generated. Specificity of the antibodies was first
established by Western blotting on recombinant GST-N-FLICE or
GST-C-FLICE. The antibody N2 reacted only with GST-N-FLICE, whereas the
antibodies C15 and C5 reacted only with GST-C-FLICE (Fig.
1A). We have recently shown
that in vitro translated 35S-labeled FLICE can
be activated in vitro by incubation with the immunoprecipitated DISC, resulting in the formation of cleavage intermediates p43 and p12, the prodomain p26, and the active subunits p18 and p10 (Fig. 1C and Ref. 13). For further
characterization of the antibodies in vitro activated
35S-labeled FLICE was used in immunoprecipitation
experiments (Fig. 1B). In addition to full-length FLICE, the
N2 antibody immunoprecipitated the p43 and the p26 cleavage products,
both containing the prodomain of FLICE. Interestingly, the band below
full-length FLICE was not immunoprecipitated by N2 (Fig.
1B). This band represents N-terminal truncated FLICE due to
the usage of an internal start site in the in vitro
translation (13). Therefore, the N2 mAb recognizes an epitope located
within the first death effector domain of FLICE. The C15 mAb directed
against the C terminus of FLICE immunoprecipitated all FLICE cleavage
products containing the p18 domain. The antibody C5 precipitated p12
and p10, both representing the very C terminus of FLICE. Therefore, C5
is directed against the p10 subunit of FLICE.
[View Larger Version of this Image (31K GIF file)]
A number of isoforms of caspase-8 have been described at
the mRNA level (9, 10). Our mAb against the three major domains of
FLICE (the prodomain and the active subunits p18 and p10) enabled us to
test which of the reported caspase-8 isoforms were actually expressed
in vivo. To this end several cell lines representing different tissues were tested for FLICE expression by Western blotting
using the N2, C15, and C5 anti-FLICE mAbs (Fig.
2). Surprisingly, all three antibodies
detected only two bands of 55 and 53 kDa of equal intensity in almost
all cells. Other caspase-8 isoforms were undetectable. The only
reported caspase-8 isoform that was not expected to be detected with
the antibodies used was caspase-8/e (Fig.
3 and Table
I).
[View Larger Version of this Image (34K GIF file)]
[View Larger Version of this Image (26K GIF file)]
Table I.
Recognition of caspase-8 isoforms by different antibodies
Volume 272, Number 43,
Issue of October 24, 1997
pp. 26953-26958
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
FLICE Is Predominantly Expressed as Two Functionally Active
Isoforms, Caspase-8/a and Caspase-8/b*
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
1/MCH5/caspase-8) (8-10).
(34), MCH2
(25), or MCH3 (26). Others function as dominant
inhibitors of apoptosis such as ICE
(34) or ICH-1s (17). For
caspase-8, eight different isoforms (designated as caspase-8/a-h),
including FLICE (CAP4/MACH1) (8), MACH2 and MACH3, MACH1-4
(9), and Mch5 (10) have been described at the mRNA level.
Fig. 1.
Characterization of anti-FLICE mAbs.
A, 50 ng of either purified GST-N-FLICE (N) or
GST-C-FLICE (C) were subjected to SDS-PAGE and immunoblotted
with anti-FLICE mAbs N2, C15, or C5 as indicated. B,
in vitro translated 35S-labeled FLICE was
processed by incubation with immunoprecipitated CD95 DISC as described
previously (13). After boiling the samples in 1% SDS to avoid
association, the different cleavage products were either directly
analyzed by SDS-PAGE (Input) or subjected to
immunoprecipitation with anti-FLICE mAbs C5, C15, or N2. The immunoprecipitates were also analyzed by SDS-PAGE and autoradiography of the dried gel. C, scheme of the GST-FLICE fusion
proteins, the FLICE cleavage products, and the domains recognized by
the anti-FLICE mAbs N2, C15, and C5 as analyzed in A and
B and described in the text. DED, death effector
domain.
Fig. 2.
Only two FLICE isoforms are expressed in cell
lines representing different tissues. 50 µg of total protein
from lysates of the indicated cells were subjected to SDS-PAGE and
immunoblotted with the anti-FLICE mAbs N2, C15, or C5 as indicated.
Cells representing the lymphoid system are MonoMac (monocytes), HUT78
(T-cells), SKW6.4, BJAB, and Raji (B-cells). The origins of the other
cells are colon (HT29), liver (HepG2), stomach (HS746T), breast
(MCF-7), cervix (HeLa), kidney (293T), muscle (KYM-1), lung (SCLC22H), and brain (SHEP).
Fig. 3.
Overview of all described caspase-8 isoforms
at the RNA level. The prodomain containing the two death effector
domains (DED) is shown in black, and the active
subunits p18 and p10 are drawn in gray. Domains that differ
from the sequence of caspase-8/a are shown in hatched boxes.
The binding sites for the two rabbit antibodies anti-FLICE-N and
anti-FLICE-C, the calculated molecular weight, and the pI
values are indicated.
indicates the absence of a binding site for the indicated antibodies. Cases where binding of an antibody cannot be predicted because the exact epitope for the anti-FLICE mAbs C15 and C5 is not
known are labeled with question marks.
Caspase
anti-FLICE-N
anti-FLICE-C
N26
C15
C5
8/a
+
+
+
+
+
8/b
+
+
+
+
8/c
+
?
+
8/d
+
+
8/e
8/f
+
+
?
8/g
+
?
8/h
+
+
+
+
Expression levels of the two detected caspase-8 isoforms were very different, spanning a range from high expression in the B-cell line SKW6.4 or the myorhabdosarcoma cell line KYM-1 to low expression in the embryonic kidney cell line 293T. Interestingly, the small lung cell carcinoma line SCLC22H was negative for FLICE expression. The third band detected only by the C5 mAb in the hepatoma line HepG2 likely represents a nonspecific background band because a FLICE isoform of this size (43 kDa) should contain the p18 subunit of FLICE and should therefore also be detected by the C15 mAb. After longer exposure of the three immunoblots, additional bands were detectable (data not shown), most of which represent unspecific binding of the anti-FLICE antibodies with cellular proteins. In summary, of the eight isoforms of caspase-8 described at the mRNA level, only two are expressed as proteins in significant amounts in all 13 cell lines tested.
Both FLICE Isoforms Are Recruited to the DISCWe have
recently shown that FLICE is recruited to the CD95 receptor in a
stimulation-dependent manner forming the DISC (4, 8). To
test whether the second FLICE isoform is also recruited to the CD95
receptor, we analyzed the DISC by one-dimensional as well as by
two-dimensional Western blotting, using the C15 anti-FLICE mAb. As
shown in Fig. 4A, both FLICE
isoforms were recruited to the CD95 receptor in a
stimulation-dependent manner. The comparison between the
two-dimensional Western blot and the DISC precipitation from
35S-labeled cells (Fig. 4B) confirmed that the
upper FLICE isoform was identical with CAP4, whereas the lower isoform
was hidden underneath a background spot in the 35S-DISC
precipitation that was also detected under unstimulated conditions.
Fig. 4. Both FLICE isoforms are recruited to the CD95 DISC. CD95 was immunoprecipitated from either untreated (unst.) or anti-APO-1-treated (5 min) (stim.) SKW6.4 cells. Immunoprecipitates were washed four times, subjected to SDS-PAGE (A) or two-dimensional gel electrophoresis (B), and immunoblotted with the anti-FLICE mAb C15. C, similarly, CD95 was immunoprecipitated from 35S-labeled SKW6.4 cells and analyzed using two-dimensional gel electrophoresis. The arrowheads indicate the position of the two expressed FLICE isoforms. Only the area of CAP4 is shown.
[View Larger Version of this Image (48K GIF file)]
Both FLICE Isoforms Are Activated upon CD95 Triggering
As
both FLICE isoforms were recruited to the DISC we tested next whether
both are cleaved upon triggering of CD95. Therefore, we analyzed the
lysate of either untreated cells or cells stimulated with the
anti-APO-1 antibody for 1 h in a Western blot experiment using the
three different anti-FLICE mAbs. Prolonged stimulation of CD95 resulted
in almost complete cleavage of both FLICE isoforms (Fig.
5A, lanes 2,
4, and 6). Cleavage of both full-length FLICE bands during stimulation resulted in the formation of only one p18 and
p10 cleavage product as detected by the C terminus-specific mAbs C15
and C5, respectively indicating that both isoforms did not differ in
their C terminus ICE-like domains (Fig. 5A, lanes 1-4). To confirm this we made use of the rabbit antibody
anti-FLICE-C, which was directed against the very C terminus. This
antibody was able to precipitate both FLICE isoforms, confirming that
they did not differ in their C terminus (Fig. 5A,
lanes 9 and 10). However, the N terminus-specific
anti-FLICE mAb N2 detected two different FLICE cleavage products, p26
and p24, after CD95 stimulation (Fig. 5A, lanes 5 and 6). In addition, two bands, p43 and p41, were also
detected, representing intermediates after cleavage between the p18 and
the p10 subunit of FLICE, because they were also weakly detected by the
C15 antibody (Fig. 5A, lanes 1, 2, 5, and 6). Therefore, the two isoforms of FLICE
differed in the size of their prodomains. Given the molecular weight
and pI of 53 kDa and 4.91, respectively, and the difference
in the prodomain, the described isoform of caspase-8 that most likely
represents the second band is caspase-8/b (MACH2) (Fig. 3). This
isoform differs from FLICE in a box of 15 amino acids that is not
present in caspase-8/b (9). To further test this assumption we made use
of the rabbit antibody anti-FLICE-N, which was directed against these
15 amino acids. Using SDS-boiled lysates from unstimulated cells the
anti-FLICE-N antibody only precipitated the upper FLICE band (Fig
5A, lanes 7 and 8). In SDS-boiled
lysates from stimulated cells, the antibody only recognized the p43
intermediate and the p26 prodomain. We therefore conclude that the
second FLICE isoform that is expressed on the protein level is
caspase-8/b that lacks the 15 amino acids recognized by the FLICE-N
antibody.
Fig. 5. The two expressed FLICE isoforms represent caspase-8/a and 8/b. A, in vivo cleavage products of caspase-8/a and 8/b were analyzed by immunoblotting lysate (lys.) of 106 untreated (
) or 1 h
anti-APO-1-treated (+) SKW6.4 cells using the anti-FLICE mAbs C15, C5,
or N2 as indicated. Similarly, the SDS-boiled lysate of 107
untreated () or 1 h anti-APO-1-treated (+) SKW6.4 cells was immunoprecipitated using either the rabbit antibody anti-FLICE-N (N-ip) or anti-FLICE-C (C-ip). The
immunprecipitates were immunoblotted with the anti-FLICE mAb N2. The
two bands recognized by the C5 antibody in both untreated and treated
cells are likely to be the result of unspecific binding. B,
the CD95 DISC was immunoprecipitated from 107
anti-APO-1-treated (10 min) SKW6.4 cells as described in Fig. 3
(left). FLICE was immunoprecipitated from 107
anti-APO-1-treated (30 min) SKW6.4 cells using the anti-FLICE-N antibody (right). Both immunoprecipitates were subjected to
two-dimensional gel electrophoresis and immunoblotted with the
anti-FLICE mAb N2. Migration positions of the full-length proteins
(caspase-8/a and 8/b), the cleavage intermediates (p43 and p41), and
the cleaved prodomains, which are identical to the recently described
new DISC components CAP5 and CAP6 (13), are indicated by
arrowheads.
[View Larger Version of this Image (48K GIF file)]
We have recently described two novel DISC components CAP5 and CAP6 representing the prodomain of FLICE after proteolytic activation (13). To test whether these new DISC components represent the two prodomains of the expressed FLICE isoforms we analyzed the DISC in a two-dimensional Western blot using the N2 anti-FLICE mAb. The p26 and p24 cleavage products comigrated with CAP5 and CAP6, respectively (Fig. 5B and data not shown). Only CAP5 was precipitated by the anti-FLICE-N antibody, confirming that CAP6 represents the prodomain of caspase-8/b that does not contain the epitope recognized by anti-FLICE-N, whereas CAP5 represents the prodomain of caspase-8/a.
Because both FLICE isoforms were recruited to and activated by the CD95
DISC, we tested next whether they showed any differences in cleavage
kinetics. Therefore, we analyzed the cleavage of caspase-8/a and 8/b at
the DISC level and in the cytosol at various time points after CD95
stimulation. Consistent with the fast kinetics of CD95-mediated apoptosis both isoforms were recruited to the DISC within 10 s (Fig. 6A). Also after 10 s the two cleavage intermediates p43 and p41 as well as the prodomain
cleavage products p26 and p24 were detectable in the DISC. In the
cytosol all the FLICE cleavage products p26, p24, p18, and p10 were
detectable as early as 10 s after activation (Fig. 6B).
The cleavage products p26 and p24 as a readout for the activation of
caspase-8/a and 8/b, respectively, increased in the cytosol during
stimulation with identical kinetics, demonstrating that both isoforms
were activated simultaneously. Interestingly, at the DISC level there
was only a slight increase in the p26 and p24 cleavage products
starting after 10 min when the amount of full-length FLICE began to
decline (Fig. 6A). This suggests that there is only a
limited capacity of the DISC to bind death effector domain-containing
proteins. Notably, FLICE cleavage at the DISC level preceded cleavage
in the cytosol, confirming that FLICE turnover takes place at the DISC
level where all cytosolic FLICE is processed (Fig. 6B and
Ref. 13). Taken together, our data show that only two different
isoforms of caspase-8 are expressed as proteins and that both are
activated simultaneously upon CD95 triggering.
Fig. 6. Both FLICE isoforms are cleaved by the CD95 DISC with identical kinetics. A, kinetics of FLICE cleavage at the DISC level. The CD95 DISC was immunoprecipitated from 5 × 106 untreated (0) or anti-APO-1-treated SKW6.4 cells as described in Fig. 3. FLICE cleavage was determined by Western blot analysis with the N2 mAb. B, kinetics of FLICE cleavage in the cytoplasm. The Lysates from A equivalent to 106 SKW6.4 cells were analyzed by immunoblotting with the anti-FLICE mAbs N2 directed against the prodomain (top and second panel), C15 directed against the p18 subunit (third panel), and C5 directed against the p10 subunit (bottom panel).
[View Larger Version of this Image (32K GIF file)]
DISCUSSION
Signal transduction through the CD95 receptor has been shown to involve activation of caspases. Recently, a new member of this family of cysteine proteases, FLICE (MACH/MCH5/caspase-8) was cloned (9, 10) that was identified to be recruited to the CD95 receptor in a stimulation-dependent manner (8, 4). Therefore, FLICE is the most upstream caspase in the CD95-induced apoptotic pathway. Several different isoforms of caspase-8 have been described as cDNA clones that were identified either by yeast two-hybrid screening (9) or by data base search for homologous expressed sequence tag sequences (10). Originally, only FLICE (caspase-8/a) was shown to be expressed on the protein level, because it was cloned by purification of a protein, CAP4, that specifically associated with the CD95 DISC (8, 4). To test if any of the other caspase-8 isoforms were expressed on the protein level, we developed specific anti-FLICE mAbs covering all different functional domains of FLICE. Only one of the described isoforms (caspase-8/e) was not expected to be detectable by these mAbs (Fig. 3 and Table I). However, such a truncated version of caspase-8 may not have a physiological function. Using the anti-FLICE mAbs we now demonstrate that only two caspase-8 isoforms are expressed at detectable levels in a number of different cell lines. Interestingly, the Burkitt lymphoma line Raji also expressed only these two isoforms as protein, although five different caspase-8 mRNA species were cloned from this cell line (9).
Both expressed caspase-8 isoforms were recruited to the CD95 receptor
in an activation-dependent manner. By comparison of the
two-dimensional Western blot with immunoprecipitated DISC from
35S-labeled cells, we could confirm that the expressed
caspase-8 isoform of 55 kDa corresponds to FLICE (caspase-8/a,
MACH1), originally described as CAP4 (4). We identified the second expressed caspase-8 isoform as caspase8/b (MACH2), because this protein could not be immunoprecipitated by the rabbit anti-peptide antibody anti-FLICE-N directed against a box of 15 amino acids not
present in caspase-8/b (MACH2).
Different caspase-8 isoforms have been suggested to function as
modulators of the activation of caspase-8 in CD95- or TNF-induced apoptosis (9). Caspase-8/c (MACH3) has been demonstrated to protect
against CD95- and TNF-induced apoptosis, whereas caspase-8/d (MACH1) was suggested to enhance the cytotoxic activity of the active caspase-8 isoforms (caspase-8/a and 8/b) (9). However, none of
these isoforms were detected by the anti-FLICE mAbs in significant
amounts in any of the cell lines tested. Whether both expressed active
isoforms caspase-8/a and 8/b have different functions remains to be
determined. The fact that both were expressed in a one to one ratio in
all cell lines tested as well as the identical CD95-induced activation
kinetics suggests the possibility that both isoforms are necessary in
equal amounts for the signal transduction of the CD95 receptor.
Recently, the number of apoptosis-inducing receptors has increased. The fact that FLICE was expressed in almost every cell line, some of which do not have the CD95 receptor or do not respond to CD95 triggering, raises the possibility that FLICE is also utilized by the signaling pathways of the other "death receptors" such as TNF receptor 1, DR3 (APO-3/TRAMP/Wsl-1/LARD), or DR4 (TRAILR) (3). Future studies should clarify the involvement of the different caspase-8 isoforms in other cell death signaling pathways.
FOOTNOTES
To whom correspondence should be addressed.
1 The abbreviations used are: TNF, tumor necrosis factor; CAP, cytotoxicitydependent APO-1-associated proteins; caspase, cysteine aspartic acid-specific protease; ICE, interleukin-1
-converting enzyme; GST, glutathione
S-transferase; DISC, death-inducing signaling complex; mAb,
monoclonal antibody; PAGE, polyacrylamide gel electrophoresis; PBS,
phosphate-buffered saline; CHAPS,
3-[cyclohexylamino]-1-propanesulfonic acid.
ACKNOWLEDGEMENTS
We are grateful to Renata Zucic and Uschi Silberzahn for expert technical assistance.
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A. Algeciras-Schimnich, L. Shen, B. C. Barnhart, A. E. Murmann, J. K. Burkhardt, and M. E. Peter Molecular Ordering of the Initial Signaling Events of CD95 Mol. Cell. Biol., January 1, 2002; 22(1): 207 - 220. [Abstract] [Full Text] [PDF]
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C. A. Martin and A. Panja Cytokine regulation of human intestinal primary epithelial cell susceptibility to Fas-mediated apoptosis Am J Physiol Gastrointest Liver Physiol, January 1, 2002; 282(1): G92 - G104. [Abstract] [Full Text] [PDF]
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F. C. Kischkel, D. A. Lawrence, A. Tinel, H. LeBlanc, A. Virmani, P. Schow, A. Gazdar, J. Blenis, D. Arnott, and A. Ashkenazi Death Receptor Recruitment of Endogenous Caspase-10 and Apoptosis Initiation in the Absence of Caspase-8 J. Biol. Chem., November 30, 2001; 276(49): 46639 - 46646. [Abstract] [Full Text] [PDF]
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K. Stahnke, S. Fulda, C. Friesen, G. Strau{beta}, and K.-M. Debatin Activation of apoptosis pathways in peripheral blood lymphocytes by in vivo chemotherapy Blood, November 15, 2001; 98(10): 3066 - 3073. [Abstract] [Full Text] [PDF]
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D. Chatterjee, I. Schmitz, A. Krueger, K. Yeung, S. Kirchhoff, P. H. Krammer, M. E. Peter, J. H. Wyche, and P. Pantazis Induction of Apoptosis in 9-Nitrocamptothecin-treated DU145 Human Prostate Carcinoma Cells Correlates with de Novo Synthesis of CD95 and CD95 Ligand and Down-Regulation of c-FLIPshort Cancer Res., October 1, 2001; 61(19): 7148 - 7154. [Abstract] [Full Text] [PDF]
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G. Dewson, G. M. Cohen, and A. J. Wardlaw Interleukin-5 inhibits translocation of Bax to the mitochondria, cytochrome c release, and activation of caspases in human eosinophils Blood, October 1, 2001; 98(7): 2239 - 2247. [Abstract] [Full Text] [PDF]
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V. M. Dirsch, H. Stuppner, and A. M. Vollmar Helenalin Triggers a CD95 Death Receptor-independent Apoptosis That Is Not Affected by Overexpression of Bcl-xL or Bcl-2 Cancer Res., August 1, 2001; 61(15): 5817 - 5823. [Abstract] [Full Text] [PDF]
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V. Poulaki, N. Mitsiades, M. E. Romero, and M. Tsokos Fas-mediated Apoptosis in Neuroblastoma Requires Mitochondrial Activation and Is Inhibited by FLICE Inhibitor Protein and bcl-2 Cancer Res., June 1, 2001; 61(12): 4864 - 4872. [Abstract] [Full Text] [PDF]
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A. S. Varadhachary, M. Edidin, A. M. Hanlon, M. E. Peter, P. H. Krammer, and P. Salgame Phosphatidylinositol 3'-Kinase Blocks CD95 Aggregation and Caspase-8 Cleavage at the Death-Inducing Signaling Complex by Modulating Lateral Diffusion of CD95 J. Immunol., June 1, 2001; 166(11): 6564 - 6569. [Abstract] [Full Text] [PDF]
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 S. R. White, P. Williams, K. R. Wojcik, S. Sun, P. S. Hiemstra, K. F. Rabe, and D. R. Dorscheid Initiation of Apoptosis by Actin Cytoskeletal Derangement in Human Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., March 1, 2001; 24(3): 282 - 294. [Abstract] [Full Text] [PDF]
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A. Hennino, M. Berard, P. H. Krammer, and T. Defrance FLICE-inhibitory Protein Is a Key Regulator of Germinal Center B Cell Apoptosis J. Exp. Med., February 12, 2001; 193(4): 447 - 458. [Abstract] [Full Text] [PDF]
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N. Droin, M. Beauchemin, E. Solary, and R. Bertrand Identification of a Caspase-2 Isoform that Behaves as an Endogenous Inhibitor of the Caspase Cascade Cancer Res., December 1, 2000; 60(24): 7039 - 7047. [Abstract] [Full Text]
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S. Kirchhoff, W. W. Muller, A. Krueger, I. Schmitz, and P. H. Krammer TCR-Mediated Up-Regulation of c-FLIPshort Correlates with Resistance Toward CD95-Mediated Apoptosis by Blocking Death-Inducing Signaling Complex Activity J. Immunol., December 1, 2000; 165(11): 6293 - 6300. [Abstract] [Full Text] [PDF]
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P. A. Svingen, J. E. Karp, S. Krajewski, P. W. Mesner Jr, S. D. Gore, P. J. Burke, J. C. Reed, Y. A. Lazebnik, and S. H. Kaufmann Evaluation of Apaf-1 and procaspases-2, -3, -7, -8, and -9 as potential prognostic markers in acute leukemia Blood, December 1, 2000; 96(12): 3922 - 3931. [Abstract] [Full Text] [PDF]
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A. D. Badley, A. A. Pilon, A. Landay, and D. H. Lynch Mechanisms of HIV-associated lymphocyte apoptosis Blood, November 1, 2000; 96(9): 2951 - 2964. [Abstract] [Full Text] [PDF]
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 B. B Aggarwal Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappa B Ann Rheum Dis, November 1, 2000; 59(90001): i6 - 16. [Abstract] [Full Text] [PDF]
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A. Hennino, M. Berard, M. Casamayor-Palleja, P. H. Krammer, and T. Defrance Regulation of the Fas Death Pathway by FLICE-Inhibitory Protein in Primary Human B Cells J. Immunol., September 15, 2000; 165(6): 3023 - 3030. [Abstract] [Full Text] [PDF]
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G. J. Inman and M. J. Allday Apoptosis Induced by TGF-{beta}1 in Burkitt's Lymphoma Cells Is Caspase 8 Dependent But Is Death Receptor Independent J. Immunol., September 1, 2000; 165(5): 2500 - 2510. [Abstract] [Full Text] [PDF]
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A. H. Stegh, H. Herrmann, S. Lampel, D. Weisenberger, K. Andrä, M. Seper, G. Wiche, P. H. Krammer, and M. E. Peter Identification of the Cytolinker Plectin as a Major Early In Vivo Substrate for Caspase 8 during CD95- and Tumor Necrosis Factor Receptor-Mediated Apoptosis Mol. Cell. Biol., August 1, 2000; 20(15): 5665 - 5679. [Abstract] [Full Text]
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 S. Zhuang and G. Simon Peroxynitrite-induced apoptosis involves activation of multiple caspases in HL-60 cells Am J Physiol Cell Physiol, August 1, 2000; 279(2): C341 - C351. [Abstract] [Full Text] [PDF]
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S. Fulda, E. Meyer, and K.-M. Debatin Metabolic Inhibitors Sensitize for CD95 (APO-1/Fas)-induced Apoptosis by Down-Regulating Fas-associated Death Domain-like Interleukin 1-Converting Enzyme Inhibitory Protein Expression Cancer Res., July 1, 2000; 60(14): 3947 - 3956. [Abstract] [Full Text]
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C. Beltinger, S. Fulda, T. Kammertoens, W. Uckert, and K.-M. Debatin Mitochondrial Amplification of Death Signals Determines Thymidine Kinase/Ganciclovir-triggered Activation of Apoptosis Cancer Res., June 1, 2000; 60(12): 3212 - 3217. [Abstract] [Full Text]
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S. Gehring, S. Rottmann, A. R. Menkel, J. Mertsching, A. Krippner-Heidenreich, and B. Luscher Inhibition of Proliferation and Apoptosis by the Transcriptional Repressor Mad1. REPRESSION OF Fas-INDUCED CASPASE-8 ACTIVATION J. Biol. Chem., March 31, 2000; 275(14): 10413 - 10420. [Abstract] [Full Text] [PDF]
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D. Tang, J. M. Lahti, and V. J. Kidd Caspase-8 Activation and Bid Cleavage Contribute to MCF7 Cellular Execution in a Caspase-3-dependent Manner during Staurosporine-mediated Apoptosis J. Biol. Chem., March 24, 2000; 275(13): 9303 - 9307. [Abstract] [Full Text] [PDF]
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 M. MacFarlane, W. Merrison, D. Dinsdale, and G. M. Cohen Active Caspases and Cleaved Cytokeratins Are Sequestered into Cytoplasmic Inclusions in TRAIL-induced Apoptosis J. Cell Biol., March 20, 2000; 148(6): 1239 - 1254. [Abstract] [Full Text] [PDF]
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K. Kimura and E. P. Gelmann Tumor Necrosis Factor-alpha and Fas Activate Complementary Fas-associated Death Domain-dependent Pathways That Enhance Apoptosis Induced by gamma -Irradiation J. Biol. Chem., March 17, 2000; 275(12): 8610 - 8617. [Abstract] [Full Text] [PDF]
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C. Grullich, M. C. Sullards, Z. Fuks, A. H. Merrill Jr., and R. Kolesnick CD95(Fas/APO-1) Signals Ceramide Generation Independent of the Effector Stage of Apoptosis J. Biol. Chem., March 17, 2000; 275(12): 8650 - 8656. [Abstract] [Full Text] [PDF]
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T. E. Witzig, M. Timm, M. Stenson, P. A. Svingen, and S. H. Kaufmann Induction of Apoptosis in Malignant B Cells by Phenylbutyrate or Phenylacetate in Combination with Chemotherapeutic Agents Clin. Cancer Res., February 1, 2000; 6(2): 681 - 692. [Abstract] [Full Text]
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C. Scaffidi, J. Volkland, I. Blomberg, I. Hoffmann, P. H. Krammer, and M. E. Peter Phosphorylation of FADD/ MORT1 at Serine 194 and Association with a 70-kDa Cell Cycle-Regulated Protein Kinase J. Immunol., February 1, 2000; 164(3): 1236 - 1242. [Abstract] [Full Text] [PDF]
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S. Fulda, G. Strauss, E. Meyer, and K.-M. Debatin Functional CD95 ligand and CD95 death-inducing signaling complex in activation-induced cell death and doxorubicin-induced apoptosis in leukemic T cells Blood, January 1, 2000; 95(1): 301 - 308. [Abstract] [Full Text] [PDF]
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A. Kawakami, T. Nakashima, H. Sakai, S. Urayama, S. Yamasaki, A. Hida, M. Tsuboi, H. Nakamura, H. Ida, K. Migita, et al. Inhibition of Caspase Cascade by HTLV-I Tax Through Induction of NF-kappa B Nuclear Translocation Blood, December 1, 1999; 94(11): 3847 - 3854. [Abstract] [Full Text] [PDF]
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C. Raoul, C. E. Henderson, and B. Pettmann Programmed Cell Death of Embryonic Motoneurons Triggered through the Fas Death Receptor J. Cell Biol., November 29, 1999; 147(5): 1049 - 1062. [Abstract] [Full Text] [PDF]
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O. Cuvillier, E. Mayhew, A. S. Janoff, and S. Spiegel Liposomal ET-18-OCH3 Induces Cytochrome c-Mediated Apoptosis Independently of CD95 (APO-1/Fas) Signaling Blood, November 15, 1999; 94(10): 3583 - 3592. [Abstract] [Full Text] [PDF]
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A. S. Varadhachary, M. E. Peter, S. N. Perdow, P. H. Krammer, and P. Salgame Selective Up-Regulation of Phosphatidylinositol 3'-Kinase Activity in Th2 Cells Inhibits Caspase-8 Cleavage at the Death-Inducing Complex: A Mechanism for Th2 Resistance from Fas-Mediated Apoptosis J. Immunol., November 1, 1999; 163(9): 4772 - 4779. [Abstract] [Full Text] [PDF]
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C. Scaffidi, I. Schmitz, J. Zha, S. J. Korsmeyer, P. H. Krammer, and M. E. Peter Differential Modulation of Apoptosis Sensitivity in CD95 Type I and Type II Cells J. Biol. Chem., August 6, 1999; 274(32): 22532 - 22538. [Abstract] [Full Text] [PDF]
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C. Beltinger, S. Fulda, T. Kammertoens, E. Meyer, W. Uckert, and K.-M. Debatin Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases PNAS, July 20, 1999; 96(15): 8699 - 8704. [Abstract] [Full Text] [PDF]
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C. Dai and S. B. Krantz Interferon {gamma} Induces Upregulation and Activation of Caspases 1, 3, and 8 to Produce Apoptosis in Human Erythroid Progenitor Cells Blood, May 15, 1999; 93(10): 3309 - 3316. [Abstract] [Full Text] [PDF]
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H. Bantel, I. H. Engels, W. Voelter, K. Schulze-Osthoff, and S. Wesselborg Mistletoe Lectin Activates Caspase-8/FLICE Independently of Death Receptor Signaling and Enhances Anticancer Drug-induced Apoptosis Cancer Res., May 1, 1999; 59(9): 2083 - 2090. [Abstract] [Full Text] [PDF]
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S. Wesselborg, I. H. Engels, E. Rossmann, M. Los, and K. Schulze-Osthoff Anticancer Drugs Induce Caspase-8/FLICE Activation and Apoptosis in the Absence of CD95 Receptor/Ligand Interaction Blood, May 1, 1999; 93(9): 3053 - 3063. [Abstract] [Full Text] [PDF]
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D. A. Martin, L. Zheng, R. M. Siegel, B. Huang, G. H. Fisher, J. Wang, C. E. Jackson, J. M. Puck, J. Dale, S. E. Straus, et al. Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia PNAS, April 13, 1999; 96(8): 4552 - 4557. [Abstract] [Full Text] [PDF]
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D. Tang, J. M. Lahti, J. Grenet, and V. J. Kidd Cycloheximide-induced T-cell Death Is Mediated by a Fas-associated Death Domain-dependent Mechanism J. Biol. Chem., March 12, 1999; 274(11): 7245 - 7252. [Abstract] [Full Text] [PDF]
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K. Ozawa, K. Kuwabara, M. Tamatani, K. Takatsuji, Y. Tsukamoto, S. Kaneda, H. Yanagi, D. M. Stern, Y. Eguchi, Y. Tsujimoto, et al. 150-kDa Oxygen-regulated Protein (ORP150) Suppresses Hypoxia-induced Apoptotic Cell Death J. Biol. Chem., March 5, 1999; 274(10): 6397 - 6404. [Abstract] [Full Text] [PDF]
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X.-M. Sun, M. MacFarlane, J. Zhuang, B. B. Wolf, D. R. Green, and G. M. Cohen Distinct Caspase Cascades Are Initiated in Receptor-mediated and Chemical-induced Apoptosis J. Biol. Chem., February 19, 1999; 274(8): 5053 - 5060. [Abstract] [Full Text] [PDF]
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K. Banki, E. Hutter, N. J. Gonchoroff, and A. Perl Elevation of Mitochondrial Transmembrane Potential and Reactive Oxygen Intermediate Levels Are Early Events and Occur Independently from Activation of Caspases in Fas Signaling J. Immunol., February 1, 1999; 162(3): 1466 - 1479. [Abstract] [Full Text] [PDF]
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C. Scaffidi, I. Schmitz, P. H. Krammer, and M. E. Peter The Role of c-FLIP in Modulation of CD95-induced Apoptosis J. Biol. Chem., January 15, 1999; 274(3): 1541 - 1548. [Abstract] [Full Text] [PDF]
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S. Fulda, C. Scaffidi, S. A. Susin, P. H. Krammer, G. Kroemer, M. E. Peter, and K.-M. Debatin Activation of Mitochondria and Release of Mitochondrial Apoptogenic Factors by Betulinic Acid J. Biol. Chem., December 18, 1998; 273(51): 33942 - 33948. [Abstract] [Full Text] [PDF]
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H. O. Fearnhead, J. Rodriguez, E.-E. Govek, W. Guo, R. Kobayashi, G. Hannon, and Y. A. Lazebnik Oncogene-dependent apoptosis is mediated by caspase-9 PNAS, November 10, 1998; 95(23): 13664 - 13669. [Abstract] [Full Text] [PDF]
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D. Ferrari, A. Stepczynska, M. Los, S. Wesselborg, and K. Schulze-Osthoff Differential Regulation and ATP Requirement for Caspase-8 and Caspase-3 Activation during CD95- and Anticancer Drug-induced Apoptosis J. Exp. Med., September 7, 1998; 188(5): 979 - 984. [Abstract] [Full Text] [PDF]
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K. Chlichlia, M. E. Peter, M. Rocha, C. Scaffidi, M. Bucur, P. H. Krammer, V. Schirrmacher, and V. Umansky Caspase Activation Is Required for Nitric Oxide-Mediated, CD95(APO-1/Fas)-Dependent and Independent Apoptosis in Human Neoplastic Lymphoid Cells Blood, June 1, 1998; 91(11): 4311 - 4320. [Abstract] [Full Text] [PDF]
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R. Schwandner, K. Wiegmann, K. Bernardo, D. Kreder, and M. Kronke TNF Receptor Death Domain-associated Proteins TRADD and FADD Signal Activation of Acid Sphingomyelinase J. Biol. Chem., March 6, 1998; 273(10): 5916 - 5922. [Abstract] [Full Text] [PDF]
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J. P. Medema, C. Scaffidi, P. H. Krammer, and M. E. Peter Bcl-xL Acts Downstream of Caspase-8 Activation by the CD95 Death-inducing Signaling Complex J. Biol. Chem., February 6, 1998; 273(6): 3388 - 3393. [Abstract] [Full Text] [PDF]
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O. Cuvillier, L. Edsall, and S. Spiegel Involvement of Sphingosine in Mitochondria-dependent Fas-induced Apoptosis of Type II Jurkat T Cells J. Biol. Chem., May 19, 2000; 275(21): 15691 - 15700. [Abstract] [Full Text] [PDF]
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