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J. Biol. Chem., Vol. 276, Issue 35, 32585-32590, August 31, 2001
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From the
Received for publication, January 17, 2001, and in revised form, May 25, 2001
Fas, a death domain-containing member of the
tumor necrosis factor receptor family and its ligand FasL have
been predominantly studied with respect to their capability to induce
cell death. However, a few studies indicate a
proliferation-inducing signaling activity of these molecules too. We
describe here a novel signaling pathway of FasL and the tumor
necrosis factor-related apoptosis-inducing ligand (TRAIL) that
triggers transcriptional activation of the proto-oncogene
c-fos, a typical target gene of mitogenic pathways. FasL- and TRAIL-mediated up-regulation of c-Fos was completely dependent on the presence of Fas-associated death domain protein (FADD)
and caspase-8, but caspase activity seemed to be dispensable as a pan
inhibitor of caspases had no inhibitory effect. Upon overexpression of the long splice form of cellular FADD-like
interleukin-1-converting enzyme (FLICE) inhibitory protein (cFLIP) in
Jurkat cells, FasL- and TRAIL-induced up-regulation of c-Fos was almost
completely blocked. The short splice form of FLIP, however, showed a
rather stimulatory effect on c-Fos induction. Together these data
demonstrate the existence of a death receptor-induced, FADD- and
caspase-8-dependent pathway leading to c-Fos induction that is
inhibited by the long splice form FLIP-L.
Fas ligand (FasL)1 and
its receptor Fas are prototypic members of the tumor necrosis factor
(TNF) ligand family and the death domain-containing receptor subgroup
of the TNF receptor superfamily, respectively. Fas and FasL have been
predominately investigated in respect to their death-inducing
capabilities. For example, Fas and FasL are involved in T-cell mediated
cytotoxicity (1, 2), apoptosis induction in activated lymphocytes
(3-6), and maintainance of the immunoprivileged state of eyes and
testis (7, 8). Consequently mouse strains bearing loss of function mutations in FasL (gld) or Fas (lpr) show
lymphoproliferation, lymphadenopathy, and production of autoimmune
antibodies (9, 10). Similarly many forms of the human autoimmune
lymphoproliferative syndrome are caused by dominant interfering Fas or
FasL gene mutations (11-13).
The molecular mechanisms of Fas/FasL-induced apoptosis have been
studied in detail during the last years. The initial event of
FasL-induced apoptosis is the multimerization of Fas by the membrane-bound form of its ligand. This receptor oligomerization leads
to the formation of a death-inducing signaling complex comprising the
adaptor molecule FADD/MORT, which binds with its C-terminal death
domain to the death domain of Fas, and the FADD-interacting initiator
caspase-8, which interacts with the N-terminal death effector domain
(DED) of FADD via its own DEDs (14). The death-inducing signaling
complex-induced proximity of procaspase-8 molecules leads to
autoproteolytic activation and initiation of the apoptotic caspase
cascade (15). This process, however, can be inhibited by FLICE
inhibitory protein (FLIP) (16), also designated as casper (17), CLARP
(18), FLAME-1 (19), I-FLICE (20), CASH (21), MRIT (22), or ursupin
(23). FLIP exists in two splice forms: FLIP-long (FLIP-L) comprising
two N-terminal DEDs and an enzymatically inactive pseudo caspase domain
and FLIP-short (FLIP-S) containing only the two DEDs. Both splice forms
of FLIP seem to act as dominant negative molecules in respect to
Fas-mediated caspase-8 processing at an intermediate state (24).
Although the apoptotic features of the FasL/Fas system are well
established, there is now also increasing evidence for functions that
are not related to induction of apoptosis such as activation of NF- Antibodies and Reagents--
Chemicals and secondary antibodies
were obtained from Sigma, and cell culture reagents were from Life
Technologies, Inc. The Jurkat T-cell lines that are deficient for FADD
and caspase-8 and the respective parental control cell line as well as
Jurkat clones overexpressing FLIP-L and FLIP-S, respectively, were
described elsewhere (16, 32, 33). An additional Jurkat clone (JB-6) deficient in caspase-8 expression was a kind gift from Shigekazu Nagata
(Osaka University Medical School, Osaka, Japan). All Jurkat clones were
maintained in RPMI 1640 medium containing 10% heat-inactivated fetal
calf serum in a humidified 5.0% CO2 environment. The
caspase-8-specific mAb was a gift from Klaus Schulze-Osthoff
(Universität Münster, Münster, Germany). The broad
spectrum caspase inhibitor
benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk) was
purchased from Bachem (Heidelberg, Germany). The anti-FLIP rat mAb
Dave-2 was from Apotech (Lausanne, Switzerland), and the anti-c-Fos
polyclonal rabbit IgG was from Santa Cruz Biotechnology (Heidelberg, Germany).
RNase Protection Assay--
Jurkat cells (10 × 106) were treated with the indicated reagents for the given
times, and total RNAs were isolated with the RNA INSTAPURE kit
(Eurogentech, Seraing, Belgium) according to the manufacturer's
recommendations. The presence of transcripts of the indicated
apoptosis-related genes as well as the internal controls L32 and
glyceraldehyde-3-phosphate dehydrogenase were analyzed using a
custom Multi-Probe template set (PharMingen, Hamburg, Germany).
Probe synthesis, hybridization, and RNase treatment were performed with
the RiboQuant Multi-Probe RNase Protection Assay System (PharMingen).
Protected transcripts were resolved by electrophoresis on denaturing
polyacrylamide gels (5%) and visualized on a PhosphorImager with the
ImageQuant software (Molecular Dynamics, Sunnyvale, CA).
Western Blotting of Caspase-8, cFLIP, and c-Fos--
For Western
blot analysis of caspase-8 and FLIP lysates were prepared in
radioimmune precipitation buffer supplemented with a protease inhibitor
mixture stock solution (Roche Molecular Biochemicals) as recommended by
the supplier. Cell debris was removed by centrifugation (10,000 × g, 10 min), and the protein concentration was determined by
the Bradford assay. For detection of c-Fos protein nuclear extracts
were prepared as described elsewhere (26) for electrophoretic mobility
shift assay analysis. Proteins (50 µg) were resolved by
SDS-polyacrylamide gel electrophoresis and transferred to
nitrocellulose membranes by electroblotting. Blots were blocked for
1 h at room temperature in Tris-buffered saline containing 0.05%
Tween 20 and 3% (w/v) dry milk, washed, and incubated with
anti-caspase-8 mouse mAb, anti-FLIP rat mAb Dave-2 (Apotech, Epalinges,
Switzerland) or anti-c-Fos rabbit IgG (Santa Cruz Biotechnology,
Heidelberg, Germany) for 1 h at room temperature. Bound antibodies
were visualized with alkaline phosphatase-conjugated goat
anti-mouse/rat/rabbit IgG (Sigma) and nitro blue tetrazolium and
5-bromo-4-chloro-3-indolyl phosphate as substrate.
Immunocomplex JNK Assay--
c-Jun N-terminal kinase assays were
performed using an anti-JNK1 rabbit antiserum for immunoprecipitation
(Santa Cruz Biotechnology) and glutathione
S-transferase-c-Jun as substrate. The in vitro kinase assay has been described elsewhere (34).
In Vitro Caspase-3 Activity Assay--
Caspase-3 activity was
measured in caspase activity assay buffer (30 mM HEPES, pH
7.5, 10 mM CaCl2, 5 mM
dithiothreitol, 10% sucrose) with 20 µM Ac-DEVD-AMC
(Calbiochem) as substrate. Activity was measured with a luminescence
spectrometer (Aminco-Bowman Series2) with excitation at 380 nm and
emission at 450 nm. Specificity of caspase-dependent
Ac-DEVD-AMC cleavage was regularly controlled with the caspase
inhibitors z-VAD-fmk and DEVD-fmk.
Activating Protein-1 (AP-1) Reporter Gene Assays--
For
monitoring AP-1 activity in transiently transfected Jurkat cells,
5 × 106 cells were electroporated (250 V, 1800 microfarad) with 30 µg of a AP-1-driven luciferase reporter gene
plasmid (pAP1-Luc, Stratagene, Amsterdam, Netherlands). After 1 day of
recovery, the cells were stimulated for 8 h with cross-linked FasL
in the presence of z-VAD-fmk or phorbol 12-myristate 13-acetate,
harvested in phosphate-buffered saline, and lysed in luciferase lysis
buffer (Promega, Mannheim, Germany), and finally luciferase activity
was determined using a Lucy2 96-well luminometer (Anthos, Krefeld, Germany).
Recent studies of FADD-deficient mice (35) or transgenic mice
overexpressing a dominant-negative deletion mutant of FADD lacking its
N-terminal DED (36-38) showed unexpectedly that mitogen or T-cell
receptor-induced proliferation of T-cells in vitro was impaired. Because FADD is involved in death receptor signaling and
T-cell receptor stimulation induces up-regulation of FasL (14) and
TRAIL (39), we have asked here whether Fas or TRAIL receptors might be
engaged in the mitogenic signaling pathways of T-cells. A potential
role of Fas in mitogenic signaling pathways was also suggested from
reports demonstrating Fas-dependent proliferation of
fibroblasts (28-30). We have analyzed the expression of the early
mitogenic response marker c-Fos in Jurkat T-cells upon TRAIL and FasL
stimulation using RNase protection analysis assays with a Multi-Probe
template set containing apoptosis- and proliferation-related templates
including c-Fos. FasL induced c-Fos mRNA in a
dose-dependent manner in Jurkat cells (Fig.
1A). Induction of c-Fos was
independent from the activation of caspase-8 and the subsequent
triggering of the apoptotic machinery because the pan caspase-inhibitor
z-VAD-fmk had no inhibitory effect on FasL-induced up-regulation of
c-Fos (Fig. 1B) at concentrations at which processing of
procaspase-8 and activation of caspase-3 were completely blocked (Fig.
1D). Up-regulation of c-Fos mRNA by the well known
potent c-Fos inducer phorbol 12-myristate 13-acetate was readily
detectable already after 30 min, peaked after 1 h, and reached
almost background levels after 3 h (data not shown). In contrast,
FasL-induced up-regulation of c-Fos occurred with delayed kinetics,
starting to become detectable after 1 h and reaching a plateau
after 6 h (Fig. 1C). Maximal phorbol 12-myristate
13-acetate-induced c-Fos mRNA levels were 5 times higher than
maximal mRNA levels induced by FasL (Fig. 1E).
Similarly, maximal c-Fos protein induced by phorbol 12-myristate 13-acetate was 5.5 times higher than maximal c-Fos protein induced by
FasL (Fig. 1E). However, one should take into account that prolonged FasL-induced up-regulation of c-Fos might have another quality compared with the rapid transient up-regulation by phorbol 12-myristate 13-acetate.
Some recent reports have demonstrated the capability of Fas to induce
NF- FADD and caspase-8 are essential components of the ligand-induced Fas
receptor-signaling complex (14). We have further analyzed FasL-induced
up-regulation of c-Fos in Jurkat clones deficient in these molecules
(32, 33, 41). In two independent FADD-deficient Jurkat clones we found
no significant c-Fos up-regulation upon treatment with FasL (Fig.
2A and data not shown).
Moreover, caspase-8-deficient Jurkat clones were also found to be
deficient in FasL-induced up-regulation of c-Fos (Fig. 2B
and data not shown). In two clones, we observed that induction of c-Fos
by phorbol ester was unaffected (data not shown). Because the pan
caspase-inhibitor z-VAD-fmk had no effect on FasL-induced up-regulation
of c-Fos but in parallel the lack of caspase-8 completely prevented
this event, our data point to a signaling function of caspase-8 that is
independent from its proteolytic activity. A function of caspase-8 to
act as a signal-transducing molecule independent of its role as an effector caspase of the apoptotic program was also observed in two
recent studies that demonstrated activation of the NF-
Fas-associated Death Domain Protein (FADD) and Caspase-8 Mediate
Up-regulation of c-Fos by Fas Ligand and Tumor Necrosis Factor-related
Apoptosis-inducing Ligand (TRAIL) via a FLICE Inhibitory Protein
(FLIP)-regulated Pathway*
,,
,,,, and
Institute of Cell Biology and Immunology,
University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany,
§ Apotech Biochemicals Ltd., Ch. des Croisettes 22, 1066 Epalinges, Switzerland, the ¶ Department of Molecular and Cellular
Biology, University of California, Berkeley, California 94720, the
Institute of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland, and the ** Department of Cell Biology, Harvard
Medical School, Boston, Massachusetts 02115
ABSTRACT
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
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INTRODUCTION
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
B and c-Jun N-terminal kinase (JNK) (25-27) or induction of
proliferation (28-30) and differentiation (31). We show here that
stimulation of Jurkat T-cells with FasL or the closely related
TNF-related apoptosis-inducing ligand (TRAIL) leads to up-regulation of
the proto-oncogene c-fos, a target gene of mitogenic
stimuli. The FasL/TRAIL-induced up-regulation of c-Fos is regulated by
FLIP and requires FADD and caspase-8, but the protease activity of the
latter is dispensable.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
RESULTS AND DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
View larger version (44K):
[in a new window]
Fig. 1.
c-Fos is up-regulated by FasL independently
of activation of NF- B and JNK.
A-C, Jurkat cells were treated as indicated with
soluble FasL cross-linked with FLAG-specific mAb M2 (1 µg/ml) and
z-VAD-fmk (Z; 10 µM). If not otherwise stated
300 ng/ml FasL were used for 6 h. Total RNAs were isolated for
RNase protection analysis, and 10 µg of each RNA sample were analyzed
with a custom Multi-Probe template set to detect the indicated
mRNAs. L32 and glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) were included in each template set as internal
controls. D, Jurkat cells were treated with cross-linked
FasL (100 ng/ml) for the indicated time in the absence or presence of
z-VAD-fmk. Cells were lysed in radioimmune precipitation buffer, and
proteins were immunoblotted with a caspase-8-specific mAb to detect
cleavage of procaspase-8 that is indicative of activation of this
enzyme. In parallel cell lysates (30 µg) were assayed for caspase-3
activity using the fluorogenic substrate Ac-DEVD-AMC (20 µM). E, Jurkat cells were stimulated for
6 h with cross-linked (1 µg/ml M2) soluble FasL (300 ng/ml) in
the presence of z-VAD-fmk (Z; 10 µM) or with
100 nM phorbol 12-myristate 13-acetate (P) or
remained untreated. Nuclear extracts were prepared, and proteins were immunoblotted
with anti-c-Fos antibody (Santa Cruz Biotechnology). The relative
protein expression levels were determined with the Bio Profil software
(Vilber Lourmat, Torcy, France). Alternatively, total RNAs were
isolated for RNase protection analysis, and 10 µg of each RNA sample
were analyzed with a custom Multi-Probe template set to detect the
indicated mRNAs. L32 and glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) were included in each template set as internal
controls. The indicated relative expression levels of c-Fos were
already normalized with respect to the endogenous L32 control.
F, cell lysates were prepared from Jurkat cells that had
been stimulated for the indicated times with M2-cross-linked (1 µg/µl) soluble FasL (100 ng/ml) in the absence or presence of
z-VAD-fmk (10 µM). JNK activity was measured by the
immunocomplex kinase assay with glutathione S-transferase
(GST)-c-Jun-(1-79) as a substrate. G,
Jurkat cells were transiently transfected with an AP-1 reporter gene
construct by electroporation. The next day cells were split and
stimulated with 100 nM phorbol 12-myristate 13-acetate
(P) or FasL (300 ng/ml) cross-linked with FLAG-specific mAb
M2 (1 µg/ml) in the presence of z-VAD-fmk (Z; 10 µM). Finally reporter gene activity was determined as
described under "Experimental Procedures." n.s.,
nonspecific.
B activation (25, 26). We here therefore tested whether this
pathway is involved in c-Fos up-regulation. Overexpression of a
nondegradable mutant of I-B did not affect Fas-induced up-regulation of c-Fos in Jurkat T-cells (data not shown) suggesting that the NF-B
pathway is not involved in this process. The c-fos gene is a
target of AP-1 that is transcriptionally up-regulated when AP-1 is
activated by JNKs (40). However, JNK is not involved in
FasL-induced up-regulation of c-Fos because the pan caspase inhibitor
z-VAD-fmk completely prevented FasL-mediated JNK activation (Fig.
1F) but not induction of c-Fos mRNA (Fig. 1,
A and C). AP-1 is a dimeric transcription factor
composed of Jun and Fos (or activating transcription factor)
subunits. We therefore looked at whether FasL-induced up-regulation of
c-Fos is accompanied by activation of an AP-1 reporter gene plasmid.
Although phorbol 12-myristate 13-acetate was able to up-regulate the
AP-1 reporter gene more than 35-fold, we found no evidence for any
activation after FasL stimulation (Fig. 1G). However, this
was not unexpected because AP-1 activity depends on phosphorylation of
its transactivation domain by JNK, but FasL does not induce this
pathway in the presence of z-VAD-fmk (Fig. 1F).
B and JNK
pathways in response to transient overexpression of caspase-8 (42, 43).
However, the caspase-8-dependent activation of the JNK
pathway shown in the latter study was not activated by FasL in Jurkat
cells. Indeed as already mentioned, FasL-induced JNK activation was
completely blocked by z-VAD-fmk (Fig. 1E) in Jurkat cells.
Thus, because JNK and NF-B activation are not critically involved in
FasL-induced up-regulation of c-Fos (see above), these data suggest
that caspase-8 links a novel non-caspase-activating signaling pathway
to Fas.
View larger version (62K):
[in a new window]
Fig. 2.
FasL- (A) and TRAIL-induced
(B) up-regulation of c-Fos is dependent on FADD and
caspase-8. Parental Jurkat cells and clones derived thereof
deficient in caspase-8 and FADD (clone I.2.1) expression were treated
for 6 h with the indicated combinations of soluble FasL (300 ng/ml) or TRAIL (100 ng/ml), each cross-linked with M2 (1 µg/ml) and
z-VAD-fmk (Z; 10 µM). Total RNAs were isolated
for RNase protection analysis, and 10 µg of each RNA sample were
analyzed with a custom Multi-Probe template set to detect the indicated
mRNAs. L32 and glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) were included in each template set as internal
controls. Similar results were also obtained with an independent
FADD-deficient clone (clone I.6.2) and the caspase-8-deficient Jurkat
clone JB-6 from the laboratory of Shigekazu Nagata.
Data from the literature indicate that the death domain-containing
TRAIL receptors TRAIL-R1 and TRAIL-R2 engage similar or at least
closely related intracellular signaling pathways as Fas leading to the
induction of apoptosis (14, 44-47), NF-B, and JNK activation (26,
48). We have found that the same is true for up-regulation of c-Fos.
Like FasL, TRAIL induced c-Fos in Jurkat cells via a
FADD/caspase-8-dependent pathway independent of the
protease activity of caspase-8 (Fig. 2B).
FLIP is a major regulator of apoptotic and non-apoptotic signaling
pathways engaged by FasL and TRAIL. We have therefore analyzed the
FasL/TRAIL-induced up-regulation of c-Fos in Jurkat clones (Fig.
3A) stably expressing the long
slice form FLIP-L or the short splice form FLIP-S. Up-regulation of
c-Fos was found to be differentially regulated by FLIP-S and FLIP-L
(Fig. 3, B and C). In Jurkat FLIP-L cells, FasL-
and TRAIL-induced c-Fos up-regulation was totally blocked (Fig. 3,
B and C). However, in Jurkat FLIP-S cells FasL-
and TRAIL-induced c-Fos expression was not reduced but was even
enhanced (Fig. 3, B and C). We regularly found a weak but significant induction of TNF mRNA by TRAIL and FasL (Fig. 1), opening the possibility that TRAIL- and FasL-induced up-regulation of c-Fos is mediated by the induction of endogenous TNF. However, in
contrast to TRAIL and FasL, the closely related TNF did not affect
c-Fos expression in Jurkat cells (data not shown). Thus, although
TRAIL, FasL, and TNF act via stimulation of members of the death
domain-containing receptor subgroup of the TNF receptor superfamily,
only TRAIL and FasL, but not TNF, induce a common pathway leading to
up-regulation of c-Fos.
|
Based on the data described in this study and data from the literature,
a model of Fas/TRAIL signaling appears possible in which the expression
level of FLIP and in particular the balance of FLIP-S and FLIP-L
expression determines the outcome of Fas and TRAIL receptor triggering.
It has been shown that in the absence of FLIP expression FasL/TRAIL
induces formation of a FADD-containing complex that "catalyzes"
repeated cycles of procaspase-8 (p55/53) recruitment, proximity-induced
activation of p55/53 to the p18/p10 form of caspase-8 via a p43/41
intermediate, and release of the receptor-bound prodomain of caspase-8
(24). Recruitment of FLIP-L arrested this cycling death-inducing
signaling complex in a state containing procaspase-8 or the p43/41
intermediate product of caspase-8 processing and FLIP-L (24) (Fig.
4A). It is now tempting to
speculate that in this FLIP-L/FLIP-S-arrested state the
receptor-signaling complexes of Fas, TRAIL-R1, and TRAIL-R2 acquire
new signaling capabilities that are not related to apoptosis
induction. According to our data, a FLIP-S-arrested complex may acquire
the capability to interact with a yet unknown protein X that couples
this FLIP-S-arrested complex to the activation of the c-fos
gene (Fig. 4B). This protein X might be replaced by TNF
receptor-associated factor (TRAF) proteins and/or receptor interacting
protein when FLIP-S is substituted by FLIP-L because FLIP-L, but
not FLIP-S, activates NF-B (42) and interacts with TRAF1, TRAF2 (17,
49), and receptor interacting protein (49) (Fig. 4C).
|
, cell death.
It has been shown that c-Fos is an important regulator of cell
proliferation and has a specific function in thymocyte development (50). Thus, it is tempting to speculate that FasL/TRAIL-induced up-regulation of c-Fos is part of the proliferative response of thymocytes and T-cells upon T-cell receptor triggering, which is
impaired in FADD-deficient mice (35) or transgenic mice overexpressing a dominant-negative deletion mutant of FADD (36-38). However, in lpr mice harboring a defective Fas molecule or
gld mice expressing dysfunctional FasL, no inhibition of
T-cell proliferation was found. This is at the first glance
contradicting to a role of Fas in T-cell proliferation. However, it
cannot be ruled out that in these mice TRAIL or other death ligands
substitute for Fas/FasL interaction with regard to c-Fos-induction but
not with regard to apoptosis induction. Furthermore, a recent study
showing that lpr mice in a nonselecting background exert
reduced proliferation in thymic T-cell development suggests that
Fas/FasL contributes to thymocyte proliferation under defined
circumstances (51). Moreover, recent studies have also shown that FasL
augmented CD3-induced proliferation, whereas Fas-Fc blocked T-cell
proliferation (49, 52-54). In contrast to the c-Fos activation
described here, T-cell proliferation was dependent on active caspases
in these studies (53, 55). Thus, up-regulation of c-Fos may reflect a
death receptor-mediated proliferative response that is, in contrast to
other components of the proliferative response, caspase-independent. However, it cannot be ruled out that the FasL/TRAIL-induced
up-regulation of c-Fos shown in this study is not related to T-cell
receptor-dependent proliferation of T-cells. Further
analysis with primary T-cells will be necessary to clarify that.
| |
ACKNOWLEDGEMENTS |
|---|
We thank Shigekazu Nagata (Osaka University Medical School, Osaka, Japan) for the caspase-8-deficient Jurkat clone JB-6 and Klaus Schulze-Osthoff (Universität Münster, Münster, Germany) for the caspase-8-specific mAb.
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FOOTNOTES |
|---|
* This work was supported by Deutsche Forschungsgemeinschaft Grant Wa 1025/11-1 and Sonderforschungsbereich 495 Project A5.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
49-711-685-7446; Fax: 49-711-685-7484.
Published, JBC Papers in Press, May 30, 2001, DOI 10.1074/jbc.M100444200
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ABBREVIATIONS |
|---|
The abbreviations used are:
FasL, Fas
ligand;
DED, death effector domain;
FADD, Fas-associated death domain
protein;
FLICE, FADD-like interleukin-1-converting enzyme;
FLIP, FLICE
inhibitory protein;
cFLIP, cellular FLIP;
FLIP-L, long splice form of
FLIP;
FLIP-S, short splice form of FLIP;
JNK, c-Jun N-terminal kinase;
NF-B, nuclear factor B;
TNF, tumor necrosis factor;
TRAIL, TNF-related apoptosis-inducing ligand;
mAb, monoclonal antibody;
z-VAD-fmk, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone;
Ac-DEVD-AMC, acetyl-Asp-Glu-Val-Asp-7-amido-4-methylcourmarin;
DEVD-fmk, Asp-Glu-Val-Asp-fluoromethylketone;
AP-1, activating
protein-1.
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REFERENCES |
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
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REFERENCES
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